The use of COP-OAc in the catalyst-controlled syntheses of 1,3-polyols

Article abstract of DOI:10.1055/s-0031-1289574

An iterative strategy to the 1,3-polyol motif is described. The use of the catalytic asymmetric Overman esterification for the construction of all stereogenic centers is broadly examined as are the sequences to extend the developing polyol chain. The iterative strategies are applied to the total syntheses of rugulactone and polyrhacitides A and B. 1 Introduction 2 Results and Discussion 2.1 Chain Elongation via RCM (Cycle A) 2.2 Total Synthesis of Rugulactone 2.3 Chain Elongation via Ando Olefination (Cycle B) and Total Syntheses of Polyrhacitides A and B 2.4 Useful Variants 3 Conclusions. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289574

3592
FEATURE ARTICLE
The Use of COP-OAc in the Catalyst-Controlled Syntheses of 1,3-Polyols
P
olyol Synthe
t
sis efan F. Kirsch,*a,b Philipp Klahn,a,b Helge Menza
a
Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: stefan.kirsch@ch.tum.de
Bergische Universität Wuppertal, Fachbereich C – Organische Chemie, Gaußstraße 20, 42119 Wuppertal, Germany
E-mail: sfkirsch@uni-wuppertal.de
b
Received 9 August 2011; revised 23 September 2011
applicability of this protocol was proven by a large num-
ber of successful natural product syntheses.8,9 Waldmann
et al. further developed this methodology and conducted
the chain elongation on a solid support for the rapid cre-
Abstract: An iterative strategy to the 1,3-polyol motif is described.
The use of the catalytic asymmetric Overman esterification for the
construction of all stereogenic centers is broadly examined as are
the sequences to extend the developing polyol chain. The iterative
strategies are applied to the total syntheses of rugulactone and ation of polyketide libraries.10 A related sequence was in-
polyrhacitides A and B.
troduced by Cossy et al. in 2000 using allyl titanium
complexes developed by Duthaler11 to achieve the asym-
1
Introduction
metric allyl transfer.12 While a remarkable level of stereo-
control is realized when using the allylboration and
allyltitanation protocols,13 the stoichiometric use of ex-
pensive chiral reagents and the concomitant production of
significant amounts of side products remain somewhat
limiting for large-scale applications. Consequently, recent
developments in the field of 1,3-polyol synthesis have ex-
amined iterative strategies that involve catalyst-controlled
construction of all stereogenic centers. A key issue is that
the catalytic asymmetric method must be capable of over-
riding the inherent stereocontrol through the chirality of
the already established 1,3-polyol chain.14
2
Results and Discussion
2.1
2.2
2.3
Chain Elongation via RCM (Cycle A)
Total Synthesis of Rugulactone
Chain Elongation via Ando Olefination (Cycle B) and Total
Syntheses of Polyrhacitides A and B
Useful Variants
2.4
3
Conclusions
Key words: polyols, palladium, catalysis, natural products, esters
1
Introduction
An early iterative reaction sequence yielding 1,3,5-triols
was introduced by Sharpless in 1982 using the asymmet-
ric Sharpless epoxidation as strategic step.15 Subsequent-
ly, major contributions to the field were achieved using
asymmetric epoxidations as the catalytic key step in the
elongation cycle.16 Only recently, other iterative strategies
were developed that rely on key steps such as proline-
catalyzed a-aminoxylation,17 chromium-mediated allyla-
tion,18 or copper-catalyzed aldol reaction with thio-
amides.19 In 2008, Krische et al. described a breakthrough
iridium-catalyzed transfer hydrogenation allylation
strategy20 that allowed for the rapid two-dimensional as-
sembly of C2-symmetrical 1,3-polyols starting from ter-
minal diols.21 Oestreich et al. showed in 2010 how the
iterative use of asymmetric conjugate silyl transfer fol-
lowed by Tamao–Fleming oxidation can give rise to poly-
hydroxylated carbon chains.22 However, possibly the
fastest access to date to 1,3,5-triols is provided by an ele-
gant triple-aldol cascade reaction developed by Yamamoto
et al.23
The 1,3-polyol unit is an archetypical motif featured in
many polyketide-derived natural products that show im-
pressive structural diversity paired with an enormous
range of biological activity.1 In the biosynthesis of
polyketides, an iterative C2-elongation of acetyl or propi-
onyl starter units by decarboxylative condensation with
malonyl-CoA extender units takes place.2 Enzymatic re-
duction of the carbonyl then delivers every possible 1,3-
polyol diastereomer. Therefore, it comes as no surprise
that chemists have developed numerous methods for the
stereoselective assembly of detached 1,3-diol units.3–5 On
the other hand, higher-order 1,3-polyol chains are typical-
ly tackled by the use of tailor-made strategies that address
a specific set of chiral centers.6
Recently, iterative approaches towards 1,3-polyols
through repetition of a simple sequence have attracted re-
newed interest, thus mimicking Nature’s way as a role
model. Among these, one of the most frequently used
methods for the synthesis of 1,3-polyol arrays is based on
the asymmetric allylation of aldehydes with chiral boron
allyl reagents developed by Brown.7 A short three-step
protocol consisting of the allylation reaction, protection of
the resulting secondary alcohol, and subsequent oxidative
cleavage of the double bond completes one iteration. The
In 2007, we reported preliminary results on the use of the
asymmetric Overman esterification as central step in an
iterative approach to 1,3-polyols.24 This palladium(II)-
catalyzed reaction of prochiral (Z)-allylic trichloroacetim-
idates with carboxylic acids provides branched allylic es-
ters with excellent enantioselectivities and high yields.25
When the palladium(II)-catalyst is either enantiomer of
COP-OAc,26 the stereogenic centers are created in a pre-
SYNTHESIS 2011, No. 22, pp 3592–3603
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Advanced online publication: 25.10.2011
DOI: 10.1055/s-0031-1289574; Art ID: T78511SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Polyol Synthesis
3593
dictable way: the (+)-(Rp,S)-enantiomer gives (3R)-allylic
esters while the (Sp,R) catalyst yields (3S)-allylic esters.25b
To assemble a general iterative strategy as shown in
Scheme 1 around the Overman esterification key step, the
main task is to develop a reliable and easy-to-perform
route for the conversion of one Overman esterification
product into the corresponding precursor for the next es-
terification including the two-carbon-chain elongation.
To this end, we studied the value of three different se-
quences in the course of our approach towards the
polyrhacitide natural products.27 We now discuss our full
results on the scope and drawbacks of each of the three se-
quences and how they can be applied to the total synthesis
of natural products such as polyrhacitide A28 and rugulac-
tone.29 Furthermore, we demonstrate a novel facet of the
Overman esterification; the direct installation of ester
moieties as novel alcohol protecting groups with potential
to be cleaved off orthogonal to other esters.
iterative sequence
OPg
R2COOH
(+)-COP-OAc
(1 mol%)
O
R1
R1
R2
O
O
O
23 °C
CH2Cl2
(ref. 25)
R1
Cl3C
NH
Cl3C
NH
OPg OPg
OPg OPg
R1
R1
∗
∗
n
O
O
Cl3C
NH
Cl3C
NH
O
O
2
Pd
N
O
Co
2
Results and Discussion
Ph
Ph
(+)-COP-OAc
Ph
Ph
Our studies began with the construction of enantiomeri-
cally pure allylic esters 3 amongst which 3a (R = C7H15)
was reasoned to lend itself to the assembly of polyrhaci-
Scheme 1 Strategy towards 1,3-polyols by use of the Overman este-
rification; Pg = protecting group
Biographical Sketches
Stefan F. Kirsch was born Feodor-Lynen postdoctoral professor in Organic Chem-
in 1976 in Berlin, Germany. fellow with L. E. Overman istry at Bergische Univer-
He received his undergradu- to the University of Califor- sität Wuppertal. He has
ate education at Philipps- nia at Irvine. In 2005, he obtained several awards in-
Universität Marburg and returned to Technische cluding Dozentenstipendi-
obtained a Diploma degree Universität München where um (2009), ADUC award
in 2000. After his Ph.D. the- he started an independent (2007), and Hans-Fischer
sis at Technische Univer- academic career as ‘Junior- award (2007).
sität München with T. Bach professor’. In 2011, he ac-
(2000–2003), he moved as a cepted an offer as full
Philipp Klahn was born in Universität München as a mischen Industrie (FCI).
1983 in Henstedt-Ulzburg, fellow of the Hans-Rudolf His areas of research are it-
Germany. From 2002 to Foundation and obtained the erative catalytic 1,3-polyol
2005, he worked as labora- Master degree in 2010. synthesis as well as the
tory technician at Altana Since then, he has worked as development
of
novel
Pharma, Konstanz. He re- a Ph.D. student in the group transition-metal-catalyzed
ceived his undergraduate of Stefan F. Kirsch as a fel- domino reactions.
education at Technische low of the Fonds der Che-
Helge Menz was born in 2010. His research interests Currently, he is a postdoc-
1979 in Berlin, Germany, in the Kirsch group focused toral fellow supported by a
and studied chemistry at the on novel synthetic concepts DFG research grant in the
Technische
Universität for the construction of group of Prof. Stephen
München from 2000 to polyketide-derived struc- Hanessian in Montréal
2006. He received his Ph.D. tures and on the develop- working on total synthesis
degree under the supervi- ment
of
noble-metal- projects.
sion of Stefan F. Kirsch in catalyzed cascade reactions.
Synthesis 2011, No. 22, 3592–3603 © Thieme Stuttgart · New York

3594
S. F. Kirsch et al.
FEATURE ARTICLE
tides A and B.27 Accordingly, the first stereogenic center
was introduced by reaction of trichloroacetimidate 2a
with benzoic acid in the presence of palladacyclic (+)-
COP-OAc (1 mol%). The reaction provided (R)-allylic es-
ter 3a in 97% yield and 96% ee (Scheme 2). At that time,
the absolute configuration of 3a was assigned in analogy
to other Overman esterifications.25 Through the same
route, allylic ester 3b (R = CH2OPMB) was obtained in
98% ee. The absolute configuration of 3b was determined
by comparison of the HPLC traces with the product of
chemical synthesis starting from commercially available
(S)-butene-1,2-diol.25a,b Herewith, the stage was set to in-
vestigate different routes for chain elongation.
O
O
1) Grubbs II
40 °C, CH2Cl
1) K2CO3
23 °C, MeOH
O
O
3
2) DBU
23 °C, CH2Cl2
2) 4, DCC, DMAP
23 °C, CH2Cl2
R
R
5a (77%)
6a (79%)
1) NaBH4, CeCl3⋅7H2O
0 °C, MeOH
OSi
R
OSi
R
AcOH
23 °C, THF–H2O
2) TBSCl, imidazole
23 °C, DMF
HO
SiO
7a (86%)
8a (73%)
8b (71%)
7b (95%)
(+)-COP-OAc
(1 mol%)
OSi OBz
R
R
Cl3CCN, DBU
OSi
(dr > 95:5)
R
O
23 °C, CH2Cl2
HO
R
Cl3CCN
DBU
10a (95%)
10b (98%)
Cl3C
NH
PhCO2H
O
2a (89%)
2b (92%)
1a R = C7H15
1b R = CH2OPMB
23 °C
CH2Cl2
23 °C
CH2Cl2
Cl3C
(–)-COP-OAc
(1 mol%)
NH
OSi OBz
PhCOOH
(+)-COP-OAc (1 mol%)
OBz
9a (96%)
9b (95%)
(dr > 95:5)
R
R
23 °C, CH2Cl2
11a (97%)
11b (99%)
3a (97%, 96% ee)
3b (95%, 96% ee)
Scheme 3 Elongation via RCM (cycle A); Si = tert-butyldimethyl-
silyl (TBS)
Scheme 2 Preparation of allylic ester 3; PMB = 4-methoxybenzyl
2.1
Chain Elongation via RCM (Cycle A)
Upon treatment of 8 with trichloroacetonitrile and DBU,
the imidates 9a and 9b were submitted to the decisive
Overman esterification conditions. The reactions with
benzoic acid in the presence of (+)-COP-OAc (1 mol%)
smoothly created the next stereogenic center. Under cata-
lyst control, syn-1,3-diols 10a and 10b were produced
with high diastereoselectivities.35 Accordingly, the corre-
sponding anti-1,3-diols 11a and 11b were obtained in
high yields and diastereoselectivities (dr > 95:5) when us-
ing the (–)-enantiomer of the catalyst.
Following our first report on catalytic iterative 1,3-polyol
syntheses,24 we probed the ring-closing metathesis30 as a
tool to construct the Z-configured olefin. Starting from al-
lylic ester 3, the envisaged C2 extension was conveniently
achieved using the multistep sequence shown in
Scheme 3. The sequence consists of ester cleavage with
potassium carbonate in methanol followed by reaction of
the free hydroxy with but-3-enoic acid (4) under Steglich
conditions.31 Disappointingly, the transesterification was
required since but-3-enoic acid did not react in the allylic
esterification reactions catalyzed by COP-OAc. Subse-
quent ring-closing metathesis using Grubbs II catalyst fol-
lowed by DBU-catalyzed isomerization10,32 set the desired
double bond configuration and led to the formation of the
a,b-unsaturated lactone 6. Next, the fully tert-butyldi-
methylsilyl-protected diol 7 was created by reduction un-
der Luche conditions33 and subsequent conversion of the
two hydroxy groups into their silyl ethers. However, the
envisaged selective cleavage of the primary TBS ether in
the presence of the secondary one turned out to be crucial
for the overall sequence as it was tricky to perform the
deprotection in satisfying yields and with the required
high reproducibility. Best results with regard to reproduc-
ibility were obtained using acetic acid in a water–tetrahy-
drofuran mixture to give the desired primary alcohols 8a
and 8b in moderate yields (71 and 73%).34 Unfortunately,
even under the optimized conditions, as well as in all other
attempts, the main side reaction remained the formation of
the fully deprotected diol in varying amounts.
2.2
Total Synthesis of Rugulactone
The elongation cycle discussed above proceeds through 6-
substituted 5,6-dihydropyrones (e.g., 6), a motif which it-
self can be found as integral part of polyketide-type natu-
ral products. A prime example of this interesting
polyketide class is rugulactone (18), which was isolated in
2009 from the leaves and twigs of Cryptocaria rugulosa
and exhibits high inhibition of the nuclear factor-kB (NK-
kB) activation pathway.29 Though several synthetic ap-
proaches to rugulactone were reported,36 we targeted the
core pyrone in analogy to the strategy discussed above
through ring-closing metathesis. As outlined in Scheme 4,
en route to rugulactone we first synthesized the 5,6-dihy-
dro-2H-pyran-2-one 15 from the known trichloroacetimi-
date 1225c featuring
a
high yielding Overman
esterification in 96% ee. The completion of the total syn-
thesis was then achieved by a sequence of desilylation,
Swern oxidation37 to aldehyde 16,38 and subsequent
Synthesis 2011, No. 22, 3592–3603 © Thieme Stuttgart · New York

FEATURE ARTICLE
Polyol Synthesis
3595
1) DIBAL-H
–78 °C, CH2Cl2
2) 4, DCC, DMAP
23 °C, CH2Cl2
(+)-COP-OAc
(1 mol%)
PhCO2H
CCl3
OBz OSi
OSi
HN
O
23°C, CH2Cl2
(97%, 96% ee)
(87%)
13
12
1) HF
23 °C, MeCN
2) (COCl)2, DMSO, Et3N
–78 °C, CH2Cl2
1) Grubbs II
40 °C, CH2Cl2
2) DBU
O
O
O
OSi
O
OSi
23 °C, CH2Cl2
(62%)
O
(88%)
15
14
O
O
(MeO)2(O)P
O
O
17
O
O
NaH
–78 °C, THF
(66%)
rugulactone
16
(18)
Scheme 4 Total synthesis of rugulactone
HWE-olefination with phosphonate 17 to give rugulac- ted to benzoate removal and subsequent silylation to form
tone in 31% yield over eight steps. The analytical data ob- TBS ether 19 (Scheme 5). Hydroboration41 followed by
tained for the synthetic material were indistinguishable oxidative work-up and the subsequent IBX-mediated
from the reported data of the naturally occurring materi- oxidation42 of the primary alcohol gave aldehyde 20 in
al.39 This example underlines the potential of combining good yields. Olefination to the desired Z-configured alk-
the COP-OAc-catalyzed esterification with a ring-closing enes was most effectively achieved using diphenyl phos-
metathesis to access 5,6-dihydro-2H-pyran-2-ones for phonate 21 under the conditions reported by Ando.40 For
polyketide synthesis.
example, 22a was isolated in 87% yield after separation of
the minor E-isomer (6%) by flash chromatography over
silica gel. Finally, the esters 22a and 22b were reduced
with DIBAL-H to the corresponding allylic alcohols 8 that
could be converted into syn- or anti-diol derivatives 10 or
11 using the Overman esterification as detailed in
2.3 Chain Elongation via Ando Olefination
(Cycle B) and Total Syntheses of Poly-
rhacitides A and B
Due to the problems we encountered in our initial iterative Scheme 3.
cycle with regard to selective TBS ether cleavage, we
In 2009,27 we showed the value of this iteration sequence
switched strategy to install the Z-configured olefin by an
(cycle B) by the successful total syntheses of polyrhaci-
tides A and B, both of which were isolated in 2008 from
the Chinese ant species Polyrhachis lamellidens.43,44
Starting from benzoate 3a, multiple use of the above-de-
tailed sequence (cycle B) produced the polyoxygenated
compounds 23 and 24 (Scheme 6). Each cycle of iteration
required the use of (+)-COP-OAc in order to install the
stereogenic centers with the configuration of the natural
product targets. To complete the synthesis of both
polyrhacitides, we now needed to construct the bicyclic
lactone core. Following our approach toward 6-substitut-
ed 5,6-dihydropyrones (see cycle A), we converted 23 and
24 into their corresponding lactones 25 and 26. Finally,
global silyl deprotection was accomplished with HF re-
sulting in mixtures of the a,b-unsaturated d-lactones 27
(not shown) and the target compounds 28 and 29. The
crude mixtures were treated with DBU under conditions
developed previously by Waldmann10 to complete the
conversion into the naturally occurring polyrhacitides.
The spectroscopic data of the synthetic samples were in
excellent agreement with those reported in the literature42
and, therefore, provide evidence for the diastereoselectiv-
ity of each cycle.
Ando olefination.40 To this end, allylic ester 3 was submit-
1) 9-BBN-H, 0 °C, THF
then NaOH, H2O2
1) K2CO3
23 °C, MeOH
OSi
3a R = C7H15
3b R = CH2OPMB
R
2) TBSCl
2) IBX, 23 °C, DMSO
imidazole
19a (83%)
19b (89%)
23 °C, DMF
O
21
(PhO)2P
NaH
–78 °C to –20 °C, THF
CO2Me
OSi
O
OSi
DIBAL-H
R
R
–78 °C, CH2Cl2
CO2Me
20a (89%)
20b (81%)
22a (87%)
22b (79%)
OSi
R
OSi OBz
OSi OBz
or
R
R
see Scheme 3
10a
10b
11a
11b
HO
8a (98%)
8b (97%)
Scheme 5 Elongation via Ando olefination (cycle B)
Synthesis 2011, No. 22, 3592–3603 © Thieme Stuttgart · New York

3596
S. F. Kirsch et al.
FEATURE ARTICLE
Typically, we utilized the Overman esterification to install
benzoate esters as these compounds are easy-to-handle
and well-detectable with UV light. However, in the course
of other studies not further discussed in this manuscript,
we realized the need to convert the ester products of the
Overman esterification into their allylic alcohols under
conditions that leave other ester functionalities in the mol-
ecule untouched. Therefore, we briefly investigated how
butanoic acid derivatives can serve as potent nucleophiles
in the asymmetric Overman esterification, which can be
easily removed under a set of conditions orthogonal to
other ester groups. For example, trichloroacetimidate 31
reacts with 4-(tert-butyldimethylsiloxy)butanoic acid (32)
in the presence of (–)-COP-OAc (1 mol%) to obtain ester
33 in excellent yield and enantiomeric excess (Scheme 8).
The ester cleavage was effectively achieved by simple
treatment with tetrabutylammonium fluoride, yielding the
free secondary alcohol 34 in 94%. Similarly, one can em-
ploy the azide-containing acid 35 to create ester 36. The
subsequent removal of the ester is accomplished best un-
der Staudinger reduction46 conditions with triphenylphos-
phine in 77% yield. By using PMB-protected 4-hydroxy-
butanoic acid 37,47 ester cleavage is possible under oxida-
tive conditions with DDQ. The latter sequence was key to
the successfully completion of the total synthesis of chlo-
riolide (41) (Scheme 9).48 Upon sequential exposure to
DDQ and potassium tert-butoxide, diester intermediate 39
was selectively transformed into acetate 40 in the pres-
ence of another ester moiety. We believe that the butanoyl
groups derived from 32, 35, and 37 are valuable for the
protection of hydroxy groups; they can be removed with-
OSi OBz
cycle B
(57%)
cycle B
(63%)
cycle B
(58%)
3a
(C7H15
)
3
23
OSi OBz
cycle B
(49%)
(C7H15
)
4
24
1) K2CO3, 23 °C, MeOH
2) 4, DCC
DMAP, CH2Cl2
3) Grubbs II (1 mol%)
38 °C, CH2Cl2
4) DBU, 23 °C, CH2Cl2
(61%)
(69%)
O
O
O
OSi
OSi
O
(C7H15
)
(C7H15)
4
3
26
25
1) HF, 23 °C, MeCN
2) DBU, 23 °C, CH2Cl2
(66%)
(75%)
O
H
OH OH
H
O
(C7H15
)
H
O
O
O
(+)-polyrhacitide B (28)
OH
OH
H
O
(+)-polyrhacitide A (29)
(C7H15
)
O
Scheme 6 Total syntheses of polyrhacitides A and B
SiO
O
32
Ph
2.4
Useful Variants
SiO
O
OH
(–)-COP-OAc
While the Ando olefination proved to be highly useful for
the construction of the Z-olefin and the two carbon elon-
gation, an alternative pathway to convert aldehyde 20 into
allylic alcohol 8 as part of an iterative cycle is outlined in
Scheme 7. For example, aldehyde 20 could be trans-
formed into the terminal alkyne followed by lithiation and
reaction with formaldehyde to give the propargylic alco-
hol 30 in good yield over two steps.45 Hydrogenation of
the propargylic system then provided the desired allylic
alcohol 8 in high yields and with perfect Z-selectivity. We
feel that this sequence (cycle C) might become advanta-
geous in cases when the Ando olefination shows poor E/Z
selectivity.
(1 mol%)
TBAF
O
Ph
OH
31
O
23 °C
CH2Cl2
23 °C
THF
Ph
Cl3C
NH
33
34
(94%)
(85%, 96% ee)
N3
O
35
N3
O
OH
(–)-COP-OAc
(1 mol%)
Ph3P
then H2O
O
31
34
23 °C
CH2Cl2
60 °C
CH2Cl2
Ph
36
(76%, 91% ee)
(77%)
PMBO
OH
O
H2
Lindlar
1) TMSCHN2, LDA
–78 °C, THF
37
OSi
PMBO
8a (95%)
8b (97%)
20a
20b
O
OH
DDQ
R
(+)-COP-OAc
(1 mol%)
2) n-BuLi, CH2O
–78 °C, THF
23 °C
EtOH
then KOt-Bu
0 °C
O
ent-34
31
30a (58%)
30b (49%)
23 °C
Ph
CH2Cl2
CH2Cl2 (pH 7)
38
(69%, 87% ee)
(86%)
Scheme 7 Alternative pathway for the construction of allylic alco-
hol 8a (cycle C)
Scheme 8 Novel ester protecting groups
Synthesis 2011, No. 22, 3592–3603 © Thieme Stuttgart · New York

FEATURE ARTICLE
Polyol Synthesis
3597
(Z)-Dec-2-en-1-yl Trichloroacetimidate (2a);Typical Procedure
for Method A
OPMB
O
DDQ
then KOt-Bu
Trichloroacetonitrile (1.60 mL, 2.31 g, 18.1 mmol, 1.1 equiv) and
DBU (231 mg, 1.6 mmol, 0.1 equiv) were added to a soln of (Z)-
dec-2-en-1-ol49 (2.50 g, 16.0 mmol) in anhyd CH2Cl2 (64 mL) at 0
°C. The resulting pale-brown soln was warmed to r.t. After stirring
for 6 h at r.t., the mixture was concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica gel, P–
EtOAc, 98:2) gave 2a (4.30 g, 14.3 mmol, 89%) as a yellowish oil;
Rf = 0.72 (P–EtOAc, 95:5).
O
OH
O
O
0 °C
CH2Cl2 (pH 7)
O
O
11
7
40
39
(87%)
O
OH
1
O
chloriolide (41)
7
IR: 3346, 2952, 2925, 2855, 1766, 1662, 1465, 1358, 1289, 1227,
1077, 979, 826, 796 cm–1.
1H NMR (360 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz, 3 H), 1.26–1.41
(m, 10 H), 2.11–2.17 (m, 2 H), 4.85 (d, J = 6.1 Hz, 2 H), 5.62–5.67
(m, 2 H), 8.28 (s, 1 H).
11
OH
Scheme 9 Oxidative ester cleavage in the total synthesis of
chloriolide48
13C NMR (90.6 MHz, CDCl3): d = 14.2, 22.8, 27.9, 29.3, 29.3, 29.6,
out causing cleavage of other ester linkages under action
of fluorides, phosphanes, or oxidants, respectively.
32.0, 65.4, 91.7, 122.7, 136.5, 162.9.
LRMS (EI): m/z (%) = 299 (3) (M+), 264 (21), 214 (23), 200 (25),
145 (35), 95 (35), 83 (56), 67 (54), 55 (100), 41 (77).
HRMS: m/z (M+) calcd for C12H20Cl3NO: 299.0610; found:
299.0614.
3
Conclusions
This study provides additional illustrations of how 1,3-
polyols can be stereoselectively prepared by the iterative
use of the asymmetric Overman esterification. In one vari-
(R)-Dec-1-en-3-yl Benzoate (3a); Typical Procedure for Method
B, the Overman Esterification Catalyzed by COP-OAc
(+)-COP-OAc (200 mg, 0.13 mmol, 1 mol%) was added in 1 por-
ant, chain elongation proceeds through 5,6-dihydropy- tion to a soln of 2a (4.03 g, 13.4 mmol) and benzoic acid (4.51 g,
40.2 mmol, 3 equiv) in anhyd CH2Cl2 (11 mL). The orange soln was
rones formed by the ring-closing metathesis of
protected from light and maintained at r.t. After 24 h (until 1H NMR
vinylacetates and base-induced double bond isomeriza-
analysis of the crude mixture indicated complete conversion), the
soln was concentrated under reduced pressure. The residue was pu-
rified by flash chromatography (silica gel) to afford 3a (3.40 g, 13.1
tion. In the second more general variant, Ando olefination
is used to construct the Z-configured olefin required for
the asymmetric esterification step. In this case, the major
drawback remains the relatively large number of synthetic
steps required for one iterative cycle (8 steps). However,
each reaction of the chain elongation is high-yielding,
well-established, and easy-to-perform, thus rendering the
iterative strategy particularly attractive. We showed for
the first time that depending upon the substrate function-
alities butanoic acid derivatives can be employed in the
asymmetric Overman esterification with the goal of easy
removal of the esters under conditions that do not affect
other esters. We also discussed applications in the total
syntheses of naturally occurring polyketides such as rug-
ulactone, polyrhacitides, and chloriolide.
mmol, 97%) as a pale yellow oil; Rf = 0.74 (P–EtOAc, 95:5).
[a]D23 –21.3 (c 0.80, CH2Cl2).
IR: 2926, 2857, 1718, 1455, 1267, 1178, 1110, 1067, 1028, 931,
710 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.87 (t, J = 6.5 Hz, 3 H), 1.26–1.49
(m, 10 H), 1.66–1.82 (m, 2 H), 5.20 (td, J = 1.2, 10.5 Hz, 1 H), 5.29
(ddd, J = 1.3, 17.2 Hz, 1 H), 5.49 (q, J = 6.2 Hz, 1 H), 5.81–5.99 (m,
1 H), 7.38–7.51 (m, 2 H), 7.56 (ddd, J = 1.4, 3.8, 6.5 Hz, 1 H), 8.03–
8.11 (m, 2 H).
13C NMR (62.9 MHz, CDCl3): d = 14.2, 22.8, 25.2, 29.3, 29.5, 31.9,
34.5, 75.5, 116.7, 128.5, 129.7, 130.8, 133.0, 136.8, 166.0.
LRMS (EI): m/z (%) = 260 (1) (M+), 138 (3), 105 (100).
HRMS: m/z (M+) calcd for C17H24O2: 260.1776; found: 260.1774.
To determine the enantiomeric purity, 3a was converted into 1-hy-
droxydecan-3-yl benzoate through hydroboration with 9-BBN-H
and subsequent oxidative workup. HPLC analysis indicated 96% ee
[Daicel Chiralpak AD-RH column; flow: 1.0 mL/min; H2O–MeCN,
80:20 to 0:100 in 30 min; 215 nm; minor enantiomer: tR = 19.79
min; major enantiomer: tR = 20.93 min].
1H NMR spectra were obtained on Bruker 500 MHz FT-NMR, 360
MHz FT-NMR, and 250 MHz FT-NMR spectrometers. 13C NMR
spectra were recorded at 62.9 MHz and 90.6 MHz. Chemical shifts
are reported relative to the solvent signal. HRMS (EI) were deter-
mined on a Finnigan MAT 95S and MAT 8200. Optical rotation
values were determined on a Perkin-Elmer 241 MC. IR spectra were
recorded on a Jasco IR-4100 spectrophotometer using ATR tech-
nique. Flash chromatography was performed with E. Merck silica
gel (43–60 mm); P = pentanes. TLC was performed on precoated
glass-backed plates (Merck Kieselgel 60 F254), and components
were visualized by observation under UV light or by treating the
plates with KMnO4/H2SO4 followed by heating. HPLC determina-
tion of enantiopurity was carried out on an Agilent 1200 LC system
using a Chiracel OJ-H column (250 mm × 4.6 mm).
Cycle A
(R)-Dec-1-en-3-yl But-3-enoate (5a)
K2CO3 (1.03 g, 7.5 mmol, 10 equiv) was added to a soln of 3a (195
mg, 0.75 mmol) in MeOH (7.5 mL) at r.t. After stirring for 12 h at
r.t., the resulting mixture was poured into a mixture of H2O (100
mL) and Et2O (20 mL). The phases were separated, and the aqueous
layer was extracted with Et2O (4 × 20 mL). The combined organic
layers were washed with brine (50 mL), dried (Na2SO4), and con-
centrated under reduced pressure. Purification by flash chromatog-
raphy (silica gel, P–EtOAc, 90:10) gave (R)-dec-1-en-3-ol (101 mg,
0.65 mmol, 86%) as a colorless liquid; for characterization data of
this compound, see Supporting Information.
Full characterization data for compounds 2a–11a, 13–18, 19a–22a
are given below. Data for compounds 2b–11b, 19b–22b, 23–29,
30a, 30b, 31–34 can be found in the Supporting Information.49
Synthesis 2011, No. 22, 3592–3603 © Thieme Stuttgart · New York

3598
S. F. Kirsch et al.
FEATURE ARTICLE
DCC (168 mg, 0.82 mmol, 1.5 equiv), DMAP (15 mg, 0.11 mmol,
0.2 equiv), and but-3-enoic acid (4, 70 mg, 0.82 mmol, 1.5 equiv)
were sequentially added to a soln of (R)-dec-1-en-3-ol (80 mg, 0.51
mmol) in anhyd CH2Cl2 (5.4 mL) at r.t. The resulting mixture was
stirred at r.t. for 20 h, filtered over Celite, and washed with sat. aq
NH4Cl soln. The solvent was removed under reduced pressure and
the residue was purified by flash chromatography (P–EtOAc, 95:5)
to give ester 5a (102 mg, 0.45 mmol, 89%) as a colorless oil;
Rf = 0.40 (P–EtOAc, 95:5).
(R,Z)-Dodec-2-ene-1,5-diol (24 mg, 0.12 mmol, 1.0 equiv) was dis-
solved in DMF (0.12 mL), and imidazole (40 mg, 0.48 mmol, 4.0
equiv) and TBSCl (65 mg, 0.42 mmol, 3.5 equiv) were added se-
quentially. The resulting mixture was stirred at r.t. for 2 h. After the
addition of H2O (20 mL), the resulting mixture was extracted with
EtOAc (5 × 10 mL). The combined organic phases were washed
with brine (15 mL) and dried (Na2SO4). The solvent was removed
under reduced pressure, and the residue was submitted to column
chromatography (P–EtOAc, 95:5) to give 7a (49 mg, 95%) as a col-
orless liquid; Rf = 0.75 (P–EtOAc, 95:5).
[a]D23 +3.02 (c 0.95, CH2Cl2).
[a]D23 +11.4 (c 0.2, CH2Cl2).
IR: 2927, 2857, 2119, 1738, 1644, 1460, 1426, 1314, 1252, 1170,
1101, 984, 920 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.88 (t, J = 6.4 Hz, 3 H), 1.27 (br
s, 10 H), 1.57–1.63 (m, 2 H), 3.10 (d, J = 7.0 Hz, 2 H), 5.13–5.28
(m, 5 H), 5.70–6.02 (m, 2 H).
13C NMR (62.9 MHz, CDCl3): d = 14.2, 22.8, 25.2, 29.3, 29.4, 31.9,
34.3, 39.6, 75.2, 116.8, 118.6, 130.5, 136.7, 171.0.
LRMS (EI): m/z (%) = 224 (4) [M+], 156 (13), 127 (23), 97 (21), 83
(54), 69 (100).
HRMS: m/z (M+) calcd for C14H24O2: 224.1776; found: 224.1776.
IR: 2953, 2927, 2856, 1469, 1358, 1254, 1090, 1009, 936, 834, 773
cm–1.
1H NMR (250 MHz, CDCl3): d = 0.04 (s, 6 H), 0.07 (s, 6 H), 0.90
(br s, 21 H), 1.26–1.43 (m, 12 H), 2.18 (t, J = 6.4 Hz, 2 H), 3.61–
3.70 (m, 1 H), 4.21 (d, J = 5.8 Hz, 2 H), 5.42–5.63 (m, 2 H).
13C NMR (62.9 MHz, CDCl3): d = –5.0, –4.4, –4.2, 14.3, 18.3, 18.5,
22.8, 25.6, 26.1, 26.1, 29.5, 29.9, 32.0, 35.7, 37.1, 59.8, 72.3, 127.1,
131.3.
LRMS (EI): m/z (%) = 371 (M+ – C4H9) (3), 317 (61), 243 (100),
189 (30), 147 (68), 73 (69).
(R)-6-Heptyl-5,6-dihydropyran-2-one (6a)
HRMS: m/z (M+ – C4H9) calcd for C20H43O2Si2: 371.2802; found:
371.2803.
Grubbs II catalyst (3 mg, 1 mol%) was added to a soln of (R)-dec-
1-en-3-yl but-3-enoate (5a, 80 mg, 0.36 mmol) in degassed CH2Cl2
(40 mL). The mixture was refluxed for 20 h. After disappearance of
the starting material, the brownish mixture was concentrated under
reduced pressure. Purification of the residue by flash chromatogra-
phy (silica gel, P–EtOAc, 80:20) gave (R)-6-heptyl-3,6-dihydro-
2H-pyran-2-one as a brownish oil (59 mg, 84%); for characteriza-
tion data of this compound, see Supporting Information.
(R,Z)-5-(tert-Butyldimethylsiloxy)dodec-2-en-1-ol (8a)
Compound 7a (45 mg, 0.11 mmol) was dissolved in a mixture of
THF–H2O–AcOH (2:1:1, 1.1 mL) and stirred at r.t. for 20 h. H2O
(10 mL) was added, and the mixture was extracted with Et2O
(3 × 15 mL). The combined organic layers were washed with aq sat.
NaHCO3 soln (5 × 20 mL). The organic phases were washed with
brine and dried (Na2SO4). The solvent was removed under reduced
pressure. Purification by flash chromatography (silica gel, P–
EtOAc, 80:10) gave the monoprotected alcohol 8a (24 mg, 73%) as
a colorless oil; Rf = 0.31 (P–EtOAc, 85:15).
DBU (4 mg, 0.1 equiv) was added to a soln of (R)-6-heptyl-3,6-di-
hydro-2H-pyran-2-one (50 mg, 0.26 mmol) in anhyd CH2Cl2 (1.3
mL) at r.t. The resulting mixture was stirred for 20 h and then con-
centrated under reduced pressure. Purification of the residue by
flash chromatography (silica gel, P–EtOAc, 80:20) gave 6a (47 mg,
0.27 mmol, 94%) as a colorless liquid; Rf = 0.43 (P–EtOAc, 80:20).
[a]D23 +10.6 (c 0.5, CH2Cl2).
IR: 3336, 2954, 2926, 2856, 1465, 1362, 1254, 1006, 936, 834, 773
cm–1.
[a]D23 –97.6 (c 0.6, CH2Cl2).
IR: 2925, 2855, 1716, 1466, 1388, 1245, 1154, 1120, 1066, 1037,
958, 815 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.87 (t, J = 6.6 Hz, 3 H), 1.20–1.51
(m, 10 H), 1.54–1.70 (m, 1 H), 1.72–1.87 (m, 1 H), 2.29–2.35 (m, 2
H), 4.35–4.46 (m, 1 H), 5.89–6.22 (m, 1 H), 6.83–6.91 (m, 1 H).
13C NMR (62.9 MHz, CDCl3): d = 14.2, 22.7, 24.9, 29.2, 29.4, 29.5,
31.9, 35.0, 78.2, 121.6, 145.2, 164.8.
1H NMR (250 MHz, CDCl3): d = 0.05 (s, 6 H), 0.88–0.91 (m, 12 H),
1.26 (br s, 10 H), 1.42 (m, 2 H), 1.58 (s, 1 H), 2.15–2.35 (m, 2 H),
3.64–3.74 (m, 1 H), 4.17 (br s, 2 H), 5.54–5.64 (m, 1 H), 5.69–5.79
(m, 1 H).
13C NMR (62.9 MHz, CDCl3): d = –4.4, –4.2, 14.2, 18.3, 22.8, 25.4,
26.1, 29.4, 29.9, 32.0, 35.2, 37.2, 58.8, 72.0, 129.7, 130.4.
LRMS (EI): m/z (%) = 243 (100), 203 (66), 73 (61).
LRMS (EI): m/z (%) = 196 (3) [M+], 136 (10), 97 (100), 68 (73).
HRMS: m/z (M+) calcd for C12H20O2: 196.1463: found: 196.1463.
HRMS: m/z (M+ – C4H7O) calcd for C14H31OSi: 243.2144; found:
243.2146.
(R,Z)-5-(tert-Butyldimethylsiloxy)dodec-2-enyl 2,2,2-Trichloro-
acetimidate (9a)
Following the typical procedure for the formation of 2,2,2-trichlo-
roacetimidates (Method A), flash chromatography (silica gel, P–
EtOAc, 95:5) gave 9a (0.39 g, 0.86 mmol, 96%) as a yellowish oil;
Rf = 0.73 (P–EtOAc, 95:5).
(R,Z)-1,5-Bis(tert-butyldimethylsiloxy)dodec-2-ene (7a)
CeCl3·7 H2O (182 mg, 0.49 mmol) was added to a soln of 6a
(39 mg, 0.2 mmol) in MeOH (0.68 mL). The resulting clear soln
was cooled to 0 °C, and NaBH4 (19 mg, 0.49 mmol) was added in
small portions; the resulting mixture was stirred for 2 h. The solvent
was removed under reduced pressure, and the residue was dissolved
in EtOAc (20 mL). H2O (20 mL) was added, and the phases were
separated; the aqueous layer was extracted with EtOAc
(3 × 10 mL). The combined organic phases were washed with brine
(20 mL) and dried (Na2SO4). The solvent was removed under re-
duced pressure. Purification by flash chromatography (P–EtOAc,
70:30) gave the desired (R,Z)-dodec-2-ene-1,5-diol as a colorless
oil (37 mg, 91%); for characterization data of this compound, see
Supporting Information.
[a]D23 +13.8 (c 1.4, CH2Cl2).
IR: 2955, 2927, 2856, 1663, 1462, 1361, 1290, 1254, 1072, 982,
829, 797, 773 cm–1.
1H NMR (360 MHz, CDCl3): d = 0.54 (s, 6 H), 0.88 (br s, 12 H),
1.26–1.34 (m, 10 H), 1.40–1.43 (m, 2 H), 2.32 (t, J = 5.8 Hz, 2 H),
3.69–3.75 (m, 1 H), 4.80–4.89 (m, 2 H), 5.71–5.82 (m, 2 H), 8.29
(s, 1 H).
Synthesis 2011, No. 22, 3592–3603 © Thieme Stuttgart · New York

FEATURE ARTICLE
Polyol Synthesis
3599
13C NMR (90.6 MHz, CDCl3): d = –4.4, –4.2, 14.2, 18.3, 22.8, 25.5,
26.0, 29.4, 29.9, 32.0, 35.6, 37.2, 65.5, 72.0, 91.7, 124.3, 132.7,
162.9.
LRMS (EI): m/z (%) = 401 (51) (M+ – C4H9), 260 (14), 220 (100),
197 (25), 183 (17), 95 (23), 75 (55).
HRMS: m/z (M+ – C4H9) calcd for C16H29Cl3NO2Si: 400.1033;
found: 400.1034.
[a]D23 –3.03 (c 0.89, CH2Cl2).
IR: 2954, 2926, 2857, 1720, 1469, 1314, 1268, 1095, 1069, 1026,
930, 833, 775, 710 cm–1.
1H NMR (360 MHz, CDCl3): d = 0.02 (s, 6 H), 0.88 (s, 9 H), 1.88–
2.11 (m, 2 H), 3.74, (t, J = 6.4 Hz, 2 H), 5.20 (d, J = 10.6 Hz, 1 H),
5.33 (dd, J = 0.9, 17.4 Hz, 1 H), 5.59–5.67 (m, 1 H), 5.85–5.99 (m,
1 H), 7.41–7.47 (m, 2 H), 7.53–7.59 (m, 1 H), 8.04–8.11 (m, 2 H).
13C NMR (90.6 MHz, CDCl3): d = –5.3, –5.3, 18.4, 26.0, 37.6, 59.3,
(3R,5R)-5-(tert-Butyldimethylsiloxy)dodec-1-en-3-yl Benzoate
(10a)
Following the typical procedure [Method B, using (+)-COP-OAc],
10a was obtained as a crude product (dr >95:5). The diastereomers
were separated by flash chromatography (silica gel, P–EtOAc,
99:1) to provide 10a (3.2 g, 7.6 mmol, 95%); Rf = 0.74 (P–EtOAc,
95:5).
72.7, 116.7, 128.5, 129.7, 130.7, 133.0, 136.6, 165.9.
LRMS (EI): m/z (%) = 263 (2) [M+ – C4H9], 179 (100), 105 (45), 67
(81).
To determine the enantiomeric purity, 13 was converted into (R)-5-
hydroxypent-1-en-3-yl benzoate through TBS deprotection with HF
in a H2O–MeCN soln. HPLC analysis indicated 96%ee [Daicel
Chiralpak AD-RH column; flow: 1.0 mL/min; H2O–MeCN, 90:10
to 0:100 in 50 min; 210 nm; minor enantiomer: tR = 9.76 min; major
enantiomer: tR = 8.71 min]. The absolute configuration was as-
signed according to the literature data.28
[a]D23 –0.7 (c 0.99, CH2Cl2).
IR: 2955, 2927, 2856, 1721, 1460, 1269, 1108, 1068, 835, 773, 710
cm–1.
1H NMR (250 MHz, CDCl3): d = 0.05 (s, 3 H), 0.08 (s, 3 H), 0.85–
0.91 (m, 12 H), 1.24–1.35 (m, 10 H), 1.45–1.54 (m, 2 H), 1.81–1.88
(m, 1 H), 1.98–2.06 (m, 1 H), 3.77–3.83 (m, 1 H), 5.21 (td, J = 1.1,
10.7 Hz, 1 H), 5.34 (td, J = 1.1, 17.3 Hz, 1 H), 5.62 (dd, J = 6.1, 13.7
Hz, 1 H), 5.86–5.95 (m, 1 H), 7.42–7.46 (m, 2 H), 7.53–7.58 (m, 1
H), 8.04–8.07 (m, 2 H).
13C NMR (90.6 MHz, CDCl3): d = –4.3, –4.1, 14.2, 18.2, 22.8, 25.1,
26.0, 29.4, 29.8, 32.0, 37.1, 42.1, 69.3, 72.9, 116.8, 128.5, 129.7,
130.7, 133.0, 136.8, 165.8.
LRMS (EI): m/z (%) = 307 (5) (M+ – C8H15), 243 (7), 179 (100), 105
(30).
HRMS: m/z (M+ – C8H15) calcd for C17H27O3Si: 307.1729; found:
307.1728.
(R)-5-(tert-Butyldimethylsiloxy)pent-1-en-3-yl But-3-enoate
(14)
A 1.2 M DIBAL-H in toluene soln (11.8 mL, 14.2 mmol, 2.0 equiv)
was added to a soln of 13 (2.56 g, 7.1 mmol) in anhyd CH2Cl2 (71
mL) at –78 °C under an argon atmosphere. The resulting mixture
was stirred at this temperature for 3 h before it was quenched by ad-
dition of potassium sodium tartrate (40 mL, 20% soln in H2O).
Glycerol (3.1 mL, 0.2 mL/mmol DIBAL-H) was added, and the re-
sulting mixture was stirred for 2 h (until a clear biphasic mixture ap-
peared). The phases were separated, and the aqueous phase was
extracted with EtOAc (3 × 30 mL). The combined organic layers
were washed with brine (50 mL), dried (Na2SO4), and concentrated
under reduced pressure. Purification by flash chromatography (sili-
ca gel, P–EtOAc, 90:10) gave (R)-5-(tert-butyldimethylsil-
oxy)pent-1-en-3-ol (1.48 g, 96%) as a colorless liquid; for
characterization data of this compound, see Supporting Informa-
tion.
(3S,5R)-5-(tert-Butyldimethylsiloxy)dodec-1-en-3-yl Benzoate
(11a)
Following the typical procedure [Method B, using (–)-COP-OAc],
11a was obtained as a crude product (dr >95:5). The diastereomers
were separated by flash chromatography (silica gel, P–EtOAc,
99:1) to provide 11a (27 mg, 0.06 mmol, 97% from 9a); Rf = 0.73
(P–EtOAc, 95:5).
DCC (2.10 g, 10.2 mmol, 1.5 equiv), DMAP (0.15 g, 1.3 mmol, 0.2
equiv), and but-3-enoic acid (4, 0.88 g, 10.2 mmol, 1.5 equiv) were
added to a soln of (R)-5-(tert-butyldimethylsiloxy)pent-1-en-3-ol
(1.47 g, 6.8 mmol) in anhyd CH2Cl2 (68 mL) at r.t. The resulting
mixture was stirred at r.t. for 20 h, filtered over Celite, and washed
with sat. aq NH4Cl soln. The solvent was removed under reduced
pressure, and the residue was purified by flash chromatography (P–
EtOAc, 95:5) to give 14 (1.76 g, 91%) as a colorless oil; Rf = 0.83
(P–EtOAc, 90:10).
[a]D23 –1.7 (c 0.76, CH2Cl2).
IR: 2954, 2927, 2856, 1723, 1460, 1269, 1109, 1068, 835, 774, 711
cm–1.
1H NMR (250 MHz, CDCl3): d = –0.03 (s, 3 H), –0.00 (s, 3 H), 0.88
(br s, 12 H), 1.28 (br s, 10 H), 1.47–1.52 (m, 2 H), 1.77 (ddd, J = 3.9,
8.3, 14.1 Hz, 1 H), 1.91–2.02 (m, 1 H), 3.84 (dt, J = 5.3, 8.9 Hz, 1
H), 5.18 (dd, J = 1.0, 10.5 Hz, 1 H), 5.30 (dd, J = 1.1, 17.2 Hz, 1 H),
5.48–5.62 (m, 1 H), 5.83–5.99 (m, 1 H), 7.41–7.47 (m, 2 H), 7.53–
7.59 (m, 1 H), 8.04–8.08 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): d = –4.8, –4.3, 14.1, 18.0, 22.6, 24.6,
25.9, 29.3, 29.7, 31.8, 37.7, 41.9, 68.6, 72.9, 116.2, 128.3, 129.5,
130.7, 132.8, 137.1, 165.7.
LRMS (EI): m/z (%) = 307 (5) (M+ – C8H15), 243 (7), 179 (100), 105
(30).
HRMS: m/z (M+ – C8H15) calcd for C17H27O3Si: 307.1729; found:
307.1728.
[a]D23 +16.6 (c 0.87, CH2Cl2).
IR: 2954, 2929, 2857, 1739, 1644, 1469, 1252, 1171, 1095, 984,
933, 835, 775 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.03 (s, 6 H), 0.88 (s, 9 H), 1.85
(m, 2 H), 3.35, (td, J = 1.3, 7.0 Hz, 2 H), 3.64 (t, J = 6.3 Hz, 2 H),
5.13–5.28 (m, 4 H), 5.35–5.43 (m, 1 H), 5.73–6.03 (m, 2 H).
13C NMR (62.9 MHz, CDCl3): d = –5.3, 18.4, 26.0, 37.3, 39.5, 59.1,
72.3, 116.8, 118.6, 130.5, 136.5, 170.7.
LRMS (EI): m/z (%) = 143 (52) [M+ – C8H13O2], 99 (36), 67 (100).
(S)-6-[2-(tert-Butyldimethylsiloxy)ethyl]-5,6-dihydro-2H-pyr-
an-2-one (15)
Grubbs II catalyst (19 mg, 3 mol%) was added to a soln of 14 (630
mg, 2.22 mmol) in degassed CH2Cl2 (222 mL); the mixture was re-
fluxed for 20 h. After the disappearance of the starting material, the
brownish mixture was concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography (silica gel, P–EtOAc,
80:20) gave (R)-6-[2-(tert-butyldimethylsiloxy)ethyl]-3,6-dihydro-
Total Synthesis of Rugulactone
(R)-5-(tert-Butyldimethylsiloxy)pent-1-en-3-yl Benzoate (13)
Following the typical procedure [Method B, using (+)-COP-OAc],
flash chromatography (silica gel, P–EtOAc, 96:4) gave 13 (1.21 g,
3.77 mmol, 97%) as a pale-yellow oil; Rf = 0.79 (P–EtOAc, 90:10).
Synthesis 2011, No. 22, 3592–3603 © Thieme Stuttgart · New York

3600
S. F. Kirsch et al.
FEATURE ARTICLE
2H-pyran-2-one (533 mg, 94%) as a colorless oil; for characteriza-
LRMS (EI): m/z (%) = 140 (7) [M+], 122 (14), 112 (12), 97 (60), 78
tion data of this compound, see Supporting Information.
(91), 68 (95), 63 (100).
DBU (30 mg, 0.2 mmol, 0.1 equiv) was added to a soln of (R)-6-
[2-(tert-butyldimethylsiloxy)ethyl]-3,6-dihydro-2H-pyran-2-one
(519 mg, 2.0 mmol) in anhyd CH2Cl2 (10 mL) at r.t. The resulting
mixture was stirred for 20 h and was then concentrated under re-
duced pressure. Purification of the residue by flash chromatography
(silica gel, P–EtOAc, 80:20) gave 15 (488 mg, 94%) as a colorless
liquid; Rf = 0.36 (P–EtOAc, 80:20).
HRMS: m/z (M+) calcd for C7H8O3: 140.0474; found: 140.0477.
(–)-Rugulactone (18)
Under an argon atmosphere, a flame-dried flask was equipped with
NaH (13 mg, 60% in mineral oil, 0.34 mmol, 1.6 equiv) and anhyd
THF (1 mL). The mixture was cooled to 0 °C, and a soln of dimethyl
2-oxo-4-phenylbutylphosphonate (17, 84 mg, 0.31 mmol, 1.5
equiv) in anhyd THF (0.4 mL) was added dropwise. The resulting
soln was stirred for 10 min at 0 °C and was then cooled to –78 °C.
Upon dropwise addition of a soln of aldehyde 16 (29 mg, 0.21
mmol, 1.0 equiv) in anhyd THF (0.6 mL), the resulting brownish
soln was stirred for 1 h at –78 °C. The reaction was quenched by the
addition of aq sat. NH4Cl soln (8 mL). The biphasic mixture was
warmed to r.t., and the phases were separated. The aqueous phase
was extracted with EtOAc (3 × 10 mL). The combined organic lay-
ers were washed with brine (20 mL), dried (Na2SO4), and concen-
trated under reduced pressure. Purification by flash
chromatography (silica gel, P–EtOAc, 70:30 to 50:50) gave rugu-
lactone (36 mg, 0.13 mmol, 66%) as a pale-yellow oil; Rf = 0.25 (P–
EtOAc, 50:50).
[a]D23 –37.6 (c 0.7, CH2Cl2).
IR: 2952, 2928, 2885, 2856, 1722, 1469, 1387, 1250, 1086, 1038,
960, 835, 775 cm–1.
1H NMR (360 MHz, CDCl3): d = 0.05 (s, 6 H), 0.88 (s, 9 H), 1.80–
1.89 (m, 1 H), 1.95–2.04 (m, 1 H), 2.36–2.40 (m, 2 H), 3.74–3.86
(m, 2 H), 4.58–4.66 (m, 1 H), 6.02 (td, J = 1.5, 9.5 Hz, 1 H), 6.86–
6.95 (m, 1 H).
13C NMR (90.6 MHz, CDCl3): d = –5.3, –5.2, 18.4, 26.0, 29.8, 38.0,
58.6, 75.3, 121.6, 145.3, 164.5.
LRMS (EI): m/z (%) = 199 (92) [M+ – C4H9], 169 (57), 131 (100),
101 (35), 75 (26).
HRMS: m/z (M+ – C4H9) calcd for C9H15O3Si: 199.0790; found:
199.0791.
[a]D23 –45.9 (c 0.69, CH2Cl2).
IR: 2928, 1716, 1672, 1631, 1493, 1452, 1387, 1245, 1148, 1042,
980, 815, 750, 700 cm–1.
2-[(S)-3,6-Dihydro-6-oxo-2H-pyran-2-yl]acetaldehyde (16)
The lactone 15 (100 mg, 0.39 mmol) was dissolved in MeCN (3.9
mL) and cooled to 0 °C. 50% aq HF soln (1.2 mL) was added drop-
wise, and the resulting mixture was stirred for 2 h at 0 °C. Sat. aq
NaHCO3 soln (10 mL) was added carefully, and the resulting mix-
ture was thoroughly extracted with CH2Cl2 and EtOAc (3 × 10 mL
each). The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. Purification by flash chromatog-
raphy (silica gel, CH2Cl2–MeOH, 98:2) gave (S)-6-(2-
hydroxyethyl)-5,6-dihydro-2H-pyran-2-one (48 mg, 86%) as a col-
orless oil; for characterization data of this compound, see Support-
ing Information.
1H NMR (500 MHz, CDCl3): d = 2.32–2.35 (m, 2 H), 2.58–2.70 (m,
2 H), 2.88–2.96 (m, 4 H), 4.52–4.57 (m, 1 H), 6.05 (td, J = 1.7, 9.8
Hz, 1 H), 6.20 (d, J = 15.9 Hz, 1 H), 6.80 (td, J = 7.2, 15.9 Hz, 1 H),
6.88 (td, J = 4.2, 9.5 Hz, 1 H), 7.19–7.20 (m, 3 H), 7.27–7.29 (m, 2
H).
13C NMR (90.6 MHz, CDCl3): d = 28.9, 30.0, 37.5, 41.7, 76.1,
121.5, 126.1, 128.4, 128.5, 133.5, 139.9, 141.0, 144.5, 163.6, 198.9.
LRMS (EI): m/z (%) = 270 (9) [M+], 252 (17), 185 (20), 159 (26),
97 (100).
HRMS: m/z (M+) calcd for C17H18O3: 270.1256; found: 270.1252.
In a flame-dried flask under argon atmosphere, oxalyl chloride (63
mg, 0.5 mmol, 1.5 equiv) was dissolved in anhyd CH2Cl2 (1 mL)
and cooled to –78 °C. A soln of DMSO (62 mg, 0.8 mmol, 2.5
equiv) in anhyd CH2Cl2 (0.2 mL) was added dropwise, and the re-
sulting soln was stirred at –78 °C for 10 min. A soln of (S)-6-(2-hy-
droxyethyl)-5,6-dihydro-2H-pyran-2-one (42 mg, 0.30 mmol, 1.0
equiv) in anhyd CH2Cl2 (0.26 mL) was added dropwise. The mix-
ture was stirred at –78 °C for 10 min and, subsequently, Et3N (98
mg, 0.90 mmol, 3.0 equiv) was added dropwise. The cooling bath
was removed and, as soon as the color turned dark (at about –30 °C),
the mixture was quenched by addition of aq sat. NH4Cl soln (10
mL). The phases were separated and the aqueous phase was extract-
ed with CH2Cl2 (3 × 10 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. Purifica-
tion by flash chromatography (silica gel, CH2Cl2–MeOH, 95:5)
gave the aldehyde 16 (29 mg, 72%) as a pale-yellow oil. The ob-
tained product is relatively unstable but can be stored at –20 °C for
several days; Rf = 0.40 (CH2Cl2–MeOH, 90:10).
Characterization data of synthetic (–)-rugulactone were indistin-
guishable from that reported for the naturally occurring material.29
Cycle B
(R)-3-(tert-Butyldimethylsiloxy)dec-1-ene (19a)
Compound 3a was saponified as described for the synthesis of 5a.
After aqueous work up, the crude (R)-dec-1-en-3-ol (2.03 g, 13
mmol) was dissolved in DMF (10 mL). Imidazole (1.77 g, 26 mmol,
2 equiv) and TBSCl (2.94 g, 19.5 mmol, 1.5 equiv) were added at 0
°C. The resulting soln was stirred for 30 min at 0 °C and then for 2
h at r.t. The mixture was poured into Et2O (50 mL) and washed with
H2O (300 mL). The phases were separated, and the aqueous layer
was extracted with Et2O (4 × 50 mL). The combined organic layers
were washed with brine (50 mL), dried (Na2SO4), and concentrated
under reduced pressure. Purification by flash chromatography (sili-
ca gel, P–EtOAc, 98:2) gave 19a (3.41 g, 12.6 mmol, 83%) as a col-
orless liquid; Rf = 0.91 (P–EtOAc, 98:2).
[a]D23 –7.4 (c 1.35, CH2Cl2).
[a]D23 –61.6 (c 1.01, CH2Cl2).
IR: 2957, 2927, 2856, 1465, 1357, 1252, 1074, 1028, 920, 835, 774
cm–1.
1H NMR (360 MHz, CDCl3): d = 0.03 (s, 3 H), 0.05 (s, 3 H), 0.86–
0.91 (m, 12 H), 1.24–1.34 (br s, 10 H), 1.44–1.51 (m, 2 H), 4.04–
4.10 (m, 1 H), 5.01 (ddd, J = 1.2, 1.9, 10.4 Hz, 1 H), 5.12 (ddd,
J = 1.4, 1.8, 17.2 Hz, 1 H), 5.80 (ddd, J = 6.1, 10.4, 17.1 Hz, 1 H).
IR: 3433, 2919, 1715, 1387, 1248, 1153, 1087, 1044, 956, 817, 728
cm–1.
1H NMR (500 MHz, CDCl3): d = 2.37 (tdd, J = 2.6, 11.8, 18.3 Hz,
1 H), 2.53 (dddd, J = 1.0, 3.9, 6.1, 18.3 Hz, 1 H), 2.81 (ddd, J = 1.0,
6.3, 17.7 Hz, 1 H), 3.03 (ddd, J = 1.4, 6.3, 17.7 Hz, 1 H), 4.96 (dtd,
J = 3.9, 6.3, 11.8 Hz, 1 H), 6.05 (ddd, J = 1.0, 2.7, 9.8 Hz, 1 H), 6.90
(ddd, J = 2.4, 6.1, 9.8 Hz, 1 H), 9.82 (t, J = 1.2 Hz, 1 H).
13C NMR (90.6 MHz, CDCl3): d = 29.1, 48.1, 72.5, 121.4, 144.6,
163.4, 198.2.
13C NMR (90.6 MHz, CDCl3): d = –4.8, –4.4, 14.1, 18.3, 22.7, 25.2,
25.9, 29.3, 29.6, 31.8, 38.1, 73.9, 113.3, 142.0.
Synthesis 2011, No. 22, 3592–3603 © Thieme Stuttgart · New York

FEATURE ARTICLE
Polyol Synthesis
3601
LRMS (EI): m/z (%) = 213 (100) (M+ – C4H9), 171 (40), 115 (17),
76 (55).
HRMS: m/z (M+ – C4H9) calcd for C12H25OSi: 213.1675; found:
213.1677.
duced pressure. Purification by flash chromatography (silica gel, P–
EtOAc, 95:5) gave 22a (2.63 g, 7.1 mmol, 87%) as a colorless oil;
the E-isomer (6% yield) was separated during flash chromatogra-
phy; Rf = 0.38 (P–EtOAc, 95:5).
[a]D23 +15.5 (c 1.3, CH2Cl2).
(R)-3-(tert-Butyldimethylsiloxy)decanal (20a)
IR: 2953, 2928, 2856, 1726, 1646, 1463, 1438, 1408, 1362, 1255,
A 0.5 M 9-BBN-H in THF soln (67 mL, 33.3 mmol, 3 equiv) was
added to a soln of 19a (3.00 g, 11.1 mmol) in anhyd THF (110 mL)
at 0 °C, and the resulting mixture was stirred at r.t. for 16 h. Then,
the clear soln was cooled to 0 °C, and 3 M aq NaOH (9.25 mL, 27.8
mmol, 2.5 equiv) and 30% aq H2O2 (9.25 mL ) were added. The re-
sulting mixture was stirred for 0.5 h at 0 °C and for 6 h at r.t. (until
white precipitation occurred). Potassium sodium tartrate (300 mL,
10% aq soln) and glycerol (0.2 mL/mmol) were added, and the bi-
phasic mixture was stirred at r.t. until both layers were clear and
readily separable. The layers were separated, and the aqueous layer
was extracted with Et2O (4 × 70 mL). The combined organic layers
were washed with brine (100 mL), dried (Na2SO4), and concentrat-
ed under reduced pressure. Purification by flash chromatography
(silica gel, P–EtOAc, 90:10) gave (R)-3-(tert-butyldimethylsil-
oxy)decan-1-ol (3.16 g, 10.9 mmol, 98%) as a colorless liquid; for
characterization data of this compound, see Supporting Informa-
tion.
1173, 1070, 1006, 941, 834, 773 cm–1.
1H NMR (360 MHz, CDCl3): d = 0.04 (s, 3 H), 0.05 (s, 3 H), 0.87–
0.89 (m, 12 H), 1.26–1.34 (m, 10 H), 1.40–1.43 (m, 2 H), 2.74–2.91
(m, 2 H), 3.70 (s, 3 H), 3.76–3.83 (m, 1 H), 5.85 (td, J = 1.8, 11.7
Hz, 1 H), 6.38 (td, J = 7.3, 11.6 Hz, 1 H).
13C NMR (62.9 MHz, CDCl3): d = –4.4, 14.2, 18.2, 22.8, 25.5, 26.0,
29.4, 29.8, 32.0, 36.5, 37.4, 51.1, 71.7, 120.4, 147.5, 167.0.
LRMS (EI): m/z (%) = 327 (4) (M+ – CH3), 285 (100), 243 (80), 205
(17), 157 (33), 89 (40), 73 (61).
HRMS: m/z (M+ – CH3) calcd for C18H35O3Si: 327.2355; found:
327.2355.
(R,Z)-5-(tert-Butyldimethylsiloxy)dodec-2-en-1-ol (8a)
Ester 22a was reduced with DIBAL-H as described for the reduc-
tion of 13. Purification by flash chromatography (silica gel, P–
EtOAc, 90:10) gave 8a (2.37 g, 7.52 mmol, 98%) as a colorless oil.
The analytical data of the isolated compound 8a were indistinguish-
able from the compound obtained using cycle A (see above).
(R)-3-(tert-Butyldimethylsiloxy)decan-1-ol (3.15 g, 10.9 mmol)
was dissolved in DMSO (22 mL), and IBX (4.60 g, 16.4 mmol, 1.5
equiv) was added at once. The resulting mixture was stirred for 15 h
at r.t., then poured into CH2Cl2 (100 mL) and stirred for 1 h. The re-
sulting white precipitate was filtered, and the filtrate was washed
with aq NaHCO3 (400 mL). The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated under
reduced pressure. Purification by flash chromatography (silica gel,
P–EtOAc, 95:5) gave 20a (2.86 g, 9.9 mmol, 91%) as a colorless
oil; Rf = 0.37 (P–EtOAc, 95:5).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
The authors thank Deutsche Forschungsgemeinschaft (DFG) for ge-
nerous support. P. K. thanks the Fonds der Chemischen Industrie
(FCI) for fellowship support. Support by the TUM Graduate School
is gratefully acknowledged. The authors thank Dr. J. T. Binder for
leading experiments in the field. Enduring support by Prof. Th.
Bach is gratefully acknowledged.
[a]D23 +2.6 (c 0.62, CH2Cl2).
IR: 2955, 2928, 2857, 1727, 1465, 1362, 1254, 1098, 1009, 835,
774 cm–1.
1H NMR (360 MHz, CDCl3): d = 0.04 (s, 3 H), 0.06 (s, 3 H), 0.85–
0.88 (m, 12 H), 1.25 (br s, 10 H), 1.43–1.52 (m, 2 H), 2.45–2.57 (m,
2 H), 4.13–4.19 (m, 1 H), 9.80 (t, J = 2.5 Hz, 1 H).
13C NMR (90.6 MHz, CDCl3): d = –4.6, –4.3, 14.3, 18.1, 22.8, 25.3,
25.8, 29.4, 29.7, 31.9, 37.9, 50.9, 68.3, 203.2.
LRMS (EI): m/z (%) = 271 (2) (M+ – CH3), 229 (100) (M+ – C4H9),
185 (16), 131 (67), 101 (77), 75 (78), 69 (79).
HRMS: m/z (M+ – C4H9) calcd for C12H25O2Si: 229.1624; found:
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Synthesis 2011, No. 22, 3592–3603 © Thieme Stuttgart · New York

FEATURE ARTICLE
Polyol Synthesis
3603
(34) It should be mentioned that the use of triethylsilyl protecting
groups does not show these deprotection issues, see: ref. 24.
(35) The syn-configuration of 10a was shown by conversion into
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data. The syn-configuration of 10b was shown by conversion
into (3R,5R)-5-(tert-butyldimethylsiloxy)-3-(triethylsil-
oxy)hexanal and comparison of the analytical data with
previously reported data: Nicolaou, K. C.; Nold, A. L.;
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Nevertheless, 16 can be isolated and stored at –20 °C over
weeks without decomposition. See the experimental section
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J. Nat. Prod. 2008, 71, 724.
(44) For subsequent total syntheses, see: (a) Mohapatra, D. K.;
Bhimireddy, E.; Krishnarao, P.; Das, P. P.; Yadav, J. S. Org.
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(38) It has to be noted that the isolation of aldehyde 16 is
somewhat troublesome, and, therefore, it is recommended to
use it without further purification (see ref. 36d).
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Synthesis 2011, No. 22, 3592–3603 © Thieme Stuttgart · New York