Total synthesis of halicholactone and neohalicholactone

Article abstract of DOI:10.1055/s-0029-1217145

New total syntheses of the marine oxylipins halicholactone and neohalicholactone are presented. The key building blocks were synthesized utilizing chemoenzymatic methods.

Full text of DOI:10.1055/s-0029-1217145

FEATURE ARTICLE
527
Total Synthesis of Halicholactone and Neohalicholactone
Synthesis of
Halicholaa
r
eohalich
t
olacto
ine na Bischop, Verena Doum, Anja C. M. Nordschild (née Rieche), Jörg Pietruszka,* Diana Sandkuhl
Institut für Bioorganische Chemie der Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich, Stetternicher Forst Geb. 15.8,
52426 Jülich, Germany
Fax +49(2461)616196; E-mail: j.pietruszka@fz-juelich.de
Received 16 October 2009; revised 29 October 2009
O
Abstract: New total syntheses of the marine oxylipins halicholac-
tone and neohalicholactone are presented. The key building blocks
were synthesized utilizing chemoenzymatic methods.
OH
O
ω-3
Key words: natural product, total synthesis, enzymes, boron re-
agents, asymmetric synthesis
OH
1 halicholactone
2 neohalicholactone
O
Introduction
OH
O
ω-3
ω-6
Natural products are not only a rich source for active
agents in general, but do also catalyze numerous synthetic
efforts towards the total synthesis of the newly found tar-
gets, often triggering the development of new synthetic
methods or the optimization of given protocols.1 The
seemingly not overly complex group of marine oxylipins
bearing a cyclopropyl lactone moiety attracted consider-
able attention in recent years and en route to their total
synthesis some elegant protocols were developed.2 Our
own endeavors focused on chemoenzymatic routes, ap-
plying enzymatic transformation3 as well as developing a
new boron reagent.4 Here we describe the total synthesis
of halicholactone (1) and neohalicholactone (2). Other
representatives of the group of marine oxylipins are the
constanolactones A–G5 and solandelactones A–I6 that dif-
fer in the ring size of the lactones and the configuration of
the stereogenic units (Figure 1).
OH
ω-6
ω-3, ω-6
constanolactone A/B
constanolactone C/D
O
OH
O
ω-3
ω-6
γ
OH
ω-6
solandelactone A/B
solandelactone C/D
solandelactone E/F
solandelactone G/H
ω-3, ω-6
ω-3, γ
ω-3, ω-6, γ
Figure 1 Members of the marine oxylipin family
yield)10 and in 2002 (13 steps, 12% yield),11 and while
preparing the manuscript, the Tang group reported anoth-
er short synthesis (11% yield).12
Halicholactone (1) and neohalicholactone (2) were isolat-
ed by the Yamada group from the marine sponge Hali-
chondria okadai off the coast of Japan in 1989.7 In 1994
Proteau et al. found another neohalicholactone from the
brown alga Laminaria sinclairii, but structural analysis
showed that the isolated natural product was the C15-
epimer of neohalicholactone (2).8 Both target molecules
were shown to be weak lipoxygenase inhibitors. For ex-
ample, halicholactone (1) exhibits inhibitory activity
against the 5-lipoxygenase of guinea pig polymorphonu-
clear leukocytes (IC50 = 630 mm).7a The first total synthe-
sis of halicholactone (1) and neohalicholactone (2) was
published in 1995 by Critcher and Wills.9 They generated
both natural products with a convergent synthetic strategy
in 18 steps and 4% [halicholactone (1)] and 2% [neohali-
cholactone (2)] yield, respectively. Two more syntheses
of halicholactone (1) were disclosed in 2000 (25 steps, 2%
Strategy
Based on our previous experience on the convergent syn-
thesis of various members of the marine oxylipin fami-
ly,3,4 we followed a similar approach for generating
halicholactone (1) and neohalicholactone (2). As a key
step we chose the highly reliable chromium(II)-mediated
coupling between aldehyde 3 and the corresponding io-
dides 4 and 5,13 respectively, that are derived from the cor-
responding propargylic alcohols 6 and 7 (Scheme 1).
Obviously, the cyclopropyl lactone moiety is identical in
both natural products 1 and 2, while the aliphatic side
chains are different. The additional Z-double bond at po-
sition C-17 (w-3) of neohalicholactone (2) presents the
special challenge that we envisaged to tackle with an allyl
addition utilizing enantiomerically pure a-substituted al-
lylboronic esters. Although (R)-oct-1-yn-3-ol (6) is com-
mercially available, we found that its enantiomeric purity
SYNTHESIS 2010, No. 3, pp 0527–0537
x
x
.
x
x
.2
0
1
0
Advanced online publication: 27.11.2009
DOI: 10.1055/s-0029-1217145; Art ID: E25809SS
© Georg Thieme Verlag Stuttgart · New York

528
M. Bischop et al.
FEATURE ARTICLE
Biographical Sketches
Martina Bischop was born in Nord- thesis at the Institute of Bioorganic reagents), which she is applying to-
horn, Germany in 1982. She received Chemistry, headed by Professor ward natural product synthesis. Since
her diploma in chemistry at the Hein- Pietruszka. Scientifically, her focus 2008 she is funded by a fellowship of
rich Heine University of Düsseldorf lies on the development of new syn- the Jürgen-Manchot-Stiftung.
in 2007. She continued her doctoral thetic methods (catalysis and boron
Verena Doum did her apprentice- ing on the synthesis of key building ber 2008 she started her undergradu-
ship as laboratory assistant at the For- blocks and the development of the ate studies on applied chemistry at
schungszentrum Jülich from 2005– corresponding analytical tools, with the FH Aachen.
2008. She joined the Institute of the final year being dedicated to the
Bioorganic Chemistry in 2006 focus- marine oxylipin project. In Septem-
Anja C. M. Nordschild (née was rewarded with the Proctor & ies were funded by fellowships of the
Rieche) was born in Stuttgart, Ger- Gamble prize. She continued her en- Degussa Foundation and the Hein-
many in 1979. After her apprentice- deavors on the total syntheses of ma- rich Heine University of Düsseldorf.
ship as chemical technical assistant, rine oxylipins first at the University Meanwhile she gained industrial ex-
she started studying chemistry at the of Stuttgart and later at the Institute perience during internships with
University of Stuttgart and spent half of Bioorganic Chemistry at the Hein- Bayer HealthCare and Evonik Indus-
a year as ERASMUS student at the rich Heine University of Düsseldorf tries.
University of Edinburgh, UK. She re- where she obtained her doctorate (Dr.
ceived her diploma in 2003, which rer. nat.) in 2009. Her doctoral stud-
Jörg Pietruszka studied chemistry at at the University of Stuttgart in 2001. sity in Gießen was declined; since
the University of Hamburg where he In 2000/2001 he was a visiting lectur- 2004 he holds the position as full pro-
also obtained his doctorate (Dr. rer. er at the University of Freiburg (Ger- fessor and chair of Bioorganic Chem-
nat.) in 1993 (Prof. W. A. König). many), 2001/2002 a guest professor istry at the Heinrich Heine University
After two postdoctoral years with at the University of Cardiff (Wales), of Düsseldorf. His research interests
Professor S. V. Ley (Cambridge, and 2002/2003 he held a substitute- include the development of new
UK), he fulfilled the requirements for professorship at the University of chemoenzymatic methods and their
his ‘Habilitation’ – funded by a Tübingen (Germany). In 2004 an of- application in the synthesis of natural
Liebig Fellowship and a DFG grant – fer for a professorship at the Univer- products.
Diana Sandkuhl was born in Düs- obtained her diploma in 2006. She chemoenzymatic syntheses and the
seldorf, Germany in 1981. She stud- continued her doctoral thesis at the application of enantiomerically pure
ied chemistry at the Heinrich Heine Institute of Bioorganic Chemistry, propargylic alcohols.
University of Düsseldorf, where she headed by Professor Pietruszka, on
Synthesis 2010, No. 3, 527–537 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Halicholactone and Neohalicholactone
529
Table 1 Enzyme Screening in the Reduction of Ketone 9a
is not highly reliable. Hence we pursued an enzymatic ap-
proach to generate enantiomerically pure starting material
in high yield. The cyclopropyl lactone aldehyde 3 could
be prepared from the Weinreb amide 8, a building block
readily available in our group.3b The Z-double bond of the
unsaturated lactone could be introduced via ring-closing
metathesis (RCM).
O
OH
enzyme
screening
9
6
Entry Enzyme
Cofactor
Conv.
(%)
Config. ee
(%)
1
2
3
4
5
6
7
8
ADH RS1
ADH RS2
NADH
NADH
NADH
NADPH
NADH
NADPH
NADPH
NADPH
13
34
R
R
R
–
99
99
O
OH
O
ADH CDX010
ADH PF
17
99
OH
1/2
34
–
ADH CP
70
R
S
>99
99
O
O
OH
ADH CDX013
ADH LB
67
OHC
I
>99
>99
S
>99
>99
4/5
3
ADH T
R
a Screening conditions: KPi buffer (100 mM K2HPO4/KH2PO4, pH 6,
1 mM MgCl2).
Me
N
OH
O
OH
KPi-buffer
(pH 6)
MeO
OAc
O
6/7
8
9
(R)-6
74%, >99% ee
Scheme 1 Retrosynthesis of halicholactone (1)/neohalicholactone
(2)
H+ + NADPH
NADP+
ADH-T
acetone
i-PrOH
Syntheses of Aliphatic Side Chains
Scheme 2 Enzymatic reduction of ketone 9
We started our endeavor with the syntheses of the re-
quired propargylic alcohols 6 and 7. While successful en-
zymatic approaches towards propargylic alcohols using
hydrolases14 and especially alcohol dehydrogenases15
have been previously reported, a high-yielding, highly R-
selective protocol is still elusive: The enzymatic reduction
of oct-1-yn-3-one (9) to the corresponding R-alcohol (R)-
6 (or related propargylic alcohols) has been reported, but
these suffer from low yield and selectivity.16 Screening
several new enzymes showed that four of them transform
ketone 9, albeit also with either low conversion or selec-
tivity [Table 1, entries 1–4: ADH-RS1,17 13% conv., 99%
ee (R); ADH-RS2, 34% conv., 99% ee (R); ADH-CDX010,
17% conv., 99% ee (R); ADH-PF, 34% conv., 0% ee].
Moderate conversion, but very good selectivity was
achieved with ADH-CP [entry 5: 70% conv., >99% ee
(R)] and ADH-CDX013 [entry 6: 67% conv., 99% ee (S)].
The best results with an excellent enantiomeric excess
showed ADH-LB [entry 7: S-selectivity, >99% conver-
sion, >99% ee] and ADH-T [entry 8: R-selectivity >99%
conversion, >99% ee] (Figure 2). The last entry proved to
be the first convincing enzymatic approach towards alco-
hol (R)-6 and when performing the transformation in pre-
parative scale including cofactor recycling with isopropyl
alcohol, 74% of the desired product was obtained in enan-
tiomerically pure form (Scheme 2). The yield was not op-
Figure 2 GLC profiles in the enzymatic reduction of ketone 9. GLC
conditions: Lipodex G, H2 (0.6 bar), 90 °C.
timized, but on a larger scale the workup of the low-
boiling product would surely allow improved results.
Next, we focused on the second propargylic alcohol (R)-7
required for the neohalicholactone (2) synthesis
(Scheme 3). As discussed above, the homoallylic alcohol
should be accessible via an allyl addition using the known
Synthesis 2010, No. 3, 527–537 © Thieme Stuttgart · New York

530
M. Bischop et al.
FEATURE ARTICLE
aldehyde 1018 and the recently established allyl boronate
11,4d,e a reagent stabilized through the auxiliary.19 Indeed,
the NMR analysis of intermediate4d boric ester 12 showed
only one diastereomer. The resulting Z-configured ho-
moallylic alcohol, which was isolated after hydrolysis on
silica gel (during column chromatography), manifested
the assumption: The enantiomeric excess – as determined
by GLC – was 98%, the intermediate (not shown) was iso-
lated in 89% yield. It should be noted that the correspond-
ing enantiomer could be obtained from the diastereomeric
boron reagent in 96% yield (95% ee). Deprotection of the
TMS group using tetrabutylammonium fluoride (TBAF)
furnished the required R-configured propargylic alcohol 7
(99%).
OH
OH
OH
I
6
7
4
44% (over 3 steps)
a, b, c
OH
I
5
60 % (over 3 steps)
Scheme 4 Preparation of vinyl iodide 4 and 5. Reagents and condi-
tions: (a) imidazole, TBSCl, THF, r.t.; (b) i. Cp2Zr(H)Cl, CH2Cl2, r.t.,
ii. I2, r.t.; (c) TBAF·3H2O, THF, 0 °C → r.t.
chemoenzymatic route starting from cinnamyl alcohol
(58% yield over 5 steps). After deprotection under basic
conditions (Schemes 5, 96%) the resulting alcohol was
oxidized with Dess–Martin periodinane (DMP)21 furnish-
ing aldehyde 134b (91%). The next stereogenic unit was
formed by an allyl addition with Leighton’s reagent 14:22
The homoallylic alcohols (73%, dr 72:28) could be sepa-
rated by chromatography. It should be noted that the ob-
tained low anti-selectivity can be explained by a
mismatched interaction while the enantiomeric Leighton’s
reagent ent-14 – used for the synthesis of the solandelac-
tones A–H4b – gave almost exclusively the syn diastereoi-
somer. Similar to the synthesis of constanolactones A–
D3a,4a we envisaged an acylation/ring-closing metathesis
sequence to finally synthesize the lactone. After esterifi-
cation of the homoallylic alcohol with hex-5-enoic acid,
we obtained the required diene 15 (94%).
O
OB*
B*
a
11
H
TMS
10
TMS
12
b, c
Ph Ph
O
OMe
OMe
OH
B*
B
=
O
Ph Ph
7
88%, 98% ee
Scheme 3 Synthesis of propargylic alcohol 7. Reagents and condi-
tions: (a) allyl addition: boronate 11, CH2Cl2, 0 °C → r.t.; (b) chroma-
tography on SiO2 (89%); (c) TBAF·3H2O, THF, r.t. (99%).
Me
N
Me
N
a, b
CHO
MeO
OAc
MeO
For the following three-step sequence towards the final
coupling partners 4 and 5 an established route was used
(Scheme 4): Silyl protection of the propargylic alcohols 6
and 7 with TBSCl (TBS: tert-butyldimethylsilyl) yielded
the corresponding ethers in 87% and 88%, respectively.
Hydrozirconation with the Schwartz reagent was fol-
lowed by quenching the intermediate with a solution of io-
dine in dichloromethane (yield: 70% and 79%). The final
deprotection with TBAF in THF lead to the first coupling
partners 4 (73%) and 5 (86%). Attempts to omit the pro-
tection-deprotection steps by a direct transformation of al-
cohols 6 and 7 to yield the iodides 4 and 5 failed,20
because a number of side-products prevented the isolation
of the pure target compounds. Concluding the first part,
87%
O
O
8
13
C6H4Br
Cl
69%, dr = 72:28
c, d
N
O
O
Si
N
Me
N
14
C6H4Br
MeO
O
15
Scheme 5 Synthesis of diene 15. Reagents and conditions: (a)
MeOH, K2CO3, r.t.; (b) DMP, CH2Cl2, 4 h, r.t.; (c) Leighton’s reagent
the acyclic side chains could be successfully synthesized: (14), CH2Cl2, 96 h, –12 °C; (d) hex-5-enoic acid, EDC·HCl, DMAP,
CH2Cl2, 20 h, r.t.
The overall yield for iodide 4 was 32% starting from ke-
tone 9 (4 steps) and 35% (5 steps) when starting from allyl
boronate 11.
While the ring-closing metathesis was successfully ap-
plied for related substrates,12 we observed difficulties
when applying standard catalysts for the synthesis of
eight- or nine-membered lactones:4b For this reason six
catalysts A–F (Figure 3) were tested using the same diene
concentration, albeit in different refluxing solvents
(Table 2, entries 1–8). While in many cases the transfor-
mation was incomplete and resulted in considerable for-
Syntheses of Natural Products
Next we focused on the synthesis of the cyclopropyl lac-
tone moiety 3. As previously reported,3b the enantiomeri-
cally pure cyclopropane 8 was obtained via a reliable
Synthesis 2010, No. 3, 527–537 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Halicholactone and Neohalicholactone
531
mation of oligomers, in our hands the best result was fording halicholactone (1) (78%, dr 59:41) and neohali-
achieved with the Neolyst M1 catalyst23 C in toluene at cholactone (2) (92%, dr 60:40) (Scheme 6). The
higher temperature (entry 8, yield of lactone 16: 61%). diastereoisomers could be successfully separated by pre-
Only minor amounts of oligomers were detected. parative HPLC.
Chemoselective reduction of amide 16 with diisobutylalu-
minum hydride (DIBAL-H) yielded 75% of the desired al-
dehyde 3. Starting material 16 was recovered (17%), since
the reaction needed to be quenched before the lactone is
reduced. The synthesis of the cyclopropyl lactone 3 was
achieved in 11 steps starting from cinnamyl alcohol.
O
O
OH
+
OHC
I
3
4/5
O
The final chromium(II)-mediated Nozaki–Hiyama–Kishi
coupling proceeded smoothly for both natural products af-
OH
O
ω-3
a
OH
1 halicholactone 78%, dr = 59:41
PCy3
PCy3
Ru
N
N
2 neohalicholactone 92%, dr = 60:40
Cl
Cl
Ph
Mes
Mes
Ph
Cl
Cl
Ru
Cl
Ru
Scheme 6 Synthesis of halicholactone (1) and neohalicholactone (2).
Reagents and conditions: (a) NiCl2, CrCl2, DMSO, r.t., 3 d.
PCy3
PCy3
Cl
PCy3
Neolyst M1
Grubbs-I
Grubbs-II
C
A
B
Conclusion
N
N
N
N
N
N
Mes
Mes Mes
Mes
Mes
Mes
In summary, with our convergent strategy for oxylipin
syntheses we added to the already published approaches
towards constanolactones A–D3a,4a and solandelactones
A–H,4b two more completed syntheses. Halicholactone
(1) and neohalicholactone (2) were synthesized from cin-
namyl alcohol in 12 steps with an overall yield of 13% (dr
59:41) and 16% yield (dr 60:40), respectively. En route
the enzymatic reduction towards propargylic alcohol (R)-
6 was established as well as a first application of boron re-
agent 11 in total synthesis given, thus demonstrating the
potential for providing Z-homoallyl alcohols (such as the
neohalicholactone intermediate 7) in high selectivity.
Cl
Cl
Cl
Cl
Ru
O
Ru
N
Cl
Ru
Cl
PCy3
Hoveyda–Grubbs II
Neolyst M2
D
E
F
Figure 3 Catalysts used in the synthesis of aldehyde 3
Table 2 Synthesis of Aldehyde 3a
O
O
Me
N
O
O
Unless specified, the reactions were carried out by using standard
Schlenk techniques under dry Ar/N2 with magnetic stirring. Glass-
ware was oven-dried overnight at 120 °C. Solvents were dried and
purified by conventional methods or by a Solvent Purification Sys-
tem (MBRAUN). Common solvents for chromatography (petro-
leum ether, EtOAc) were distilled prior to use; petroleum ether (PE)
refers to the fraction with a boiling point between 4060 °C. Column
chromatography and flash column chromatography were performed
on silica gel 60, 0.040–0.063 mm (230–400 mesh). TLC (monitor-
ing the course of the reactions) was performed on precoated plastic
sheets (Polygram® SIL G/UV254, Macherey-Nagel) with detection
by UV (254 nm) or by coloration with cerium molybdenum solution
[phosphomolybdic acid (25 g), Ce(SO4)2·H2O (10 g), concd H2SO4
(60 mL), H2O (940 mL)]. 1H and 13C NMR spectra were recorded at
r.t. in CDCl3 with Bruker Avance DRX 600 spectrometer. Chemical
shifts are given in ppm relative to TMS as internal standard [1H:
Me4Si = 0.00 ppm] or relative to the resonance of the solvent (13C:
CDCl3 = 77.0 ppm); coupling constants J are given in Hz. Higher
order d and J values are not corrected. 13C signals were (re)assigned
by means of H–H COSY and HSQC or HMBC spectroscopy. IR
spectra were obtained on a PerkinElmer Spectrum One spectropho-
tometer. MS were recorded on a Finnigan MAT 95 [EI, CI], a Vari-
an MAT 711 (EI), a Finnigan MAT LC-Q (ESI, LC-MS-MS), or a
Applied Biosystems/MDS SCIEX 4000 Q TRAP (ESI, LC-MS-
MS) spectrometer.
a
H
b
15
MeO
75%
O
O
16
3
Entry
Catalyst Solvent
Temp
(°C)
Time
(h)
Yield
(%) of 16
1
2
3
4
5
6
7
8
A
B
F
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
37
37
12
18
30
48
24
3
37b,c
16c
b
37
–
b,c
D
E
C
E
C
37
–
37
52b,c
58b,c
44c
37
105
105
18
24
61c
a Reaction conditions: (a) catalyst A–F, solvent, temperature,
Ti(Oi-Pr)4; (b) DIBAL-H, THF, 1 h, –78 °C, 75% (92% brsm).
b Side-product: starting material.
c Side-product: oligomer.
Synthesis 2010, No. 3, 527–537 © Thieme Stuttgart · New York

532
M. Bischop et al.
FEATURE ARTICLE
20
(R)-Oct-1-yn-3-ol (6)
(1.35 g, 70%); Rf = 0.63 (n-pentane); [a]D +33.9 (c = 0.83,
Ketone 9 (124 mg, 1.00 mmol, 1.0 equiv) in i-PrOH (1.00 mL),
NADPH (83.3 mg, 0.06 mmol, 0.06 equiv), and ADH-T-solution
(~50% in glycerine, 100 mL, as supplied by Jülich Chiral Solutions,
now Codexis) were added to KPi-buffer (100 mM K2HPO4/
KH2PO4, pH 6, 1 mM MgCl2, 100 mL). The reaction mixture was
stirred for 96 h (100% turnover as judged by GC) at r.t. After filtra-
tion, the aqueous solution was extracted with MTBE (3 × 100 mL).
The combined organic layers were dried (MgSO4), filtered, and the
solvents were removed under reduced pressure. Purification of the
crude product by flash column chromatography on silica gel (PE–
EtOAc, 90:10) yielded 93 mg (74%) of alcohol (R)-6 as a colorless
liquid; Rf = 0.18 (PE–EtOAc, 90:10); [a]D20 +5.3 (c = 1.00, CHCl3),
99% ee (R-enantiomer), as determined by GLC [Lipodex G, H2
CHCl3).
IR (film): 2955, 2929, 2857, 1607, 1463, 1361, 1254, 1203, 1164,
1118, 1086, 1005, 942, 919, 834, 810, 789, 698 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.03, 0.04 [2 s, 6 H, Si(CH3)2],
0.88 (t, 3J = 7.3 Hz, 3 H, 8-H), 0.89 [s, 9 H, SiC(CH3)3], 1.22–1.36
(m, 6 H, 5-H, 6-H, 7-H), 1.41–1.50 (m, 2 H, 4-H), 4.07 (tdd, 3J = 6.1
Hz, J = 6.0 Hz, J = 1.3 Hz, 1 H, 3-H), 6.19 (dd, 3J = 14.4 Hz,
3
4
4J = 1.3 Hz, 1 H, 1-H), 6.52 (dd, 3J = 14.4 Hz, 3J = 6.0 Hz, 1 H, 2-
H).
13C NMR (151 MHz, CDCl3): d = –4.9, –4.5 (CH3), 14.0 (C-8), 18.2
[C(CH3)3], 22.6 (C-6), 24.6 (C-5), 25.8 [C(CH3)3], 31.8 (C-7), 37.5
(C-4), 75.2 (C-3), 75.4 (C-1), 149.4 (C-2).
(0.6 bar),
150 °C
iso:
tR = 13.50 min;
S-enantiomer:
MS (EI, 70 eV): m/z (%) = 367 (<1, [(M – H)+]), 311 (100, [(M –
tR = 13.33 min].
C4H9)+]), 297 (26, [(M – C5H11)+]).
1H NMR (600 MHz, CDCl3): d = 0.89 (t, J = 6.8 Hz, 3 H, 8-H),
1.26–1.32 (m, 4 H, 6-H and 7-H), 1.56–1.65 (m, 2 H, 5-H), 1.72 (mc,
2 H, 4-H), 2.00 (br, 1 H, OH), 2.45 (d, 4J = 2.1 Hz, 1 H, 1-H), 4.40
(dt, 4J = 2.1 Hz, 3J = 6.6 Hz, 1 H, 3-H).
13C NMR (151 MHz, CDCl3): d = 13.9 (C-8), 22.5 (C-5), 24.7 (C-
7), 31.4 (C-6), 37.6 (C-4), 62.4 (C-3), 72.8 (C-1), 85.0 (C-2).
3
Anal. Calcd for C14H29IOSi (368.37): C, 45.65; H, 7.94. Found: C,
45.50; H, 7.93.
The analytical and spectral data were in full agreement with those
previously reported.26,27
(R,E)-1-Iodooct-1-en-3-ol (4)
The analytical and spectral data were in full agreement with those
previously reported.24
(R,E)-tert-Butyl(1-iodooct-1-en-3-yloxy)dimethylsilane (270 mg,
762 mmol, 1.0 equiv) in anhyd THF (8 mL) was cooled to 0 °C and
solid TBAF·3H2O (268 mg, 848 mmol, 1.1 equiv) was added. The
mixture was warmed to r.t. and stirred for 3 h; TLC indicated the
complete conversion of the starting material. After hydrolysis with
H2O (4 mL), the aqueous layer was separated and extracted with
Et2O (3 × 20 mL). The combined organic layers were washed with
H2O (2 × 20 mL), dried (MgSO4), and filtered. The solvents were
removed under reduced pressure and the crude product subjected to
flash column chromatography (SiO2; eluent: CH2Cl2). Product 4
(141 mg, 73%) was obtained as a colorless liquid; Rf = 0.53
(CH2Cl2); [a]D24 –7.5 (c = 0.59, MeOH).
(R)-tert-Butyldimethyl(oct-1-yn-3-yloxy)silane
To a stirred solution of (R)-oct-1-yn-3-ol (6; 950 mg, 7.53 mmol,
1.0 equiv) in anhyd CH2Cl2 (17 mL) was added imidazole (923 mg,
13.6 mmol, 1.8 equiv), followed by TBSCl (1.35 g, 8.96 mmol,
1.19 equiv) and the stirring was continued overnight at r.t. After hy-
drolysis with H2O (10 mL), the layers were separated and the aque-
ous layer was extracted with n-pentane (3 × 50 mL). The combined
organic layers were washed with H2O (2 × 50 mL), dried (MgSO4),
filtered, and the solvents were removed under reduced pressure. The
crude product was subjected to flash column chromatography
(SiO2; eluent: n-pentane–Et2O, 98:2). The product was obtained as
a colorless liquid (1.57 g, 87%); Rf = 0.32 (n-pentane); [a]D20 +47.3
(c = 1.30, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 0.11, 0.14 [2 s, 6 H, Si(CH3)2],
0.89 (t, 3J = 7.2 Hz, 3 H, 8-H), 0.90 [s, 9 H, SiC(CH3)3], 1.26–1.34
(m, 4 H, 6-H, 7-H), 1.38–1.47 (m, 2 H, 5-H), 1.62–1.71 (m, 3J = 6.5
Hz, 2 H, 4-H), 2.37 (d, 3J = 2.1 Hz, 1 H, 1-H), 4.33 (td, 3J = 6.5 Hz,
4J = 2.1 Hz, 1 H, 3-H).
IR (film): 3333 (OH), 2955, 2928, 2858, 1607, 1465, 1378, 1269,
1169, 1126, 1052, 1023, 941, 777, 725, 673 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.89 (t, J = 7.1 Hz, 3 H, 8-H),
1.14–1.33 (m, 6 H, 5-H, 6-H, 7-H), 1.38–1.46 (m, 2 H, 4-H), 1.49
(d, J = 4.4 Hz, 1 H, OH), 4.00 (dddd, J = 11.9 Hz, J = 6.3 Hz,
3J = 4.4 Hz, 3J = 1.2 Hz, 1 H, 3-H), 6.25 (dd, 3J = 14.4 Hz, 4J = 1.2
Hz, 1 H, 1-H), 6.58 (dd, 3J = 14.4 Hz, 3J = 6.3 Hz, 1 H, 2-H).
13C NMR (151 MHz, CDCl3): d = 14.0 (C-8), 22.6 (C-6), 24.8 (C-
5), 31.7 (C-7), 36.6 (C-4), 74.8 (C-3), 77.1 (C-1), 148.7 (C-2).
3
3
3
3
13C NMR (151 MHz, CDCl3): d = –5.1, –4.6 (CH3), 14.0 (C-8), 18.2
[C(CH3)3], 22.6 (C-6), 24.8 (C-5), 25.7 [C(CH3)3], 31.4 (C-7), 38.6
(C-4), 62.8 (C-3), 71.8 (C-1), 85.8 (C-2).
MS (EI, 70 eV): m/z (%) = 254 (<1, [M+]), 236 (4, [M – H2O+]), 183
(100, [(M – C5H11)+]).
The analytical and spectral data were in full agreement with those
previously reported.28,29
The analytical and spectral data were in full agreement with those
previously reported.25,26
(R,Z)-1-Trimethylsilyloct-5-en-1-yn-3-ol
(R,E)-tert-Butyl(1-iodooct-1-en-3-yloxy)dimethylsilane
Allylboronic ester 114d,e (515 mg, 970 mmol, 1.0 equiv) was dis-
solved in anhyd (0.5 mL) CH2Cl2 (0.5 mL/mmol allyl boronic ester
11) and cooled to 0 °C. Freshly prepared 3-(trimethylsilyl)propiola-
ldehyde (10;18 150 mg, 1.16 mmol, 1.2 equiv) was slowly added to
the stirred solution. The cooling bath was removed and the reaction
mixture warmed to r.t. Complete conversion of the starting material
– as judged by TLC – was detected after 3 d. The solvent was evap-
orated and the crude product evaluated by NMR spectroscopy and
purified by flash column chromatography (SiO2; eluent: PE–
EtOAc, 98:2). The product was obtained as a colorless liquid
The Schwartz reagent (3.10 g, 12.0 mmol, 2.2 equiv) in anhyd
CH2Cl2 (24 mL) was placed in a 250 mL Schlenk flask under dry
N2. A solution of (R)-tert-butyldimethyl(oct-1-yn-3-yloxy)silane
(1.31 g, 5.45 mmol, 1.0 equiv) in anhyd CH2Cl2 (34 mL) was added
and the mixture stirred for 15 min at r.t. The mixture was cooled
with an ice bath and then a solution of I2 (1.52 g, 5.99 mmol,
1.1 equiv) in CH2Cl2 (34 mL) was added. The mixture was allowed
to warm to r.t. and stirring was continued for 15 min. The reaction
was quenched by pouring it into 10% aq Na2S2O3 (150 mL). The re-
sulting white precipitate was filtered. The organic layer was sepa-
rated and the aqueous layer was extracted with n-pentane (3 × 100
mL). The combined organic layers were washed with brine (100
mL), dried (MgSO4), filtered, and the solvents were removed under
reduced pressure. The crude product was subjected to flash column
chromatography (SiO2; eluent: n-pentane) to give a yellow liquid
20
(170 mg, 89%); Rf = 0.39 (PE–EtOAc, 85:15); [a]D +4.2
(c = 0.15, CHCl3); 98% ee, as determined by GLC [Hydrodex-b-
TBDAc, H2 (0.6 bar), 150 °C iso, tR = 77.6 min].
IR (film): 3341 (OH), 2963, 1472, 1407, 1334, 1250, 1124, 1042,
959, 886, 842, 759, 699 cm–1.
Synthesis 2010, No. 3, 527–537 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Halicholactone and Neohalicholactone
533
1H NMR (600 MHz, CDCl3): d = 0.17 [s, 9 H, Si(CH3)3], 0.98 (t,
13C NMR (151 MHz, CDCl3): d = –5.0, –4.6 (CH3), 14.2 (C-8), 18.3
[C(CH3)3], 20.8 (C-7), 25.7 [C(CH3)3], 36.5 (C-4), 62.8 (C-3), 72.1
(C-1), 85.4 (C-2), 123.6 (C-5), 134.5 (C-6).
MS (EI, 70 eV): m/z (%) = 238 (<1%, M+), 223 (4, [(M – CH3)+]),
209 (3), 181 (52), 169 (53), 153 (10), 139 (10), 115 (8), 113 (49),
107 (9), 99 (9), 91 (7), 83 (38).
3
3J = 7.5 Hz, 3 H, 8-H), 1.85 (d, J = 6.0 Hz, 1 H, OH), 2.09 (qdd,
3J = 7.5 Hz, 3J = 7.5 Hz, 4J = 1.6 Hz, 2 H, 7-H), 2.48 (mc, 2 H, 4-H),
4.38 (q, 3J = 6.0 Hz, 1 H, 3-H), 5.43 (dtt, 3J = 10.6 Hz, 3J = 7.5 Hz,
4J = 1.6 Hz, 1 H, 5-H), 5.63 (dtt, 3J = 10.6 Hz, 3J = 7.5 Hz, 4J = 1.6
Hz, 1 H, 6-H).
13C NMR (151 MHz, CDCl3): d = 0.1 [Si(CH3)3], 14.4 (C-8), 20.9
(C-7), 35.7 (C-4), 62.5 (C-3), 89.6 (C-1 or C-2), 106.4 (C-1 or C-2),
122.9 (C-5), 136.0 (C-6).
Anal. Calcd for C14H26OSi (238.44): C, 70.52; H, 10.99. Found: C,
69.03; H, 10.85.
The analytical and spectral data were in full agreement with those
previously reported.30
MS (EI, 70 eV): m/z (%) = 195 (<1, [(M – H)+]), 181 (11, [(M –
CH3)+]), 127 (61, [(M – C5H9)+]), 99 (100, [(C6H11O)+]).
Anal. Calcd for C11H20OSi (196.36): C, 67.28; H, 10.27. Found: C,
67.07; H, 10.20.
(R,1E,5Z)-tert-Butyl[1-iodoocta-1,5-dien-3-yloxy]dimethyl-
silane
The Schwartz reagent (744 mg, 2.89 mmol, 2.2 equiv) in anhyd
CH2Cl2 (6 mL) was placed in a 50 mL Schlenk flask under dry N2.
A solution of (R,Z)-tert-butyl(oct-5-en-1-yn-3-yloxy)dimethyl-
silane (313 mg, 1.31 mmol, 1.0 equiv) in anhyd CH2Cl2 (8 mL) was
added and stirred for 20 min at r.t. The mixture was cooled with an
ice bath and then a solution of I2 (366 mg, 1.44 mmol, 1.1 equiv) in
CH2Cl2 (8 mL) was added. The mixture was allowed to warm to r.t.
and stirring was continued for 1 h. The reaction was quenched by
pouring the mixture into 10% aq Na2S2O3 (150 mL). The resulting
white precipitate was filtered. The organic layer was separated and
the aqueous layer was extracted with n-pentane (3 × 100 mL). The
combined organic layers were washed with brine (100 mL), dried
(MgSO4), filtered, and the solvents were removed under reduced
pressure. The crude product was subjected to flash column chroma-
tography (SiO2; eluent: n-pentane). The pure vinyl iodide product
was obtained as a yellow liquid (382 mg, 79%), which was directly
used in the next step; Rf = 0.49 (n-pentane); [a]D20 +12.3 (c = 0.20,
CHCl3).
(R,Z)-Oct-5-en-1-yn-3-ol (7)
TBAF·3H2O (2.24 g, 7.1 mmol, 1.5 equiv) in anhyd THF (12 mL)
was placed in a 100 mL Schlenk flask. A solution of (R,Z)-1-tri-
methylsilyloct-5-en-1-yn-3-ol (928 mg, 4.72 mmol, 1.0 equiv) in
anhyd THF (19 mL) was slowly added. Stirring was continued for
1 h until the desilylation was complete (as judged by TLC). After
hydrolysis with brine (50 mL), the aqueous layer was extracted with
Et2O (3 × 60 mL). The combined organic layers were dried
(MgSO4), filtered, and the solvents were removed under reduced
pressure. The crude propargylic alcohol was subjected to flash col-
umn chromatography (SiO2; eluent: n-pentane-Et2O, 95:5). The
product 7 (582 mg, 99%) was obtained as a colorless liquid;
Rf = 0.34 (PE–EtOAc, 85:15); [a]D20 +33.6 (c = 0.25, CHCl3).
IR (film): 3298 (OH), 3014, 2964, 2934, 2876, 1457, 1304, 1123,
1037, 955, 867, 793, 628 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.98 (t, J = 7.5 Hz, 3 H, 8-H),
3
1.93 (d, 3J = 6.1 Hz, 1 H, OH), 2.10 (qdd, 3J = 7.5 Hz, 3J = 7.3 Hz,
IR (film): 2957, 2930, 2857, 1607, 1472, 1463, 1405, 1389, 1361,
1253, 1212, 1163, 1086, 1006, 941, 894, 832, 811, 785 cm–1.
4J = 1.7 Hz, 2 H, 7-H), 2.47 (d, J = 2.1 Hz, 1 H, 1-H), 2.46–2.54
4
3
3
(m, 2 H, 4-H), 4.40 (dddd, J = 6.2 Hz, 3J = 6.2 Hz, J = 6.1 Hz,
4J = 2.1 Hz, 1 H, 3-H), 5.45 (dddt, 3J = 10.6 Hz, 3J = 7.4 Hz,
3J = 7.4 Hz, 4J = 1.7 Hz, 1 H, 5-H), 5.64 (dddt, 3J = 10.6 Hz,
3J = 7.3 Hz, 3J = 7.3 Hz, 4J = 1.7 Hz, 1 H, 6-H).
1H NMR (600 MHz, CDCl3): d = 0.04, 0.05 [2 s, 6 H, Si(CH3)2],
0.89 [s, 9 H, SiC(CH3)3], 0.96 (t, 3J = 7.5 Hz, 3 H, 8-H), 2.03 (mc,
3
2 H, 7-H), 2.24 (mc, 2 H, 4-H), 4.09 (tdd, J = 6.1 Hz, 3J = 5.8 Hz,
4J = 1.4 Hz, 1 H, 3-H), 5.31 (dddt, 3J = 10.6 Hz, 3J = 7.5 Hz,
3J = 7.5 Hz, 4J = 1.6 Hz, 1 H, 5-H), 5.48 (dddt, 3J = 10.6 Hz,
3J = 7.3 Hz, 3J = 7.3 Hz, 4J = 1.6 Hz, 1 H, 6-H), 6.21 (dd, 3J = 14.3
Hz, 4J = 1.4 Hz, 1 H, 1-H), 6.54 (dd, 3J = 14.3 Hz, 3J = 5.8 Hz, 1 H,
2-H).
13C NMR (151 MHz, CDCl3): d = 14.2 (C-8), 20.8 (C-7), 35.4 (C-
4), 61.8 (C-3), 73.0 (C-2), 84.5 (C-1), 122.3 (C-5), 136.2 (C-6).
MS (EI, 70 eV): m/z (%) = 123 [3, (M – H)+], 109 (29, [(M –
CH3)+]), 95 (49, [(M – C2H5)+]).
13C NMR (151 MHz, CDCl3): d = –5.0, –4.5 (CH3), 14.2 (C-8), 18.4
[C(CH3)3], 20.8 (C-7), 25.8 [C(CH3)3], 35.6 (C-4), 73.7 (C-3), 75.3
(C-1), 123.6 (C-5), 134.3 (C-6), 148.7 (C-2).
The analytical and spectral data were in full agreement with those
previously reported.30,31
(R,Z)-tert-Butyl(oct-5-en-1-yn-3-yloxy)dimethylsilane
MS (EI, 70 eV): m/z (%) = 351 (2, [(M – CH3)+]), 309 (29, [(M –
To a stirred solution of 7 (585 mg, 4.71 mmol, 1.0 equiv) in anhyd
CH2Cl2 (11 mL) were added imidazole (578 mg, 8.49 mmol,
1.8 equiv) and TBSCl (847 mg, 5.62 mmol, 1.19 equiv) and the
mixture was stirred overnight. After hydrolysis with H2O (10 mL),
the layers were separated, and the aqueous layer was extracted with
n-pentane (3 × 50 mL). The combined organic layers were washed
with H2O (2 × 50 mL), dried (MgSO4), filtered, and the solvents
were removed under reduced pressure. The crude product was sub-
jected to flash column chromatography (SiO2; eluent: n-pentane–
Et2O, 99:1). The pure product (992 mg, 88%) was obtained as a col-
C4H9)+]), 297 (100, [(M – C5H9)+]).
(R,1E,5Z)-1-Iodoocta-1,5-dien-3-ol (5)
(R,1E,5Z)-tert-Butyl[1-iodoocta-1,5-dien-3-yloxy]dimethylsilane
(339 mg, 925 mmol, 1.0 equiv) in anhyd THF (10 mL) was cooled
to 0 °C and solid TBAF·3H2O (328 mg, 1.04 mmol, 1.12 equiv)
was added. The mixture was warmed to r.t. and stirred for 2 h; TLC
indicated the complete conversion of the starting material. After hy-
drolysis with H2O (10 mL), the aqueous layer was separated and ex-
tracted with Et2O (3 × 30 mL). The combined organic layers were
washed with H2O (2 × 30 mL), dried (MgSO4), and filtered. The
solvents were removed under reduced pressure and the crude prod-
uct subjected to flash column chromatography (SiO2; eluent: n-pen-
tane–Et2O, 99:1). Product 5 (200 mg, 86%) was obtained as a
yellow slightly impure liquid; Rf = 0.06 (n-pentane–Et2O, 95:5);
[a]D20 +16.4 (c = 1.2, CHCl3).
20
orless liquid; Rf = 0.53 (n-pentane–Et2O, 99:1); [a]D +34.0
(c = 0.07, CHCl3).
IR (film): 3312, 2959, 2931, 2858, 1473, 1464, 1390, 1362, 1342,
1252, 1086, 1006, 939, 874, 835, 786 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.11, 0.13 [2 s, 6 H, Si(CH3)2],
0.91 [s, 9 H, SiC(CH3)3], 0.97 (t, 3J = 7.5 Hz, 3 H, 8-H), 2.07 (qd,
3J = 7.5 Hz, 3J = 7.5 Hz, 2 H, 7-H), 2.39 (d, 4J = 2.1 Hz, 1 H, 1-H),
2.45 (dd, 3J = 7.0 Hz, 3J = 7.0 Hz, 2 H, 4-H), 4.34 (td, 3J = 7.0 Hz,
4J = 2.1 Hz, 1 H, 3-H), 5.41 (mc, 1 H, 5-H), 5.53 (mc, 1 H, 6-H).
IR (film): 3332 (OH), 3011, 2960, 2930, 2856, 1607, 1463, 1254,
1208, 1165, 1038, 944, 863, 837, 774, 706, 669 cm–1.
Synthesis 2010, No. 3, 527–537 © Thieme Stuttgart · New York

534
M. Bischop et al.
FEATURE ARTICLE
3
1H NMR (600 MHz, CDCl3): d = 0.98 (t, J = 7.6 Hz, 3 H, 8-H),
1.72 (br, 1 H, OH), 2.07 (qddd, 3J = 7.6 Hz, 3J = 7.6 Hz, 4J = 1.5 Hz,
5J = 0.8 Hz, 2 H, 7-H), 2.31 (mc, 2 H, 4-H), 4.13 (mc, 1 H, 3-H),
5.33 (dddt, 3J = 11.1 Hz, 3J = 7.6 Hz, 3J = 7.2 Hz, 4J = 1.5 Hz, 1 H,
5-H), 5.61 (dddt, 3J = 11.1 Hz, 3J = 7.6 Hz, 3J = 7.2 Hz,4J = 1.5 Hz,
1 H, 6-H), 6.37 (dd, 3J = 14.4 Hz, 4J = 1.5 Hz, 1 H, 1-H), 6.60 (dd,
3J = 14.4 Hz, 3J = 5.7 Hz, 1 H, 2-H).
(PE–EtOAc, 50:50); [a]D20 –49.9 (c = 0.7, CHCl3, dr 96:4, ee
>98%).
IR (film): 3079, 2977, 2939, 1731 (C=O), 1658 (C=O), 1462, 1423,
1385, 1226, 1245, 1174, 1107, 1049, 990, 916 cm–1.
3
3
1H NMR (600 MHz, CDCl3): d = 0.82 (ddd, J = 8.5 Hz, J = 6.0
2
3
3
Hz, J = 4.2 Hz, 1 H, 3¢¢-Ha), 1.24 (ddd, J = 9.0 Hz, J = 5.0 Hz,
2J = 4.2 Hz, 1 H, 3¢¢-Hb), 1.64 (dddd, 3J = 9.0 Hz, 3J = 8.9 Hz,
3J = 6.0 Hz, 3J = 4.1 Hz, 1 H, 1¢¢-H), 1.65–1.78 (m, 2 H, 3-H), 2.08
(tddd, 3J = 7.4 Hz, 3J = 7.2 Hz, 4J = 1.3 Hz, 4J = 1.3 Hz, 1 H, 4-H),
2.29 (br mc, 3 H, 2¢¢-H, 2-H), 2.42 (ddddd, 2J = 14.3 Hz, 3J = 7.2 Hz,
13C NMR (151 MHz, CDCl3): d = 14.2 (C-8), 20.8 (C-7), 34.6 (C-
4), 73.9 (C-3), 77.3 (C-1), 122.7 (C-5), 136.2 (C-6), 147.8 (C-2).
MS (EI, 70 eV): m/z (%) = 234 [4, (M – H2O)+], 183 (100, [(M –
C5H9)+]).
3J = 7.0 Hz, J = 1.2 Hz, 4J = 1.2 Hz, 1 H, 2¢-Ha), 2.47 (ddddd,
4
2J = 14.3 Hz, 3J = 6.7 Hz, 3J = 5.5 Hz, 4J = 1.2 Hz, 4J = 1.2 Hz, 1 H,
2¢-Hb), 3.18 (s, 3 H, NCH3), 3.71 (s, 3 H, OCH3), 4.47 (ddd, 3J = 8.9
(1R,2R,1¢S)-2-(1¢-Hydroxybut-3-enyl)-N-methoxy-N-methylcy-
clopropanecarboxamide
3
3
3
Hz, J = 7.0 Hz, J = 5.5 Hz, 1 H, 1¢-H), 4.99 (ddt, J = 10.2 Hz,
2J = 2.0 Hz, 4J = 1.3 Hz, 1 H, 6-Ha), 5.02 (ddt, 3J = 17.1 Hz, 2J = 2.0
Hz, 4J = 1.3 Hz, 1 H, 6-Hb), 5.07 (dddd, 3J = 10.2 Hz, 2J = 2.1 Hz,
4J = 1.2 Hz, 4J = 1.2 Hz, 1 H, 4-Ha), 5.11 (dddd, 3J = 17.1 Hz,
2J = 2.1 Hz, 4J = 1.2 Hz, 4J = 1.2 Hz, 1 H, 4-Hb), 5.73–5.81 (m, 2 H,
3¢-H, 5-H).
Under dry N2, the Leighton reagent 1421,22 (3.13 g, 5.66 mmol,
2.0 equiv) in CH2Cl2 (30 mL) was placed in a 100 mL Schlenk flask
and cooled to –12 °C. Aldehyde 134b (445 mg, 2.83 mmol,
1.0 equiv) in CH2Cl2 (8 mL) was slowly added and the temperature
was kept constant for 72 h. The mixture was diluted and quenched
with EtOAc (10 mL) and aq 1 M HCl (10 mL); stirring was contin-
ued for ~10 min at –12 °C and at r.t. until the layers separated. The
aqueous layer was extracted with EtOAc (5 × 20 mL) and the com-
bined organic layers were dried (Na2SO4), filtered, and the solvent
removed under reduced pressure. The crude product was subjected
to flash column chromatography (SiO2; eluent: PE–EtOAc, 50:50);
to give a colorless oil; yield: 413 mg (73%, dr 96:4, ee >98%). The
separation of diastereoisomers was not possible; Rf = 0.22 (PE–
EtOAc, 50:50); [a]D20 –27.5 (c = 0.70, CHCl3, dr 96:4, ee >98%).
13C NMR (151 MHz, CDCl3): d = 12.7 (C-3¢¢), 16.1 (C-2¢¢), 24.2
(C-3), 25.3 (C-1¢¢), 32.5 (NCH3), 33.0 (C-4), 33.8 (C-2), 39.0 (C-2'),
61.6 (OCH3), 74.3 (C-1¢), 115.4 (C-6), 118.0 (C-4), 133.2 (C-5),
137.7 (C-3), 173.0 (NCO), 173.1 (C-1).
MS (EI, 70 eV): m/z (%) = 295 (<5, [M+]), 254 (<5, [M – C3H5 ]).
+
Conversion of Ester 15 to (1R,2R,2¢S,Z)-N-Methoxy-N-methyl-
2-(9¢-oxo-2¢,3¢,6¢,7¢,8¢,9¢-hexahydrooxonin-2¢-yl)cyclopropane-
carboxamide (16) by Ring-Closing Metathesis; General Proce-
dure (Table 2, Entries 1–8)
IR (film): 3412 (OH), 3184, 3159, 3075, 3006, 2973, 2936, 2900,
1730 (C=O), 1630, 1558, 1465, 1422, 1386, 1260, 1177, 1149,
1107, 1046, 993, 961, 913, 821, 763, 647 cm–1.
Under an atmosphere of dry argon, in an oven-dried 2 L-three-neck
flask, diene 15 (1.0 equiv) was dissolved in the desired anhyd sol-
vent and Ti(Oi-Pr)4 (0.3 equiv) was added. The mixture was re-
fluxed for 1 h. Then the catalyst was dissolved in of the same
solvent (ca. 2 mL) and added to the reaction mixture. The mixture
was stirred at a higher temperature (see Table 2). TLC indicated
complete conversion of the starting material. The solvent was re-
moved under reduced pressure (the bath temperature should not ex-
ceed 30 °C) until about 1 mL volume was left. The crude product
was purified by flash column chromatography (SiO2, eluent: PE–
EtOAc, 70:30). For exact conditions and yield, see Table 2. The
product 16 was obtained as a colorless oil; Rf = 0.46 (PE–EtOAc,
50:50); [a]D20 –136 (c = 0.90, CHCl3, dr 91:9).
1H NMR (600 MHz, CDCl3): d = 0.85 (ddd, J = 8.4 Hz, J = 6.2
3
3
2
3
3
Hz, J = 4.1 Hz, 1 H, 3-Ha), 1.24 (ddd, J = 9.0 Hz, J = 5.0 Hz,
2J = 4.1 Hz, 1 H, 3-Hb), 1.54 (dddd, 3J = 9.0 Hz, 3J = 7.6 Hz,
3J = 6.2 Hz, J = 4.2 Hz, 1 H, 2-H), 1.64 (br, 1 H, OH), 2.22 (br,
3
1 H, 1-H), 2.32 (dddt, 2J = 13.9 Hz, 3J = 7.8 Hz, 3J = 7.7 Hz,
4J = 1.1 Hz, 1 H, 2¢-Ha), 2.44 (dddt, 2J = 13.9 Hz, 3J = 6.5 Hz,
3J = 4.5 Hz, J = 1.1 Hz, 1 H, 2¢-b), 3.21 (s, 3 H, NCH3), 3.24 (br
4
ddd, 3J = 7.7 Hz, 3J = 7.6 Hz, 3J = 4.5 Hz, 1 H, 1¢-H), 3.79 (s, 3 H,
OCH3), 5.15 (ddt, 3J = 10.2, 2J = 2.0, 4J = 1.1 Hz, 1 H, 4¢-Ha), 5.17
(ddt, 3J = 16.9 Hz, 2J = 2.0 Hz, 3J = 1.1 Hz, 1 H, 4¢-Hb), 5.86 (dddd,
3J = 16.9 Hz, 3J = 10.2 Hz, 3J = 7.8 Hz, 3J = 6.5 Hz, 1 H, 3¢-H).
13C NMR (151 MHz, CDCl3): d = 12.0 (C-3), 15.2 (C-1), 27.7 (C-
2), 32.5 (NCH3), 41.8 (C-2¢), 61.6 (OCH3), 72.9 (C-1¢), 118.5 (C-
4¢), 134.2 (C-3¢), 171.8 (C=O).
IR (film): 3010, 2941, 2864, 1737 (C=O), 1653 (C=O), 1449, 1426,
1385, 1353, 1331, 1258, 1224, 1209, 1177, 1134, 1111, 1087, 1051,
1015, 985, 964, 917, 899, 876, 861, 840, 790, 767, 730 cm–1.
+
3
3
MS (EI, 70 eV): m/z (%) = 199 (5, [M+]), 158 (50, [M – C3H5 ]),
1H NMR (600 MHz, CDCl3): d = 0.89 (ddd, J = 8.5 Hz, J = 6.0
139 (85, [M – C2H6NO+]).
Hz, J = 4.2 Hz, 1 H, 3-Ha), 1.29 (ddd, J = 8.9 Hz, J = 5.0 Hz,
2J = 4.2 Hz, 1 H, 3-Hb), 1.70 (dddd, 3J = 8.9 Hz, 3J = 8.8 Hz,
3J = 6.0 Hz, 3J = 4.1 Hz, 1 H, 2-H), 1.78 (mc, 1 H, 7-Ha), 2.04–2.10
(m, 2 H, 7-Hb, 8¢-Ha), 2.19–2.33 (m, 2 H, 6¢-H), 2.20 (ddd, 2J = 13.7
Hz, 3J = 7.4 Hz, 3J = 1.6 Hz, 1 H, 3¢-Ha), 2.26 (br, 1 H, 1-H), 2.47–
2.56 (m, 1 H, 8-Hb), 2.54 (dddd, 2J = 13.7 Hz, 3J = 10.6 Hz, 3J = 7.2
2
3
3
HRMS (EI, 70 eV): m/z calcd for C10H17NO3: 199.1208; found:
199.1208.
Ester 15
To a stirred solution of (1R,2R,1¢S)-2-(1¢-hydroxybut-3-enyl)-N-
methoxy-N-methylcyclopropanecarboxamide (404 mg, 2.03 mmol,
1.0 equiv) in anhyd CH2Cl2 (31 mL) were added N-3-diethylamino-
propyl-N¢-ethylcarbodiimide hydrochloride (EDC-hydrochloride)
(572 mg, 2.98 mmol, 1.5 equiv), DMAP (126 mg, 1.10 mmol,
0.5 equiv) and hex-5-enoic acid (364 mL, 3.10 mmol, 1.5 equiv) at
0 °C. The stirring was continued for 20 h at r.t. After hydrolysis
with sat. aq NH4Cl (30 mL), the aqueous layer was extracted with
CH2Cl2 (4 × 20 mL). The combined organic layers were dried
(MgSO4), filtered, and the solvent was removed under reduced pres-
sure. The crude product was subjected to flash column chromatog-
raphy (SiO2; eluent: PE–EtOAc, 70:30). The slightly impure
product 15 (562 mg, 94%) was obtained as a colorless oil; Rf = 0.63
5
Hz, J = 0.9 Hz, 1 H, 3¢-Hb), 3.21 (s, 3 H, NCH3), 3.72 (s, 3 H,
3
3
3
OCH3), 4.25 (ddd, J = 10.6 Hz, J = 8.8 Hz, J = 1.6 Hz, 1 H, 2¢-
H), 5.45–5.51 (m, 2 H, 4¢-H, 5¢-H).
13C NMR (151 MHz, CDCl3): d = 12.7 (C-3), 16.1 (C-1), 25.0 (C-
2), 25.3 (C-8¢), 26.4 (C-7¢), 32.5 (NCH3), 33.5 (C-6¢), 33.8 (C-3¢),
61.5 (OCH3), 75.8 (C-2¢), 124.5 (C-4), 134.9 (C-5), 173.7 (NCO),
174.0 (C-8¢).
MS (EI, 70 eV): m/z (%) = 268 (53, (M + H)+]), 250 (24, [(M –
OH)+]).
HRMS (ESI, positive ion): m/z calcd for C14H21NO4: 268.1543;
found: 268.1534.
Synthesis 2010, No. 3, 527–537 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Halicholactone and Neohalicholactone
535
3
3
(1R,2R,2¢S,Z)-2-[9¢-Oxo-2¢,3¢,6¢,7¢,8¢,9¢-hexahydrooxonin-2¢-
yl)cyclopropanecarbaldehyde (3)
1H NMR (600 MHz, CDCl3): d = 0.62 (ddd, J = 8.5 Hz, J = 5.1
2
3
3
Hz, J = 5.1 Hz, 1 H, 10-Ha), 0.72 (ddd, J = 8.7 Hz, J = 5.2 Hz,
3
Under an atmosphere of dry argon, in a Schlenk flask Weinreb
amide 16 (36 mg, 135 mmol, 1.0 equiv) was dissolved in anhyd
THF (225 mL, c = 0.6) and cooled to –78 °C. A solution of DIBAL-
H (135 mL, 135 mmol, 1 M solution in hexane) was slowly added
and stirring was continued for an additional 50 min at this tempera-
ture. The reaction mixture was hydrolyzed with two drops of H2O,
one drop of aq NaOH (15%), and two drops of H2O. The two phase
mixture was warmed to r.t. and directly subjected to flash column
chromatography (SiO2; eluent: PE–EtOAc, 70:30). First the alde-
hyde 3 (21 mg, 75%) was eluted, and then the Weinreb amide 16
was recovered (7 mg, 17%). The product 3 was obtained as a color-
less oil; Rf = 0.69 (PE–EtOAc, 50:50); [a]D20 –240 (c = 0.5, CHCl3,
ee >98%, dr 91:9).
2J = 5.1 Hz, 1 H, 10-Hb), 0.89 (t, J = 7.0 Hz, 3 H, 20-H), 1.03
(dddd, 3J = 8.7 Hz, 3J = 8.3 Hz, 3J = 5.1 Hz, 3J = 4.8 Hz, 1 H, 9-H),
1.10 (dddd, 3J = 8.5 Hz, 3J = 7.4 Hz, 3J = 5.2 Hz, 3J = 4.8 Hz, 1 H,
11-H), 1.26–1.43 (m, 6 H, 17-H, 18-H, 19-H), 1.48-1.58 (m, 3 H,
16-Ha, 16-Hb, OHC-15), 1.65 (br, 1 H, OHC-12), 1.78 (mc, 1 H, 3-Ha),
2.03–2.09 (m, 2 H, 3-Hb,4-Ha), 2.15 (ddd, 2J = 13.5 Hz, 3J = 7.2 Hz,
3J = 1.7 Hz, 1 H, 7-Ha), 2.23–2.32 (m, 2 H, 2-H), 2.44–2.52 (m,
2 H, 4-Hb, 7-Hb), 3.70 (br ddd, 3J = 7.4 Hz, 3J = 3.8 Hz, 3J = 3.7 Hz,
1 H, 12-H), 4.11 (br mc, 1 H, 15-H), 4.23 (ddd, 3J = 10.9 Hz,
3J = 8.3 Hz, J = 1.7 Hz, 1 H, 8-H), 5.44–5.49 (m, 2 H, 5-H, 6-H),
3
5.75–5.77 (m, 2 H, 13-H, 14-H).
1H NMR (600 MHz, C6D6): d = 0.34 (ddd, 3J = 8.5 Hz, 3J = 5.0 Hz,
2J = 5.0 Hz, 1 H, 10-Ha), 0.53 (ddd, 3J = 8.7 Hz, 3J = 5.2 Hz,
3
IR (film): 3011, 2948, 2858, 2733, 1737 (C=O), 1708 (C=O), 1449,
1353, 1259, 1224, 1208, 1167, 1134, 1088, 1058, 1015, 985, 938,
882, 855, 728 cm–1.
2J = 5.1 Hz, 1 H, 10-Hb), 0.89 (t, J = 7.1 Hz, 3 H, 20-H), 0.90
(dddd, 3J = 8.7 Hz, 3J = 8.4 Hz, 3J = 5.0 Hz, 3J = 4.4 Hz, 1 H, 9-H),
1.10 (dddd, 3J = 8.5 Hz, 3J = 7.0 Hz, 3J = 5.2 Hz, 3J = 4.4 Hz, 1 H,
11-H), 1.21–1.60 (m, 11 H, 3-Ha, 16-Ha, 16-Hb, 17-H, 18-H, 19-H,
OHC-12, OHC-15), 1.73–1.89 (m, 2 H, 3-Hb, 4-Ha), 1.92 (ddd,
3
3
1H NMR (600 MHz, CDCl3): d = 1.12 (ddd, J = 8.4 Hz, J = 6.4
2
3
3
Hz, J = 4.9 Hz, 1 H, 3-Ha), 1.38 (ddd, J = 9.0 Hz, J = 4.9 Hz,
2J = 13.4 Hz, J = 7.3 Hz, J = 1.6 Hz, 1 H, 7-Ha), 2.05–2.14 (m,
2 H, 2-H), 2.33–2.39 (m, 2 H, 4-Hb, 7-Hb), 3.60 (mc, 1 H, 12-H),
3.99–4.02 (br m, 1 H, 15-H), 4.33 (ddd, 3J = 10.8 Hz, 3J = 8.4 Hz,
3J = 1.6 Hz, 1 H, 8-H), 5.34–5.44 (m, 2 H, 5-H, 6-H), 5.71–5.76 (m,
2 H, 13-H, 14-H).
3
3
2J = 4.9 Hz, 1 H, 3-Hb), 1.74–1.79 (m, 1 H, 7¢-Ha), 1.80 (dddd,
3J = 9.0 Hz, J = 7.9 Hz, J = 6.4 Hz, J = 4.0 Hz, 1 H, 2-H), 2.02
(dddd, 3J = 8.4 Hz, 3J = 4.9 Hz, 3J = 4.6 Hz, 3J = 4.0 Hz, 1 H, 1-H),
2.04–2.11 (m, 2 H, 7¢-Hb, 6¢-Ha), 2.17 (ddd, 2J = 13.6 Hz, 3J = 7.3
3
3
3
3
Hz, J = 1.6 Hz, 1 H, 3¢-Ha), 2.24–2.33 (m, 2 H, 8¢-H), 2.44–2.53
(m, 1 H, 6¢-Hb), 2.52 (dddd, 2J = 13.6 Hz, 3J = 10.9 Hz, 3J = 7.8 Hz,
4J = 0.8 Hz, 1 H, 3¢-Hb), 4.39 (ddd, 3J = 10.9 Hz, 3J = 7.9 Hz,
3J = 1.6 Hz, 1 H, 2¢-H), 5.46 (dddd, 3J = 11.2 Hz, 3J = 7.8 Hz,
3J = 7.3 Hz, 4J = 1.2 Hz, 1 H, 4¢-H), 5.46–5.22 (m, 1 H, 5¢-H), 9.24
(d, 3J = 4.6 Hz, 1 H, CHO).
13C NMR (151 MHz, CDCl3): d = 8.3 (C-10), 14.1 (C-20), 19.5 (C-
9), 22.6 (C-17 or C-18 or C-19), 23.4 (C-11), 25.1 (C-17 or C-18 or
C-19), 25.3 (C-4), 26.5 (C-3), 31.7 (C-17 or C-18 or C-19), 33.6 (C-
2), 33.9 (C-7), 37.2 (C-16), 72.3 (C-15), 74.2 (C-12), 76.2 (C-8),
124.7 (C-5 or C-6), 131.6 (C-13 or C-14), 134.6 (C-13 or C-14),
134.7 (C-5 or C-6), 174.1 (C-1).
13C NMR (151 MHz, C6D6): d = 7.9 (C-10), 14.3 (C-20), 19.7 (C-
9), 22.6 (C-17 or C-18 or C-19), 23.4 (C-11), 25.6 (C-17 or C-18 or
C-19), 25.6 (C-4), 26.6 (C-3), 32.2 (C-17 or C-18 or C-19), 33.7 (C-
2), 34.1 (C-7), 37.9 (C-16), 72.2 (C-15), 72.4 (C-12), 76.3 (C-8),
125.0 (C-5 or C-6), 132.1 (C-13 or C-14), 134.1 (C-13 or C-14),
134.7 (C-5 or C-6), 173.2 (C-1).
13C NMR (151 MHz, CDCl3): d = 12.7 (C-3), 25.3 (C-6¢), 25.6 (C-
2), 26.4 (C-7¢), 27.9 (C-1), 33.5 (C-3¢), 33.8 (C-8¢), 74.1(C-2¢),
124.1 (C-4¢), 135.1 (C-5¢), 173.8 (C-8¢), 200.0 (CHO).
MS (EI, 70 eV): m/z (%) = 208 (47, [M+]), 191 (23, [(M – OH)+]),
110 (100, [(M – C5H6O2)+]).
HRMS (ESI, positive ion): m/z calcd for C12H16O3: 209.1172;
found: 209.1163.
HRMS (ESI, positive ion): m/z calcd for C20H32O4 + Na: 359.21928;
found: 359.21965.
Halicholactone (1)
Freshly prepared aldehyde 3 (27 mg, 130 mmol, 1.0 equiv) and vi-
nyl iodide 4 (100 mg, 389 mmol, 3.0 equiv) in DMSO (7.6 mL)
were placed in a 25 mL Schlenk flask and the mixture was degassed
three times (at –78 °C/<10–2 mbar). CrCl2 (104 mg, 843 mmol,
6.5 equiv) and NiCl2 (4 mg, 33 mmol, 0.25 equiv) were added to the
stirred solution under dry argon. After 2 d, no aldehyde 3 was de-
tected by TLC. The mixture was poured into a separating funnel
containing sat. aq NH4Cl (15 mL). The aqueous layer was extracted
with EtOAc (5 × 20 mL). The combined organic layers were washed
with H2O (50 mL), dried (MgSO4), filtered, and the solvent was re-
moved under reduced pressure (the bath temperature should not ex-
ceed 25 °C). In cases where traces of DMSO were still present,
extraction with EtOAc and washing the organic layer with H2O
were repeated. The crude product was subjected to flash column
chromatography (SiO2; eluent: first PE–EtOAc, 60:40, then PE–
EtOAc, 50:50, and pure EtOAc). Halicholactone (1) and its C12-
epimer were obtained as a mixture (34 mg, 78%, dr 59:41). Separa-
tion of the epimers by semi-preparative HPLC [Maxsil, 5 m Si 250
mm × 4.6 mm; n-heptane–i-PrOH (90:10), 3 mL/min, 24 bar,
tR = 53.2 min; C12-epimer: tR = 49.8 min] yielded halicholactone (1)
(dr 93:7) as a colorless oil; Rf = 0.55 (EtOAc); [a]D15 –79.7
(c = 0.75, CHCl3); [a]D23 –79.0 (c = 0.75, CHCl3).
HRMS (ESI, positive ion): m/z calcd for C20H31O3: 319.22677;
found: 319.22707.
C12-epi-Halicholactone
dr 93:7; [a]D15 –73.6 (c = 0.55, CHCl3); [a]D23 –73.3 (c = 0.55,
CHCl3).
3
3
1H NMR (600 MHz, CDCl3): d = 0.60 (ddd, J = 8.6 Hz, J = 5.2
2
3
3
Hz, J = 5.2 Hz, 1 H, 10-Ha), 0.63 (ddd, J = 8.1 Hz, J = 5.3 Hz,
2J = 5.2 Hz, 1 H, 10-Hb), 0.89 (t, J = 7.0 Hz, 3 H, 20-H), 1.08
3
3
3
3
3
(dddd, J = 8.6 Hz, J = 7.6 Hz, J = 5.3 Hz, J = 4.4 Hz, 1 H, 11-
H), 1.11 (dddd, J = 8.3 Hz, 3J = 8.1 Hz, J = 5.2 Hz, J = 4.4 Hz,
1 H, 9-H), 1.26–1.42 (m, 6 H, 17-H, 18-H, 19-H), 1.47–1.59 (m,
3 H, 16-Ha, 16-Hb, OHC-15), 1.65 (br, 1 H, OHC-12), 1.78 (mc, 1 H, 3-
Ha), 2.03–2.09 (m, 2 H, 3-Hb, 4-Ha), 2.18 (ddd, 2J = 15.0 Hz,
3J = 7.3 Hz, 3J = 1.6 Hz, 1 H, 7-Ha), 2.23–2.26 (m, 1 H, 2-Ha), 2.33
(mc, 1 H, 2-Hb), 2.47–2.53 (m, 2 H, 4-Hb, 7-Hb), 3.60 (br dd,
3J = 7.6 Hz, 3J = 4.4 Hz, 1 H, 12-H), 4.10–4.13 (br m, 1 H, 15-H),
3
3
3
4.19 (ddd, 3J = 10.8 Hz, J = 8.3 Hz, 3J = 1.6 Hz, 1 H, 8-H), 5.44–
3
5.50 (m, 2 H, 5-H, 6-H), 5.73–5.74 (m, 2 H, 13-H, 14-H).
13C NMR (151 MHz, CDCl3): d = 7.9 (C-10), 14.0 (C-20), 20.6 (C-
9), 22.6 (C-17 or C-18 or C-19), 23.8 (C-11), 25.1 (C-17 or C-18 or
C-19), 25.3 (C-4), 26.5 (C-3), 31.7 (C-17 or C-18 or C-19), 33.7 (C-
2), 33.9 (C-7), 37.2 (C-16), 72.4 (C-15), 74.7 (C-12), 76.1 (C-8),
124.6 (C-5 or C-6), 131.6 (C-13 or C-14), 134.0 (C-13 or C-14),
134.7 (C-5 or C-6), 174.1 (C-1).
IR (film): 3398 (OH), 3008, 2929, 2858, 1738 (C=O), 1714, 1448,
1401, 1354, 1328, 1261, 1224, 1204, 1135, 1085, 1013, 971, 915,
727 cm–1.
Synthesis 2010, No. 3, 527–537 © Thieme Stuttgart · New York

536
M. Bischop et al.
FEATURE ARTICLE
Neohalicholactone (2)
17), 124.7 (C-5 or C-6), 131.8 (C-14), 133.2 (C-13), 134.7 (C-5 or
C-6), 135.4 (C-18), 174.1 (C-1).
Freshly prepared aldehyde 3 (27 mg, 130 mmol, 1.0 equiv) and vi-
nyl iodide 5 (78 mg, 347 mmol, 2.67 equiv) in DMSO (7.6 mL)
were placed in a 25 mL Schlenk flask and the mixture was degassed
three times (at –78 °C/<10–2 mbar). CrCl2 (104 mg, 843 mmol,
6.5 equiv) and NiCl2 (4 mg, 33 mmol, 0.25 equiv) were added to the
stirred solution under dry argon. After 3 d, no aldehyde 3 was de-
tected by TLC. The mixture was poured into a separating funnel
containing sat. aq NH4Cl (15 mL). The aqueous layer was extracted
with EtOAc (5 × 20 mL). The combined organic layers were washed
with H2O (50 mL), dried (MgSO4), filtered, and the solvent was re-
moved under reduced pressure (the bath temperature should not ex-
ceed 25 °C). In cases where traces of DMSO were still present,
extraction with EtOAc and washing the organic layer with H2O
were repeated. The crude product was subjected to flash column
chromatography (SiO2; eluent: first PE–EtOAc, 60:40, then PE–
EtOAc, 50:50, and pure EtOAc). Neohalicholactone (2) and its C12-
epimer was obtained as a mixture (40 mg, 92%, dr 60:40). Separa-
tion of the epimers by semi-preparative HPLC [Maxsil, 5 m Si 250
mm × 4.6 mm; n-hexane–i-PrOH (90:10), 3 mL/min, 24 bar,
tR = 58.5 min; C12-epimer: tR = 52.3 min] yielded neohalicholac-
tone (2) (dr 98:2) as a colorless oil; Rf = 0.6 (EtOAc); [a]D18 –89.9
(c = 0.25, CHCl3).
13C NMR (151 MHz, C6D6): d = 7.8 (C-10), 14.4 (C-20), 19.6 (C-
9), 21.0 (C-19), 23.8 (C-11), 25.6 (C-4), 26.6 (C-3), 33.7 (C-2), 34.1
(C-7), 35.8 (C-16), 71.7 (C-15), 73.4 (C-12), 76.1 (C-8), 124.7 (C-
17 or C-7), 125.1 (C-17 or C-7), 132.2 (C-13 or C-14), 133.2 (C-13
or C-14), 134.6 (C-6 or C-18), 134.7 (C-18 or C-6), 173.0 (C-1).
HRMS (ESI, positive ion): m/z calcd for C40H60O8 + Na: 691.41823;
found: 691.41824.
HRMS (ESI, positive ion): m/z calcd for C20H30O4 + Na: 357.20387;
found: 357.20388.
C12-epi-Neohalicholactone
[a]D18 69.1 (c = 0.49, CHCl3).
1H NMR (600 MHz, CDCl3): d = 0.60 (ddd, J = 8.7 Hz, J = 5.2
3
3
2
3
3
Hz, J = 5.2 Hz, 1 H, 10-Ha), 0.63 (ddd, J = 8.4 Hz, J = 5.2 Hz,
2J = 5.2 Hz, 1 H, 10-Hb), 0.97 (t, J = 7.5 Hz, 3 H, 20-H), 1.08
3
3
3
3
3
(dddd, J = 8.7 Hz, J = 7.6 Hz, J = 5.2 Hz, J = 4.4 Hz, 1 H, 11-
3
3
3
3
H), 1.12 (dddd, J = 8.4 Hz, J = 8.3 Hz, J = 5.2 Hz, J = 4.4 Hz,
1 H, 9-H), 1.66 (br, 1 H, OHC-12), 1.71 (d, 3J = 3.4 Hz, OHC-15), 1.77
(mc, 1 H, 3-Ha), 2.03–2.08 (m, 2 H, 3-Hb, 4-Ha), 2.07 (qdddd,
3J = 7.5 Hz, 3J = 7.4 Hz, 4J = 1.6 Hz, 5J = 0.8 Hz, 5J = 0.8 Hz, 2 H,
19-H), 2.16 (ddd, 2J = 13.6 Hz, 3J = 7.3 Hz, 3J = 1.6 Hz, 1 H, 7-Ha),
2.23–2.26 (mc, 1 H, 2-Ha), 2.28–2.35 (m, 1 H, 2-Hb), 2.29 (ddddt,
2J = 14.3 Hz, 3J = 7.7 Hz, 3J = 5.8 Hz, 4J = 1.8 Hz, 5J = 0.8 Hz, 1 H,
16-Ha), 2.34 (ddddt, 2J = 14.3 Hz, 3J = 8.6 Hz, 3J = 7.1 Hz, 4J = 1.5
Hz, 5J = 0.8 Hz, 1 H, 16-Hb), 2.47–2.53 (m, 1 H, 4-Hb), 2.51 (ddd,
IR (film): 3391 (OH), 3009, 2957, 2868, 1737 (C=O), 1448, 1354,
1332, 1263, 1224, 1208, 1136, 1089, 1014, 973, 917, 873, 790, 728
cm–1.
3
3
1H NMR (600 MHz, CDCl3): d = 0.61 (ddd, J = 8.5 Hz, J = 5.1
2
3
3
Hz, J = 5.1 Hz, 1 H, 10-Ha), 0.72 (ddd, J = 8.5 Hz, J = 5.1 Hz,
3
3
2J = 13.6 Hz, J = 10.7 Hz, J = 3.7 Hz, 1 H, 7-Hb), 3.61 (br dd,
2J = 5.1 Hz, 1 H, 10-Hb), 0.97 (t, J = 7.5 Hz, 3 H, 20-H), 1.03
3
3J = 7.6 Hz, J = 3.6 Hz, 1 H, 12-H), 4.17 (mc, 1 H, 15-H), 4.19
3
(dddd, 3J = 8.5 Hz, 3J = 8.4 Hz, 3J = 5.1 Hz, 3J = 4.4 Hz, 1 H, 9-H),
1.10 (dddd, 3J = 8.5 Hz, 3J = 7.3 Hz, 3J = 5.1 Hz, 3J = 4.4 Hz, 1 H,
11-H), 1.55 (d, 3J = 3.7 Hz, 1 H, OHC-12), 1.65 (d, 3J = 3.8 Hz, 1 H,
OHC-15), 1.78 (mc, 1 H, 3-Ha), 2.02–2.09 (m, 2 H, 3-Hb, 4-Ha), 2.07
(qdddd, 3J = 7.5 Hz, 3J = 7.4 Hz, 4J = 1.6 Hz, 5J = 0.7 Hz, 5J = 0.7
(ddd, 3J = 10.7 Hz, 3J = 8.3 Hz, 3J = 1.6 Hz, 1 H, 8-H), 5.35 (dddt,
3
3
4
3J = 10.9 Hz, J = 7.7 Hz, J = 7.1 Hz, J = 1.6 Hz, 1 H, 17-H),
5.44–5.50 (m, 2 H, 5-H, 6-H), 5.58 (dtdd, 3J = 10.9 Hz, 3J = 7.4 Hz,
4J = 1.5 Hz, 4J = 1.5 Hz, 1 H, 18-H), 5.74–5.80 (m, 2 H, 14-H, 13-
H).
2
3
3
Hz, 2 H, 19-H), 2.15 (ddd, J = 13.5 Hz, J = 7.3 Hz, J = 1.6 Hz,
2
13C NMR (151 MHz, CDCl3): d = 7.8 (C-10), 14.2 (C-20), 20.5 (C-
9), 20.7 (C-19), 23.7 (C-11), 25.3 (C-4), 26.5 (C-3), 33.7 (C-2), 33.8
(C-7), 35.2 (C-16), 71.6 (C-15), 74.6 (C-12), 76.4 (C-8), 123.6 (C-
17), 124.7 (C-6 or C-5), 131.7 (C-13), 133.1 (C-14), 134.7 (C-5 or
C-6), 135.4 (C-18), 174.2 (C-1).
1 H, 7-Ha), 2.22–2.30 (m, 2 H, 2-H), 2.31 (ddddt, J = 14.1 Hz,
3J = 7.3 Hz, 3J = 5.1 Hz, 4J = 1.8 Hz, 5J = 0.7 Hz, 1 H, 16-Ha), 2.33
(ddddt, 2J = 14.1 Hz, 3J = 7.6 Hz, 3J = 7.0 Hz, 4J = 1.5 Hz, 5J = 0.7
Hz, 1 H, 16-Hb), 2.44–2.48 (m, 1 H, 4-Hb), 2.50 (ddd, 2J = 13.5 Hz,
3J = 10.9 Hz, J = 7.2 Hz, 1 H, 7-Hb), 3.70 (br ddd, J = 7.3 Hz,
3J = 3.7 Hz, 3J = 3.7 Hz, 1 H, 12-H), 4.17 (br mc, 1 H, 15-H), 4.23
(ddd, 3J = 10.9 Hz, 3J = 8.4 Hz, 3J = 1.6 Hz, 1 H, 8-H), 5.35 (dddt,
3
3
3J = 10.6 Hz, J = 7.6 Hz, J = 7.3 Hz, J = 1.6 Hz, 1 H, 17-H), Acknowledgment
3
3
4
5.44–5.55 (m, 2 H, 5-H, 6-H), 5.58 (dtdd, 3J = 10.6 Hz, 3J = 7.4 Hz,
We gratefully acknowledge the Deutsche Forschungsgemeinschaft
4J = 1.8 Hz, 4J = 1.6 Hz, 1 H, 18-H), 5.75–5.82 (m, 2 H, 13-H, 14-
and the Ministry of Innovation, Science, Research and Technology
of the German federal state of North Rhine-Westphalia for the ge-
nerous support of our projects. Donations from the Umicore AG &
Co KG, the Jülich Chiral Solutions GmbH (now Codexis), the Wak-
ker AG, and the Forschungszentrum Jülich (Prof. Dr. H. Sahm,
Prof. Dr. Wandrey) are greatly appreciated. This work was ge-
nerously supported through grants from the Jürgen Manchot Stif-
tung (for M.B.), the Degussa Stiftung and the Heinrich-Heine-
Universität Düsseldorf (scholarships for A.C.M.N.). Furthermore,
we thank the analytical departments at the University of Stuttgart
and the FZ Jülich as well as Rainer Goldbaum, Monika Gehsing,
Birgit Henßen, Christoph Lorenz, Erik Kranz, David Müller, Vera
Ophoven, Bea Paschold, and Truc Pham for their ongoing support.
H).
1H NMR (600 MHz, C6D6): d = 0.27 (ddd, 3J = 8.5 Hz, 3J = 5.0 Hz,
2J = 5.0 Hz, 1 H, 10-Ha), 0.46 (ddd, 3J = 8.6 Hz, 3J = 5.0 Hz,
2J = 5.0 Hz, 1 H, 10-Hb), 0.86 (dddd, 3J = 8.6 Hz, 3J = 8.4 Hz,
3J = 5.0 Hz, 3J = 4.5 Hz, 1 H, 9-H), 0.89 (t, 3J = 7.5 Hz, 3 H, 20-H),
1.04 (dddd, 3J = 8.5 Hz, 3J = 6.9 Hz, 3J = 5.1 Hz, 3J = 4.5 Hz, 1 H,
11-H), 1.23 (br, 1 H, OHC-12), 1.41 (br, 1 H, OHC-15), 1.49–1.58 (m,
2 H, 3-H), 1.72–1.77 (m, 1 H, 4-Ha), 1.86 (ddd, 2J = 13.4 Hz,
3J = 7.3 Hz, 3J = 1.6 Hz, 1 H, 7-Ha), 1.97 (qdddd, 3J = 7.5 Hz,
3J = 7.4 Hz, 4J = 1.6 Hz, 5J = 0.8 Hz, 5J = 0.8 Hz, 2 H, 19-H), 2.05–
2.12 (m, 2 H, 2-H), 2.22 (ddddt, 2J = 14.1 Hz, 3J = 7.3 Hz, 3J = 5.9
Hz, 4J = 1.6 Hz, 5J = 0.8 Hz, 1 H, 16-Ha), 2.27 (ddddt, 2J = 14.1 Hz,
3J = 8.4 Hz, 3J = 6.9 Hz, 4J = 1.6 Hz, 5J = 0.8 Hz, 1 H, 16-Hb), 2.32–
2.38 (m, 2 H, 4-Hb, 7-Hb), 3.54 (br mc, 1 H, 12-H), 4.00 (mc, 1 H,
15-H), 4.32 (ddd, 3J = 10.8 Hz, 3J = 8.4 Hz, 3J = 1.6 Hz, 1 H, 8-H),
5.34–5.43 (m, 3 H, 5-H, 6-H, 17-H), 5.50 (dtdd, 3J = 10.8 Hz,
3J = 7.4 Hz, 4J = 1.6 Hz, 4J = 1.6 Hz, 1 H, 18-H), 5.73 (mc, 2 H, 13-
H, 14-H).
References
(1) (a) Cragg, G. M.; Grothaus, P. G.; Newman, D. J. Chem.
Rev. 2009, 109, 3012. (b) Blunt, J. W.; Copp, B. R.; Hu,
W.-P.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R.
Nat. Prod. Rep. 2009, 26, 170. (c) Li, M.-Y.; Xiao, Q.; Pan,
J.-Y.; Wu, J. Nat. Prod. Rep. 2009, 26, 281.
13C NMR (151 MHz, CDCl3): d = 8.2 (C-10), 14.2 (C-20), 19.5 (C-
9), 20.8 (C-19), 23.4 (C-11), 25.3 (C-4), 26.5 (C-3), 33.6 (C-2), 33.7
(C-7), 35.2 (C-16), 71.5 (C-15), 74.2 (C-12), 76.1 (C-8), 123.6 (C-
(2) White, J. D.; Yang, J. Synlett 2009, 1713.
Synthesis 2010, No. 3, 527–537 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Halicholactone and Neohalicholactone
537
(3) Synthesis of constanolactones A + B: (a) Pietruszka, J.;
Wilhelm, T. Synlett 2003, 1698. Enzymatic approaches:
(b) Pietruszka, J.; Rieche, A. C. M.; Wilhelm, T.; Witt, A.
Adv. Synth. Catal. 2003, 345, 1273. (c) Fischer, T.;
Pietruszka, J. Adv. Synth. Catal. 2007, 349, 1533.
(4) Synthesis of constanolactones C + D: (a) Pietruszka, J.;
Rieche, A. C. M.; Schöne, N. Synlett 2007, 2525. Synthesis
of solandelactones A–H: (b) Pietruszka, J.; Rieche, A. C. M.
Adv. Synth. Catal. 2008, 350, 1407. Boron reagents:
(c) Pietruszka, J.; Schöne, N. Angew. Chem. Intl. Ed. 2003,
42, 5638. (d) Pietruszka, J.; Schöne, N. Eur. J. Org. Chem.
2004, 5011. (e) Pietruszka, J.; Schöne, N. Synthesis 2006,
24. (f) Pietruszka, J.; Schöne, N.; Frey, W.; Grundl, L.
Chem. Eur. J. 2008, 14, 5178. (g) Fernandez, E.;
(11) Takahashi, T.; Watanabe, H.; Kitahara, T. Heterocycles
2002, 58, 99.
(12) Zhu, C.-Y.; Cao, X.-Y.; Zhu, B.-H.; Deng, C.; Sun, X.-L.;
Wang, B.-Q.; Shen, Q.; Tang, Y. Chem. Eur. J. 2009, 15,
11465.
(13) (a) Chen, C.; Tagami, K.; Kishi, Y. J. Org. Chem. 1995, 60,
5386. (b) Kishi, Y. Tetrahedron 2002, 58, 6239.
(14) For example: Schmidt, M.; Hasenpusch, D.; Kähler, M.;
Kirchner, U.; Wiggenhorn, K.; Langel, W.; Bornscheuer, U.
T. ChemBioChem 2006, 805; and references cited therein.
(15) Review: Müller, M.; Wolberg, M.; Schubert, T.; Hummel,
W. Adv. Biochem. Eng. Biotechnol. 2005, 92, 261; and
references cited therein.
(16) (a) Schubert, T.; Hummel, W.; Kula, M.-R.; Müller, M. Eur.
J. Org. Chem. 2001, 4181. (b) Heiss, C.; Phillips, R. S.
J. Chem. Soc., Perkin Trans. 1 2000, 2821.
Pietruszka, J. Synlett 2009, 1474.
(5) Isolation: (a) Nagle, D. G.; Gerwick, W. H. Tetrahedron
Lett. 1990, 31, 2995. (b) Nagle, D. G.; Gerwick, W. H.
J. Org. Chem. 1994, 59, 7227. Completed total syntheses:
(c) White, J. D.; Jensen, M. S. J. Am. Chem. Soc. 1995, 117,
6224. (d) Barloy-Da Silva, C.; Benkouider, A.; Pale, P.
Tetrahedron Lett. 2000, 41, 3077. (e) Yu, J.; Lai, J.-Y.; Ye,
J.; Balu, N.; Reddy, L. M.; Duan, W.; Fogel, E. R.;
Capdevila, J. H.; Falck, J. R. Tetrahedron Lett. 2002, 43,
3939. (f) Miyaoka, H.; Shigemoto, T.; Yamada, Y.
Heterocycles 1998, 47, 415. (g) Miyaoka, H.; Shigemoto,
T.; Tamura, M.; Yamada, Y. Heterocycles 1998, 40, 205.
(h) Miyaoka, H.; Shigemoto, T.; Yamada, Y. Tetrahedron
Lett. 1996, 37, 7407. (i) See also references 3a and 4a.
(6) Isolation: (a) Seo, Y.; Cho, K. W.; Rho, J.-R.; Shin, J.
Tetrahedron 1996, 52, 10583. Completed total syntheses
(A, B, E, and F): (b) Davoren, J. E.; Martin, S. F. J. Am.
Chem. Soc. 2007, 129, 510. (c) White, J. D.; Martin, W. H.
C.; Lincoln, C.; Yang, J. Org. Lett. 2007, 9, 3481.
(d) Davoren, J. E.; Harcken, C.; Martin, S. F. J. Org. Chem.
2008, 73, 391. (e) White, J. D.; Lincoln, C. M.; Yang, J.;
Martin, W. H. C.; Chan, D. B. J. Org. Chem. 2008, 73,
4139. (f) See also reference 4b.
(17) All enzymes are commercially available from Codexis Inc.
and were used as purchased.
(18) (a) Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47,
4595. (b) Harris, N. J.; Gajewski, J. J. J. Am. Chem. Soc.
1994, 116, 6121. (c) Plater, M. J.; Aiken, S.; Bourhill, G.
Tetrahedron 2002, 58, 2415.
(19) Bischop, M.; Cmrecki, V.; Ophoven, V.; Pietruszka, J.
Synthesis 2008, 2488.
(20) Zhang, D.; Ready, J. M. J. Am. Chem. Soc. 2007, 129,
12088.
(21) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277. (b) Wavrin, L.; Viala, J. Synthesis 2002, 326.
(22) Kubota, K.; Leighton, J. L. Angew. Chem. Int. Ed. 2003, 42,
946.
(23) (a) Fürstner, A.; Guth, O.; Düffels, A.; Seidel, G.; Liebl, M.;
Gabor, B.; Mynott, R. Chem. Eur. J. 2001, 7, 4811.
(b) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012.
(24) Sasaki, H.; Boyall, D.; Carreira, E. M. Helv. Chim. Acta
2001, 84, 964.
(25) Prakesch, M.; Gree, D.; Gree, R. J. Org. Chem. 2001, 66,
3146.
(7) (a) Niwa, H.; Wakamatsu, K.; Yamada, K. Tetrahedron Lett.
1989, 30, 4543. (b) Kigoshi, H.; Niwa, H.; Yamada, K.;
Stout, T. J.; Clardy, J. Tetrahedron Lett. 1991, 32, 2427.
(8) Proteau, P. J.; Rossi, J. V.; Gerwick, W. H. J. Nat. Prod.
1994, 57, 1717.
(9) (a) Critcher, D. J.; Connolly, S.; Wills, M. Tetrahedron Lett.
1995, 36, 3763. (b) Critcher, D. J.; Connolly, S.; Mahon, M.
F.; Wills, M. Chem. Commun. 1995, 139. (c) Critcher, D. J.;
Connolly, S.; Wills, M. J. Org. Chem. 1997, 62, 6638.
(10) (a) Takemoto, Y.; Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.;
Tanaka, T.; Ibuka, T. Tetrahedron Lett. 2000, 41, 3653.
(b) Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.;
Ibuka, T.; Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001, 66,
81.
(26) Suzuki, M.; Kiho, T.; Tomokiyo, K.; Furuta, K.; Fukushima,
S.; Takeuchi, Y.; Nakanishi, M.; Noyori, R. J. Med. Chem.
1998, 41, 3084.
(27) Luo, F.-T.; Negishi, E.-i. J. Org. Chem. 1985, 50, 4762.
(28) Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc.
1972, 94, 7827.
(29) Bernady, K. F.; Floyd, M. B.; Poletto, J. F.; Weiss, M. J.
J. Org. Chem. 1979, 44, 1438.
(30) Sha, W.; Salomon, R. G. J. Org. Chem. 2000, 65, 5315.
(31) Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M.
Tetrahedron 1992, 48, 4465.
Synthesis 2010, No. 3, 527–537 © Thieme Stuttgart · New York