Synthesis of the tetraketide lactones from the pikromycin biosynthetic pathway

Article abstract of DOI:10.1002/ejoc.200700254

Synthesis of tetraketide lactones 2 and 3, which are likely to be produced by a model pikromycin polyketide synthase (PKS), has been investigated. The tetraketide lactones with six-membered rings, 2a and 2b, were synthesized successfully by the asymmetric

Full text of DOI:10.1002/ejoc.200700254

FULL PAPER
DOI: 10.1002/ejoc.200700254
Synthesis of the Tetraketide Lactones from the Pikromycin
Biosynthetic Pathway
Hong-Se Oh,[a] Ji-Suk Yun,[a] Ki-Hyun Nah,[a] Han-Young Kang,*[a] and David H. Sherman[b]
Keywords: Polyketide / Pikromycin / Biosynthesis / Lactones / Asymmetric synthesis
Synthesis of tetraketide lactones 2 and 3, which are likely to
be produced by a model pikromycin polyketide synthase
(PKS), has been investigated. The tetraketide lactones with
six-membered rings, 2a and 2b, were synthesized success-
fully by the asymmetric aldol reaction, allylation, and the Re-
formatsky reaction. The attempted synthesis of tetraketide
lactones with eight-membered rings, 3a and 3b, led to the
formation of the compounds 2a and 2b. The synthesis of an-
other tetraketide lactone compounds 35 was attempted with
the hope that introducing an additional methyl group would
lead to a change in thermodynamic stability. However, it pro-
duced the corresponding tetraketide lactone 34 with a six-
membered ring.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
PKS is a gigantic enzyme that is involved in the synthesis
of macrolide antibiotics including methymycin and pikro-
mycin.[3] This is fascinating because a single enzyme pro-
duces macrocyclic compounds with two different ring sizes,
12- and 14-membered rings (methymycin and pikromycin).
The pikromycin PKS also possesses additional post-modifi-
cation functions (i.e. glycosylation and oxidation) for the
macrolides. These features make PKS an ideal system for
generating a diverse range of macrolides through so-called
combinatorial biosynthesis, which is a brilliant concept that
involves cutting and reshuffling the genes responsible for
individual biochemical transformations for the synthesis of
iterating structural units.[4] Figure 1 shows the genetic mod-
ular arrangement of the pikromycin PKS system. Whilst
understanding the nature of the PKS is essential for investi-
gating the biosynthetic pathway, the structural complexity
of the macrolides has been an impediment to the progress
of the biosynthetic research. Although, in principle, the
concept of combinatorial biosynthesis for generating struc-
turally new compounds by mixing and combining genetic
modules is intriguing, biosynthetic research in this area has
been hindered by the limited availability of the biosynthes-
ized compounds due to the interrupted function of the re-
sulting hybrid PKS.
A research program was, therefore, initiated with the aim
of developing the systematic methods for the synthesis of
the possible intermediates; particularly polyketide lactones
from the pikromycin biosynthetic pathway with the view to
understand further the importance of securing polyketide
intermediates from the anticipated biosynthetic pathway.
The structure of the products from the genetic work is so
complex that we became interested in the simpler PKS sys-
tem which could, in turn, generate intermediate polyketides
with simpler structures. This concept has been demon-
Introduction
The development of the modern synthetic methods has
made important contributions to not only answering the
emerging questions from chemistry but also explaining a
variety of phenomena originating from the biological fields.
Recently, studies on natural product chemistry based on ge-
netic techniques have enjoyed a dramatic growth.[1] The
driving force of this is mainly attributed to the power of
modern organic synthesis and the fast-developing genetic
knowledge and techniques. Polyketide macrolides belong to
a well-studied class of compounds in natural products, and
the investigation of their biosynthesis is dependent on ge-
netic techniques. For example, erythromycin is a typical
macrolide that has been a target for examining various bio-
synthetic pathways using the newly developed genetic con-
cepts.[2] Polyketide synthase (PKS), an enzyme responsible
for producing erythromycin, is made up of characteristic
modular structures. Studies on 6-deoxyerythronolide B po-
lyketide synthase have made a significant contribution to
expanding our understanding of the bacterial type I PKS,
which is organized of modules, each of which catalyzes one
cycle of elongation of the chain.[3]
Pikromycin is another polyketide macrolide that has at-
tracted considerable attention in biosynthetic research on
account of the remarkable ability of the PKS enzyme to
produce this large ring-sized polyketide lactone. Pikromycin
[a] Department of Chemistry, Chungbuk National University,
Cheongju, Chungbuk 361-763, Republic of Korea
Fax: +82-43-267-2279
E-mail: hykang@chungbuk.ac.kr
[b] Department of Medicinal Chemistry, University of Michigan,
Ann Arbor, MI 48109, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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H.-Y. Kang et al.
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Figure 1. Modular organization of the pikromycin PKS.
strated with smaller hybrid PKS systems such as DEBS1
(DEBS = 6-deoxyerythronolide B synthase) + TE (thioes-
terase),[5] or DEBS1-TE[6] truncated version of erythromy-
cin PKS. Both these simpler PKSs have been used exten-
sively to examine the biosynthesis of 6-deoxyerythrolide B.
These hybrid PKSs have produced the expected smaller po-
lyketide lactones.[7]
Inspired by the simpler erythromycin PKS systems, a
similar truncated version of the hybrid PKS system was de-
signed for pikromycin biosynthesis. The model PKS system
used in this study involved cutting the genes between the
AT and DH domain in module 2 and between AT and KR
domain in module 5 and combining the two modules. It
was anticipated that this fused PKS would produce tri- and
tetraketide lactones, i.e. six-membered and eight-membered
lactones, as shown in Figure 2. Therefore, the hybrid model
PKS could serve not only as a model system but also as a
valuable tool for investigating the function and role of mod-
ules 5 and 6, which is expected to make a significant contri-
bution to the understanding of the pikromycin PKS sys-
tem.[8]
Figure 2. Model Pik PKS system for the synthetic targets. Fusion
of pik AI mod::pik AIII mod 5.
In order to achieve a combinatorial biosynthesis using a
polyketide synthase, it is essential to understand the biosyn-
thetic pathways and experiences of handling the intermedi- mycin PKS system, the initial focus was on synthesizing the
ates efficiently. Therefore, the aim of this study is to develop polyketide lactones 1, 2, and 3. The synthesis of simple six-
synthetic routes to prepare polyketide lactones through the membered δ-lactones 1 is reported previously.[9,10] Here, we
pikromycin biosynthetic pathways. In connection with the describe the results of the synthetic studies of the tetrake-
generation of a simple hybrid PKSs derived from the pikro- tide lactones 2 and 3.
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Synthesis of the Tetraketide Lactones
FULL PAPER
Results and Discussion
The retrosynthetic analysis of the lactones shown in
Scheme 1 indicates that the target tetraketide lactone 2,
which mainly exists as an enol form, could be synthesized
from the linear intermediate A through a simple consecutive
two-carbon chain elongation of the intermediate, which was
previously prepared during the synthesis of the triketide δ-
lactone 1.[9] Because it is preferable to secure all the possible
intermediate polyketide lactones for future biosynthetic re-
search, we believed that it would be more appropriate to
develop a synthetic route to prepare not only the lactones
2 and 3 but also their stereoisomers. Therefore, an attempt
was made to synthesize the target lactones and their dia-
stereomers (i.e. C5-epimers, vide infra).
Scheme 2. Reagents and conditions: (a) Swern Oxidation (83%) (b)
6a, Bu2OTf, Et3N, CH2Cl2 (68%) (c) Dess–Martin periodinane
(DMP), CH2Cl2 (80%) (d) (1) H2O2, LiOH (2) 1  HCl/THF, 5:1
(68%, two steps) (e) DMP, CH2Cl2 (85%).
lecular Claisen condensation was employed for the efficient
construction of the six-membered lactones for a similar tet-
raketide lactone.
Scheme 3. An example of the Claisen condensation approach.
Scheme 1. Retrosynthetic scheme.
The tetraketide lactones synthesized in this study could
be achieved using a similar procedure because the only dif-
ference between the tetraketide lactone in Scheme 3 and the
target lactone 2a is the existence of a methyl group. It was
believed that this synthesis would be quite straightforward.
Scheme 4 summarizes the synthesis according to the
Claisen condensation route.
Scheme 2 shows the synthetic route according to the ret-
rosynthetic analysis (Route a). Aldehyde 5 was obtained by
the oxidation of the alcohol 4.[9] The aldol reaction pro-
ceeded without incident to give the aldol product 7. Oxi-
dation provided the 1,3-keto compound 8, which was hy-
drolyzed to the corresponding carboxylic acid. However,
cyclization of the resulting carboxylic acid was unsuccess-
ful. Because this failure might be due to the enolization of
the 1,3-keto compound 8, cyclization was attempted using
the aldol product 7. Cyclization was achieved successfully
and oxidation with the resulting lactone provided the keto
lactone 9. Unfortunately, the deprotection of the benzyl
group was unsuccessful, even with various known methods.
The difficulty in deprotection led us to examine other ap-
proaches for preparing the tetraketide lactones.
The synthetic route was re-analyzed and an attempt was
made to devise a common route for synthesizing both tetra-
ketide lactones 2 and 3 (a six-membered and a eight-mem-
bered lactone, respectively). Retrosynthetic analysis re-
vealed that the paths that lead to the intermediates B and
C in Scheme 1 (which would lead to compounds 2 and 3,
Scheme 4. Attempt to synthesize the tetraketide lactone according
to the Claisen condensation route.
The acylated product 11a, which was prepared by the
respectively, route b) would have the advantage of em- propionation of the previously reported alcohol 10, was
ploying similar intermediates for the synthesis of both tetra- treated with a strong base (KHMDS) with the aim of pro-
ketide lactones. Moreover, the synthesis of a similar tetrake- ducing the desired lactone. However, the product formed is
tide lactone has been reported (Scheme 3).[11] An intramo- believed to be the α,β-unsaturated compound 12a. The
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H.-Y. Kang et al.
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anion formed by proton abstraction at the α position can
The asymmetric intermolecular Reformatsky reaction
lead to the elimination of the EtCO2 group (Scheme 4). The mediated by samarium(II) iodide[13] provided the epimeric
absence of a methyl group at the α position created a differ- aldol products 14a and 14b (with no diastereoselectivity).
ence in the course of the reaction. Hoping that the acidity After chromatographic separation, the aldol product 14a (a
of the α-proton might be altered by changing the chiral aux- series) was converted to a TBS-protected triol 15a, by re-
iliary with other group, the oxazolidinone moiety was duction followed by silylation of the newly formed primary
switched to the Weinreb amide (10b). However, this change hydroxy group. The required ester for the intramolecular
did not lead to the production of the desired lactone. The Reformatsky reaction was prepared by esterification with
formation of the elimination product 12b was observed. DCC. The hydroxy group was deprotected under acidic
Therefore, it was necessary to modify the synthetic route. conditions, and the aldehyde 16a, which is a precursor for
The use of the intramolecular samarium(II) iodide-medi- cyclization, was secured. The key samarium(II) iodide-me-
ated Reformatsky reaction to produce various cyclic prod- diated intramolecular Reformatsky reaction was performed
ucts including six- and eight-membered rings was consid- successfully (SmI2, THF, –78 °C). The resulting lactone (ca.
ered (Scheme 5).[12] The intramolecular Reformatsky reac- 24:1 diastereoselectivity) was oxidized and deprotected to
tion mediated by samarium(II) iodide has been used suc- afford the desired tetraketide lactone 2a. The epimeric lac-
cessfully by many researchers, including Molander and Mu- tone 2b was synthesized by an identical reaction sequence
kaiyama, to prepare cyclic products.
starting from the aldol product 14b (b series). Therefore, the
Reformatsky reaction mediated by samarium(II) iodide
with aldehyde 16b yielded the lactone 17b (diastereoselectiv-
ity = 20:1). Oxidation followed by deprotection produced
the desired tetraketide lactone 2b.
The synthesis of the eight-membered tetraketide lactones
3 was attempted after successfully synthesizing the six-
membered ring tetraketide lactones 2a and 2b. The plan was
Scheme 5. Intramolecular SmI2-mediated Reformatsky reaction.
The samarium(II) iodide-mediated intramolecular Re- to use the same protected triol intermediate, which was
formatsky reaction was used to synthesize the desired tetra- thought to give both target tetraketide lactones 2 and 3 de-
ketide lactones 2a and 2b, as summarized in Scheme 6. Al- pending on which hydroxy group was chosen for acylation.
though the biosynthetic mechanism suggests compound 2b The asymmetric Reformatsky reaction of compound 6a
to be the expected product with the correct stereochemistry, with the aldehyde 13b gave a 13:1 mixture of the com-
a decision was made to synthesize both epimers for the fu- pounds 18a and 18b (Scheme 7).[14] The same reaction with
ture biosynthetic studies.
compound 6b provided a lower ratio (3:1) as a consequence
of a mismatched pair. After protecting the free hydroxy
group at the 3-position of the major isomer 18a with a silyl
group, the chiral auxilary was removed by reduction with
LiBH4. The resulting primary alcohol was protected with
the TBS group. The secondary alcohol 19a was obtained by
deprotecting the PMB group. It was expected that this
alcohol would be converted into the desired eight-mem-
bered lactones 3a.
The free secondary hydroxy group of compound 19a was
esterified with 2-bromopropanoic acid. The removal of the
TBS group followed by oxidation gave the aldehyde 20a,
which was subjected to the key samarium(II) iodide-medi-
1
ated intramolecular Reformatsky reaction. H NMR spec-
tral analysis showed that the Reformatsky reaction gave the
eight-membered lactone 21a as a mixture of two dia-
stereomers with a ratio of 7:1. The precise stereochemistry
of the products in the mixture was not determined. The
mixture was further oxidized to produce compound 22a as
an 8:1 mixture with a C-2 stereocenter. Therefore, the intra-
molecular Reformatsky reaction was expected to be highly
stereoselective with respect to the chiral C-3 atom. It was
hoped that the stereochemistry at C-2 would be controlled
by the thermodynamic stability. The only remaining step to
complete the synthesis of the eight-membered lactone 3a
was the deprotection of the hydroxy group. Surprisingly, al-
though understandable under the deprotection condition
(HF/CH3CN), the protected lactone 22a was converted into
Scheme 6. Reagents and conditions: (a) ref.[9] [SmI2, THF, –78 °C]
(b) (1) LiBH4, H2O (78%) (2) imidazole, TBSCl (97%) (c) (1)
CH3CHBrCOOH, DCC, DMAP (96%) (2) CSA(cat.), MeOH
(63%) (3) DMP (72%) (d) SmI2, –78 °C (24:1 selectivity, 59%) (e)
(1) DMP (68%), (2) HF/CH3CN (74%) (f) (1) LiBH4, H2O (70%),
(2) imidazole, TBSCl (99%) (g) (1) CH3CHBrCOOH, DCC,
DMAP (97%) (2) CSA(cat.), MeOH (88%) (3) DMP (89%) (h)
SmI2, THF, –78 °C (20:1 selectivity, 60%) (i) (1) DMP (68%) (2)
HF/CH3CN (70%).
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Synthesis of the Tetraketide Lactones
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product 23b exclusively were determined,[10] a simple, prac-
tical, substrate-controlled approach was adopted for the
synthesis of compound 23b. The aldehyde 13b was allylated
to give a 3:2 mixture of compounds 23a and 23b. The unde-
sired isomer 23a was recycled to the desired isomer 23b by
oxidation followed by reduction. The allylated alcohol 23b
was obtained in 40% yield after this oxidation-reduction
sequence. The alcohol 23b was converted into the aldehyde
25b through protection of the free hydroxy and oxidative
cleavage of the vinyl group. The aldehyde 25b was then re-
duced, and the resulting primary hydroxy group was pro-
tected with the TBS group. The PMB ether was deprotected
and acylated. After regenerating the primary hydroxy group
followed by oxidation, the key intramolecular Reformatsky
reaction was performed using the aldehyde 20b. The desired
eight-membered ring was formed as a mixture of two dia-
stereomers with a ratio of 1:2. The two products are be-
lieved to be the diastereomeric mixture of C-2 (and C-3)
isomers. Furthermore, although not precisely identified,
two diastereomeric products appeared to be mainly C-2
stereoisomers. This was supported by the fact that the β-
keto ester 22b, which was formed by the oxidation of com-
pound 21b, maintained a similar isomeric ratio (2:1). Un-
Scheme 7. Reagents and conditions: (a) SmI2, THF, –78 °C (65%)
[dr = 13:1 (18a/18b)] (b) SmI2, THF, –78 °C (74%) [dr = 3:1 (a:b)]
(c) 2,6-Lutidine, TBSOTf (82%) (d) (1) LiBH4, H2O (94%) (2)
imidazole, TBSCl (95%) (3) DDQ (74%) (e) (1) CH3CHBrCOOH,
DCC (97%) (2) CSA(cat.), MeOH (88%) (3) DMP (91%) (f) SmI2,
–78 °C (72%, 7:1 mixture) (g) DMP (88%, 8:1 mixture) (h) HF/
CH3CN (58%).
the tetraketide δ-lactone 2a. The attempted deprotection of
the lactone removed the silyl group and caused the translac-
tonization to produce the lactone 2a, which was identical
to the lactone prepared previously (Scheme 6). This trans-
lactonization is likely driven by the thermodynamic sta-
bility.[15] Desilylation 22a under acidic conditions (HCl,
AcOH, or CSA) also tried but failed to produce the desired
lactone 3a. Only decomposition was observed. The lactone
having the PMB-protected hydroxy group (22c) was also
prepared to find out any difference upon changing the pro-
tecting group. However, only 2a was formed under the stan-
dard deprotection condition (DDQ, CH2Cl2:H2O = 10:1,
1
0 °C). The structure of the lactone 2a was confirmed by H
1
NMR, 13C NMR, and H-1H COSY spectra.
It was believed that it would be preferable to secure the
possible diastereomers of the target lactones for the future
biosynthetic studies. Therefore, an attempt was made to
synthesize the diastereomeric lactone 3b. The main interest
in this attempt was to determine the effect of the stereo-
chemistry at the C-5 position. The synthesis of the epimeric
tetraketide lactone 3b was initiated using a modified pro-
cedure from that used in the attempted synthesis of 3a. It
was hoped that the hydroxy group with the epimeric stereo-
chemistry at C-5 would lead to an eight-membered ring
structure or render the resulting oxygen-centered anion,
which had been formed by the deprotection of the silyl
group, unable to attack the carbonyl carbon of the lactone.
At the time of performing this synthesis, a more practical
synthetic route was adopted to prepare the required precur-
sors for the key Reformatsky reaction (Scheme 8; b series).
In other words, the allylation reaction was used instead of
the aldol reaction based on the Evans’ chiral auxiliaries.
Scheme 8. Reagents and conditions: (a) In, allyl bromide,
THF:H2O = 1:1 (70%) (b) TBSOTf, 2,6-lutidine, 0 °C, CH2Cl2
(98%) (c) (1) DMP, (2) NaBH4 (2:3 mixture) (recycled, 40%) (d)
(1) NMO-OsO4 (2) NaIO4 (tBuOH:THF:H2O = 10:2:1) (92%, two
steps) (e) (1) NaBH4, MeOH, 0 °C (94%) (2) TBSOTf, 2,6-lutidine,
0 °C, CH2Cl2 (99%) (f) DDQ, DCM:pH7 buffer = 10:1 (96%) (g)
(1) CH3CHBrCOOH, DMAP(cat), DCC (95%) (2) CSA, MeOH
(91%) (3) DMP (90%) (h) SmI2, CH2Cl2 (84%, 2:1 mixture) (i)
Although, the conditions for producing the desired allylated DMP (96%, 2:1 mixture) (j) HF/CH3CN, room temp. (97%).
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H.-Y. Kang et al.
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fortunately, it was found that deprotection of the silyl group
The major isomer of 32 was oxidized to a keto ester 33
of 22b did not lead to isolate the desired eight-membered using Dess–Martin periodinane to give a mixture of dia-
lactone 3b but instead, produced the tetraketide lactone 2b. stereomers (2:1, C-2 isomers). Deprotection of the TBS
Therefore, the translactonization to an eight-membered lac- ether also afforded the δ-lactone 34 instead of the desired
tone by attacking the anionic oxygen atom, which was ξ-lactone 35. The hydroxy group of compound 32 was de-
formed by deprotecting of the ester carbonyl group, was protected and treated with HF in order to determine the
favored.
effect of the keto group. In this case, the corresponding δ-
We were unable to obtain the desired eight-membered lactone was also formed but the formation of the eight-
lactones with free hydroxy groups 3a and 3b, even though membered lactone was not observed.
the synthesis of eight-membered lactone rings has been suc-
cessful using the samarium(II) iodide-promoted intramolec-
ular Reformatsky reaction. As a result, a decision was made
to further examine the factors that influence the stability.
Conclusions
We have experienced that the existence of a methyl group
The overall aim of this study was to synthesize the inter-
can make a critical difference in acidity that can enable the mediates and products to investigate various biosynthetic
desired Claisen condensation to proceed. Therefore, it pathways. The main focus was on developing synthetic
would be interesting to check the behavior of a similar routes to prepare polyketide lactones, which are involved in
structure in cyclization with the presence of the methyl the pikromycin biosynthetic pathway. A model PKS system
group at the C-4 position. A lactone with a similar structure was devised to simplify the investigation. This study exam-
to the compound 2 could be prepared with an additional ined the synthetic routes for the simpler tetraketide lactones
methyl group at the C-4 position. Scheme 9 shows the syn- with the six- or eight-membered rings anticipated by this
thetic pathway of the lactone. The aldol reaction was per- model PKS. The routes were developed based on an iden-
formed with compounds 27 and 13b to provide compound tical key intermediate used to synthesize both tetraketide
28. This aldol product 28 was converted into the fully pro- lactones with six- and eight-membered rings. The tetrake-
tected triol 29 in a straightforward manner. After deprotec- tide lactones 2a and 2b with six-membered rings were syn-
tion of the PMB group, the same procedure as that used in thesized efficiently utilizing the asymmetric aldol reaction
the previous attempt to prepare compound 3 was applied. and the samarium(II) iodide-mediated Reformatsky reac-
The aldehyde 31, which is the precursor for the Reformat- tion as the key reactions. The formation of eight-membered
sky reaction, was treated with samarium(II) iodide in THF. lactone derivatives was also successfully achieved using the
The desired eight-membered lactone (with a methyl group samarium(II) iodide-mediated Reformatsky reactions.
at C-4) 32 was formed efficiently as a diastereomeric mix- Therefore, a synthetic route for the tetraketide lactone de-
ture with a ratio of 5:1.
rivatives with eight-membered rings has been developed.
However, the synthesis of the final target tetraketide lac-
tones with a free hydroxy group was unsuccessful. The hy-
droxy lactones with an eight-membered ring, which were
obtained from the final deprotection of the silyl groups,
spontaneously converted into the tetraketide lactones 2a
and 2b prepared previously. This indicates that the tetrake-
tide hydroxy lactones with six-membered ring are thermo-
dynamically more stable than those with eight-membered
rings. The results of this study strongly indicate that the
model PKS would produce only the tetraketide lactones
with six-membered rings from the future incubation study.
The eight-membered hydroxy lactone with an additional
methyl group was also transformed to the corresponding
six-membered lactone 34. This confirms the stability of the
tetraketide lactones with six-membered rings, which is in
contrast to the corresponding lactones with eight-mem-
bered rings.
The results from this synthetic investigation are expected
to provide important information for the future biosyn-
thetic research with the model PKS. We are planning to
carry out an incubation study with the model PKS to eluci-
date the pikromycin biosynthetic mechanisms. The tetrake-
tide lactones prepared in this study will facilitate the investi-
gation by resolving the difficulty in identifying the key in-
termediates formed by the model PKS. This synthetic study
would also provide valuable experience and knowledge to
Scheme 9. Reagents and conditions: (a) 13b, Bu2BOTf, Et3N (80%)
(b) (1) 2,6-lutidine, TBSOTf, DCM, 0 °C (89%) (2) LiAlH4, H2O
(86%) (3) 2,6-lutidine, TBSOTf (94%) (c) DDQ, DCM:pH7 buffer
=
10:1 (99%) (d) (1) CH3CHBrCOOH, DMAP(cat), DCC,
CH2Cl2, 0 °C (89%) (2) CSA, MeOH, 0 °C (85%) (3) DMP,
CH2Cl2 (91%) (e) SmI2, THF, –78 °C (62%) (f) DMP, CH2Cl2,
room temp. (77%) (g) HF, CH3CN (69%).
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Synthesis of the Tetraketide Lactones
FULL PAPER
as a colorless oil. IR (film): ν = 3453, 2957, 2857, 1641, 1471, 1389,
˜
prepare related and more complex polyketide lactones from
the pikromycin biosynthetic pathway. Further synthetic in-
vestigations into more complicated polyketide lactones will
be reported in the future.
1
1361, 1255 cm–1. H NMR (300 MHz, CDCl3): δ = 3.88 (m, 1 H,
CHOH), 3.65–3.80 (m, 3 H, CH2OSi, CHOSi), 3.25 (s, 1 H,
CHOH), 1.68 (m, 1 H, CHCH3), 1.58–1.62 (m, 2 H, CH2CHOH),
1.51 (m, 2 H, CH2CH3), 0.86 [m, 21 H, SiC(CH3)3, SiC(CH3)3,
CHCH3] 0.78 (t, J = 7.4 Hz, 3 H, CH2CH3), 0.03 [s, 12 H, Si-
(CH3)2, Si(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ = 77.6,
72.9, 61.9, 40.4, 37.4, 27.2, 25.9, 25.9, 18.2, 18.0, 9.8, 7.1, –3.8,
–4.6, –5.5 ppm. [α]2D7.6 = +8.1 (c = 1.15, CHCl3). MS (EI): m/z (%)
= 390 [M+], 343, 333, 241, 201, 189, 173, 145, 133, 109, 89, 75 (100),
73. HRMS: m/z calcd. for C20H46O3Si2: 390.2986, found 390.2968.
Experimental Section
1H NMR and 13C NMR spectra were recorded with a Bruker
DPX-300 and Bruker Avance 500 NMR Spectrometer. The chemi-
cal shifts are reported in ppm on scale downfield from TMS, and
signal patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; m, multiplet; br, broad peak. IR spectra were recorded with
a JASCO FT/IR-300E. Optical rotations were measured by JASCO
DIP-1000 digital polarometer in solution in a 1-dm cell. Mass spec-
tra (and HRMS) were obtained with a VG AUTOSPEC Ultma
GC/MS system using direct insertion probe (DIP) and electron-
impact method (EI, 70 eV). All reagent and solvents were reagent
grade and used without further purification unless specified other-
wise. Technical grade ethyl acetate, hexane, and pentane used for
column chromatography were distilled prior to use. Tetra-
hydrofuran (THF) and diethyl ether, when used as solvents for reac-
tions, were freshly distilled from sodium/benzophenone ketyl. Di-
methylformamide (DMF) was stored over 4-Å molecular sieves,
and triethylamine was distilled before use. Flash chromatography
was carried out on Woelm 32–64 µm silica packed in glass col-
umns.[16]
(1S,2R,3R)-3-(tert-Butyldimethylsilyloxy)-2-methyl-1-(2-oxoethyl)-
pentyl 2-Bromopropanoate (16a): 2-Bromopropionic acid (313 µL,
3.48 mmol) and DMAP (114 mg, 0.93 mmol) was added to a solu-
tion of 15a (453 mg, 1.16 mmol) in CH2Cl2 (5 mL) at room tem-
perature. After the solution was cooled to 0 °C, N,N-dicyclohex-
ylcarbodiimide (264 mg, 1.28 mmol) was added. The resulting solu-
tion was stirred for 5 min at 0 °C before it was warmed to room
temperature. After additional stirring for 30 min at room tempera-
ture, the precipitate was filtered. The filtrate was concentrated and
purified by flash chromatography (hexane/EtOAc, 10:1). The de-
sired bromo ester was obtained as a colorless liquid (582 mg, 96%).
1
IR (film): ν = 2928, 2857, 1738, 1471, 1381, 1256 cm–1. H NMR
˜
(300 MHz, CDCl3): δ = 5.12 [m, 1 H, CHO(C=O)], 4.32 [q, J =
7.0 Hz, 1 H, –C(O)CH], 3.60 (m, 3 H, CH2OSi, CHOSi), 1.89 [m,
3 H, CH2CH2CH(O), CHCH(CH3)CH], 1.78 (d, J = 6.9 Hz, 3 H,
BrCHCH3), 1.5 (m, 2 H, CH2CH3), 0.90 (m, 6 H, CHCH3,
CH2CH3), 0.86 [s, 18 H, SiC(CH3)3, SiC(CH3)3], 0.02 (s, 6 H,
2ϫSiCH3), 0.00 (s, 6 H, 2ϫSiCH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.5, 75.2, 75.1, 60.6, 41.9, 41.5, 36.9, 27.8, 27.0,
22.8, 19.3, 11.3, 10.4, –2.94, –3.38, –4.33 ppm. [α]2D4.5 = +5.9 (c =
1.21, CHCl3). MS (EI): m/z (%) = 524 [M+], 526, 343, 290, 241, 211,
173, 121 (100), 109, 89, 73. HRMS: m/z calcd. for C23H49BrO4Si2:
524.2353, found 524.2335.
(3S,4R,5R)-1,5-Bis(tert-butyldimethylsilyloxy)-4-methyl-3-heptanol
(15a): Distilled water (41 µL, 2.3 mmol) was added to a solution of
(4S,3ЈS,4ЈR,5ЈR)-4-benzyl-3-[5Ј-(tert-butyldimethylsilyloxy)-3Ј-hy-
droxy-4Ј-methylheptanoyl]-2-oxazolidinone (14a)[9] (689 mg,
1.53 mmol) in diethyl ether (5 mL). After the solution was cooled
to 0 °C, lithium borohydride (1.10 mL of a 2.0  solution in THF,
2.30 mmol) was added slowly with stirring. After 10 min, the tem-
perature of the solution was raised to room temperature, and
stirred for additional 2 h. The reaction was terminated with ad-
dition of aqueous NaOH solution (1.0 , 10 mL) and extracted
with diethyl ether (3ϫ10 mL). After the organic layer was washed
with saturated sodium chloride solution (20 mL), the ethereal solu-
tion was dried (MgSO4) and concentrated. Purification of the resi-
due by flash chromatography (hexane/EtOAc, 2:1) provided the de-
The bromo ester (582 mg, 1.11 mmol) obtained as described above
was dissolved in MeOH (3 mL). To this solution -10-cam-
phorsulfonic acid (51 mg, 0.22 mmol) was added. The resulting
solution was stirred at 0 °C for 1 h. The reaction was terminated
by addition of Et3N (162 µL, 1.17 mmol). After the solution was
concentrated, purification of the residue by flash chromatography
(hexane/EtOAc, 3:1) gave the desired primary alcohol (285 mg,
sired diol as a colorless liquid (329 mg, 78%). IR (thin film): ν =
˜
3387, 2957, 1641, 1462, 1256, 1057 cm–1 1H NMR (300 MHz,
.
63%) as a colorless liquid. IR (film): ν = 3425, 2932, 2856, 1737,
˜
1
1471, 1380, 1257 cm–1. H NMR (300 MHz, CDCl3): δ = 5.20 [m,
CDCl3): δ = 3.92 (dt, J = 9.8, 2.7 Hz, 1 H, CHOSi), 3.74 (m, 3 H,
CH2OH, CHOH), 3.51 (s, 2 H, CH2OH, CHOH), 1.75 (m, 1 H,
CHCH3), 1.50 (m, 4 H, CH2CHOH, CH2CH3), 0.85 (d, J = 3.6 Hz,
3 H, CHCH3), 0.83 [s, 9 H, SiC(CH3)3], 0.76 (t, J = 7.3 Hz, 3 H,
CH2CH3), 0.03 [s, 6 H, Si(CH3)2] ppm. 13C NMR (75 MHz,
CDCl3): δ = 79.2, 75.5, 62.2, 40.5, 37.4, 27.9, 27.0, 18.6, 10.4, 6.8,
–3.1, –4.0 ppm. [α]2D6.2 = +19.7 (c = 1.61, CHCl3). MS (EI): m/z
(%) = 276 [M+], 219, 202, 175, 145, 134, 117, 109, 77, 71, 68 (100),
58. HRMS: m/z calcd. for C14H32O3Si: 276.2120, found 276.2117.
1 H, CHO(C=O)], 4.38 [q, J = 6.9 Hz, 1 H, C(=O)CHBr], 3.60 (m,
3 H, CH2OH, CHOSi), 2.23 (s, 1 H, CH2OH), 1.92 (m, 1 H,
CHCH3), 1.86 (d, J = 6.9 Hz, 3 H, BrCHCH3) 1.46 (dq, J = 7.7,
5.9 Hz, 2 H, CH2CH3), 0.96 (d, J = 6.9 Hz, 3 H, CHCH3), 0.89 [s,
9 H, SiC(CH3)3], 0.84 (t, J = 7.5 Hz, 3 H, CH2CH3), 0.05 (s, 3 H,
SiCH3), 0.04 (s, 3 H, SiCH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 171.6, 74.9, 74.4, 59.2, 41.9, 40.9, 36.6, 27.2, 26.6, 22.4, 18.8,
11.0, 10.2, –3.40, –3.78 ppm. [α]2D3.9 = +4.4 (c = 1.43, CHCl3). MS
(EI): m/z (%) = 410 [M+], 351, 267, 229, 201, 173 (100), 153, 127,
109, 73, 55. HRMS: m/z calcd. for C17H35BrO4Si: 410.1488, found
410.1486.
The diol (329 mg, 1.19 mmol) obtained above was dissolved in
CH2Cl2 (4 mL). To this solution was added a solution of imidazole
(122 mg, 1.79 mmol) and tert-butyldimethylsilyl chloride (215 mg,
1.43 mmol) in CH2Cl2 (1 mL) at 0 °C under nitrogen. After it was
stirred for 10 min at 0 °C, the solution was warmed to room tem-
perature and stirred for additional 1 h at room temperature. After
the reaction was completed, aqueous saturated NH4Cl (5 mL) was
added and the mixture was extracted with CH2Cl2 (3ϫ10 mL). The
organic layer was separated, dried (MgSO4), and concentrated. Pu-
rification of the residue by flash chromatography (hexan/EtOAc,
10:1) offered the desired TBS-protected alcohol 15a (453 mg, 97%)
The alcohol (285 mg, 0.69 mmol) obtained as describe above was
dissolved in CH2Cl2 (5 mL). To this solution was added Dess–Mar-
tin periodinane (DMP) (352 mg, 0.83 mmol). The resulting solu-
tion was stirred for 30 min at room temperature. After the reaction
was completed, aqueous saturated NaHCO3 (10 mL) was added
and the mixture was extracted with CH2Cl2 (3ϫ10 mL). The or-
ganic layer was separated, dried (MgSO4), and concentrated. Puri-
fication of the residue by flash chromatography (hexane/EtOAc,
Eur. J. Org. Chem. 2007, 3369–3379
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3375

H.-Y. Kang et al.
FULL PAPER
7:1) offered the desired aldehyde 16a (204 mg, 72%) as a yellow
liquid. 1H NMR (300 MHz, CDCl3): δ = 9.67 [s, 1 H, C(O)H], 5.40
[dt, J = 6.9, 4.2 Hz, 1 H, CHO(C=O)], 4.27 [q, J = 6.8 Hz, 1 H,
C(=O)CHBr], 3.56 (m, 1 H, CHOSi), 2.79 [dd, J = 16.6, 4.0 Hz, 1
H, one of CH2C(=O)H], 2.66 (ddd, J = 20.7, 16.6, 3.0 Hz, 1 H,
BrCHCH3), 1.86 (m, 1 H, CHCH3), 1.74 (d, J = 6.9 Hz, 3 H,
BrCHCH3), 1.47 (dq, J = 13.7, 6.3 Hz, 2 H, CH2CH3), 0.90 (d, J
stirred for 1 h at room temperature. The reaction was terminated
by addition of solid CaCO3 (30 mg). After the mixture was filtered
with aid of Celite and washed with diethyl ether (3ϫ10 mL) and
the filtrate was concentrated. Purification of the residue by flash
chromatography (hexane/EtOAc, 1:1 to 1:2) provided the desired
lactone 2a (14 mg, 74%) as a white solid: M.p. 108–110 °C. IR
(film): ν = 3427, 2970, 1724, 1255 cm–1 1H NMR (500 MHz,
.
˜
= 7.8 Hz, 3 H, CHCH3), 0.84 [s, 9 H, SiC(CH3)3], 0.80 (t, J = MeOH): δ = 4.24 [ddd, J = 12.3, 6.4, 3.8 Hz, 1 H, CHOC(=O)],
7.4 Hz, 3 H, CH2CH3), 0.05 (s, 3 H, SiCH3), 0.03 (s, 3 H, SiCH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 200.1, 170.3, 74.9, 72.4,
47.5, 41.3, 40.4, 27.2, 26.6, 22.2, 18.8, 11.1, 10.5, –3.30, –3.71 ppm.
3.53 (dt, J = 6.6, 3.4 Hz, 1 H, CHOH), 2.59–2.65 (m, 1 H, one of
CH2COH), 2.38 (dd, J = 16.9, 3.3 Hz, 1 H, one of CH2COH), 1.69
(quintet of d, J = 6.8, 3.4 Hz, 1 H, CHCH3), 1.63 (s, 3 H,
–C=CCH3), 1.43 (quintet, J = 7.2 Hz, 2 H, CH2CH3), 0.95 (d, J =
6.9 Hz, 3 H, CHCH3), 0.87 (t, J = 7.4 Hz, 3 H, CH2CH3) ppm.
13C NMR (75 MHz, MeOH): δ = 173, 169, 99.2, 79.1, 73.9, 43.3,
32.6, 28.9, 11.4, 9.78, 8.95 ppm. [α]2D6.5 = 13.53 (c = 0.82, MeOH).
MS (EI): m/z (%) = 214 [M+], 167, 157, 141, 129, 116, 111, 101,
83, 71, 55 (100). HRMS: m/z calcd. for C11H18O4: 214.1205, found
214.1205.
(6S)-6-[(1R,2R)-2-(tert-Butyldimethylsilyloxy)-1-methylbutyl]-4-
hydroxy-3-methyltetrahydro-2H-pyran-2-one (17a): Diiodomethane
(79 µL, 0.98 mmol) was added to a mixture of samarium (powder,
162 mg, 1.07 mmol) in THF (5 mL) at room temperature under
nitrogen. Samarium(II) iodide was obtained as a blue-colored solu-
tion which was used after stirring for 2 h. After the solution was
cooled to –78 °C, a solution of aldehyde 16a (200 mg, 0.49 mmol)
in THF (1 mL) was added under nitrogen. After being stirred for
1 h at –78 °C, the solution was warmed to room temperature and
0.1  HCl (8 mL) was added. The mixture was extracted with di-
ethyl ether (3ϫ20 mL). After the organic layer was washed with
saturated sodium thiosulfate solution (15 mL) and sodium chloride
solution (15 mL), the ethereal solution was dried (MgSO4) and
concentrated. Purification of the residue by flash chromatography
(hexane/EtOAc, 3:1) provided the desired lactone 17a as a yellow
liquid [92 mg (57%) and 3.9 mg (2.4%), selectivity 24:1]; Rf = 0.57
and 0.50 (hexane/EtOAc, 1:1), respectively. Spectroscopic data for
(6R)-4-Hydroxy-6-[(1S,2R)-2-hydroxy-1-methylbutyl]-3-methyl-5,6-
dihydro-2H-pyran-2-one (2b): Lactone 17b (83 mg, 0.25 mmol) (a
20:1 mixture of diastereomers) obtained above was dissolved in
CH2Cl2 (2 mL). To this solution was added Dess–Martin reagent
(213 mg, 0.50 mmol) and the resulting solution was stirred for
30 min at room temperature. After the reaction was completed,
aqueous saturated NaHCO3 (5 mL) was added and mixture was
extracted with CH2Cl2 (3ϫ10 mL). The organic layer was sepa-
rated, dried (MgSO4), and concentrated. Purification of the residue
by flash chromatography (hexane/EtOAc, 3:1) offered the desired
ketone (56 mg, 68%) as a colorless liquid. 1H NMR (300 MHz,
CDCl3): δ = 7.99 (br., 1 H, C-OH), 4.22 [dd, J = 16.8, 8.7 Hz, 1
the major isomer is as follows. IR (film): ν = 3442, 2933, 2856,
˜
1713, 1462, 1380, 1258, 1197 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 4.79 [m, 1 H, CHO(C=O)], 4.14 (s, 1 H, CHOH), 3.61 (m, 1 H, CHOC(=O)], 4.04 (ddd, J = 9.7, 6.0, 1.6 Hz, 1 H, CHOSi), 2.50
H, CHOSi), 2.44 [qd, J = 7.2, 3.2 Hz, 1 H, C(=O)CHCH3], 2.04
(m, 1 H, CHCH3), 1.82 (m, 2 H, CH2CHOH), 1.67 (m, 2 H,
(d, J = 7.6 Hz, 2 H, CH2C-OH), 1.84 (m, 1 H, CHCH3), 1.79 (s, 3
H, C=CCH3), 1.49 (m, 2 H, CH2CH3), 0.84 [m, 15 H, CHCH3,
CH2CH3), 1.28 (d, J = 7.2 Hz, 3 H, CHCH3), 0.96 (d, J = 6.9 Hz, CH2CH3, SiC(CH3)3], 0.04 (s, 3 H, SiCH3), 0.00 (s, 3 H, SiCH3)
3 H, CHCH3), 0.83 [m, 12 H, CH2CH3, Si(CH3)3], 0.00 (s, 6 H,
SiCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.9, 75.1, 68.5,
42.5, 37.1, 27.1, 26.6, 18.8, 11.7, 10.9, 10.3, –3.3, –3.8 ppm. MS
(EI): m/z (%) = 330 [M+], 301, 215, 197, 173, 73 (100), 57. HRMS:
m/z calcd. for C17H34O4Si: 330.2226, found 330.2229.
ppm. 13C NMR (75 MHz, CDCl3): δ = 202.5, 75.6, 71.5, 52.3, 42.4,
41.1, 32.4, 28.3, 26.5, 18.7, 10.7, 8.97, 8.46, 8.23, –3.55, –4.04 ppm.
The lactone (45 mg, 0.14 mmol) prepared as described above was
dissolved in HF/CH3CN [48% HF/CH3CN, 1:19 (v/v)] (1 mL) and
the resulting solution was stirred for 1 h at room temperature. The
(6S)-4-Hydroxy-6-[(1S,2R)-2-hydroxy-1-methylbutyl]-3-methyl-5,6- reaction was terminated by addition of solid CaCO3 (30 mg) After
dihydro-2H-pyran-2-one (2a): Lactone 17a (50 mg, 0.15 mmol) (a
24:1 mixture of diastereomers) obtained as described above was
dissolved in CH2Cl2 (1 mL). To this solution was added Dess–Mar-
tin periodinane (DMP) (127 mg, 0.30 mmol) and the resulting solu-
tion was stirred for 30 min at room temperature. After the reaction
was completed, aqueous saturated NaHCO3 (5 mL) was added and
the mixture was extracted with CH2Cl2 (3ϫ10 mL). The organic
layer was separated, dried (MgSO4), and concentrated. Purification
of the residue by flash chromatography (hexane/EtOAc, 3:1) of-
fered the desired ketone (34 mg, 68 %) as a colorless liquid. 1H
NMR (300 MHz, CDCl3): δ = 4.76 [ddd, J = 11.8, 6.1, 2.8 Hz, 1
the mixture was filtered with diethyl ether (3ϫ10 mL) and concen-
trated. Purification by flash chromatography (hexane/EtOAc, 1:1
to 1:2) provided the desired lactone 2b (20.5 mg, 70%) as a white
solid. m.p. 106–107 °C. IR (film): ν = 3431, 2931, 1728, 1255,
˜
1
1138 cm–1. H NMR (300 MHz, MeOH): δ = 4.24 [ddd, J = 11.6,
8.5, 4.8 Hz, 1 H, CHOC(=O)], 3.80 (ddd, J = 11.6, 5.1, 2.0 Hz, 1
H, CHOH), 2.49 (dd, J = 11.7, 1.7 Hz, 1 H, one of CH2C-OH),
2.34–2.52 (m, 1 H, CH2C-OH), 1.72 (m, 1 H, CHCH3), 1.62 (s, 3
H, -C=CCH3), 1.28–1.52 (m, 2 H, CH2CH3), 0.87 (t, J = 7.4 Hz,
3 H, CH2CH3), 0.79 (d, J = 7.0 Hz, 3 H, CHCH3) ppm. 13C NMR
(75 MHz, MeOH): δ = 172.8, 168.8, 99.4, 78.2, 72.4, 43.4, 32.8,
H, CHO(C=O)], 3.59 [dt, J = 6.4, 3.5 Hz, 1 H, C(=O)CHCH3], 29.1, 11.5, 8.9, 8.6 ppm. [α]2D3.8 = 4.17 (c = 0.42 MeOH). MS (EI):
3.54 [q, J = 6.6 Hz, 1 H, C(=O)CHCH3], 2.73 [dd, J = 19.0, 2.9 Hz,
1 H, one of CH2C(=O)], 2.49 [dd, J = 19.0, 11.8 Hz, 1 H, one of
m/z (%) = 214 [M+], 179, 167, 156, 141, 127, 121, 111, 101 (100),
95, 83, 71, 55. HRMS: m/z calcd. for C11H18O4: 214.1205, found
CH2C(=O)], 1.83 (m, 1 H, CHCHCH3), 1.36–1.61 (m, 2 H, 214.1206.
CH2CH3), 1.32 [d, J = 6.6 Hz, 3 H, C(=O)CHCH3], 1.04 (d, J =
(4R,3ЈS,4ЈR,5ЈR)-4-Benzyl-3-[5Ј-[(4-methoxybenzyl)oxy]-3Ј-
6.9 Hz, 3 H, CH2CH3), 0.87 [m, 12 H, SiC(CH3)3, CH2CH3], 0.04
(s, 3 H, SiCH3), 0.00 (s, 3 H, SiCH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 202.7, 170.7, 75.8, 75.2, 52.3, 42.5, 42.2, 26.9, 26.5,
18.8, 11.1, 10.9, 8.42, –3.30, –3.80 ppm.
hydroxy-4Ј-methylheptanoyl]-2-oxazolidinone (18a) and
(4R,3ЈR,4ЈR,5ЈR)-4-Benzyl-3-[5Ј-[(4-methoxybenzyl)oxy]-3Ј-hy-
droxy-4Ј-methylheptanoyl]-2-oxazolidinone (18b): Diiodomethane
(256 µL, 3.17 mmol) was added to a mixture of samarium (powder,
573 mg, 3.81 mmol) in THF (5 mL) at room temperature under
The lactone (29 mg, 0.09 mmol) prepared as described above was
dissolved in HF/CH3CN [48% HF/CH3CN, 1:19 (v/v)] (1 mL) was nitrogen. Samarium(II) iodide was obtained as a greenish blue
3376 Eur. J. Org. Chem. 2007, 3369–3379
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of the Tetraketide Lactones
FULL PAPER
solution which was used after stirring for 2 h. After the solution
was cooled to –78 °C, a solution of aldehyde 13b (300 mg,
1.27 mmol) and oxazolidinone 6b (379 mg, 1.27 mmol) in THF
(5 mL) was added under nitrogen. After it was stirred for 1 h at
–78 °C, the solution was warmed to room temperature and 0.1 
HCl (10 mL) was added. The mixture was extracted with diethyl
ether (3ϫ15 mL). After the organic layer was washed with satu-
rated sodium thiosulfate solution (20 mL) and sodium chloride
solution (20 mL), the ethereal solution was dried (MgSO4) and
concentrated. Purification of the residue by flash chromatography
(hexane/EtOAc, 3:1) provided the desired 18a and 18b as yellow
liquids 344 mg (60%) and 26 mg (4.5%) (selectivity 13:1) [minor
compound 18b: Rf = 0.38 and major compound 18a: Rf = 0.31.
(hexane/EtOAc, 2:1)].
J = 8.6 Hz, 2 H, –OCH2ArOCH3), 4.54 (m, 1 H, PhCH2-
CHN–), 4.44 (d, J = 11.0 Hz, 1 H, –OCH2ArOCH3), 4.30 (m, 2
H, –OCH2ArOCH3, –CH2CHOTBS), 4.03 (d, J = 5.0 Hz, 2 H,
PhCH2CHCH2O–), 3.69 (s, 3 H, –OCH2ArOCH3), 3.43 (dd, J =
1 6 . 0 , 9 . 2 H z , 1 H , – C H C H O C H 2 A r ) , 3 . 1 8 ( m , 2 H ,
PhCH2CHCH2O–), 2.67 (dd, J = 16.0, 2.6 Hz, 1 H, COCH2CH),
2.56 (dd, J = 13.3, 9.9 Hz, 1 H, COCH2CH), 1.85 (m, 1 H,
TBSOCHCHCHO–), 1.56 (m, 2 H, –CH2CH3), 0.95 (d, J = 6.1 Hz,
3 H, –CH CH3), 0.84 [m, 12 H, –CHCH3, –Si(CH3)2C(CH3)3],
–0.01 [d, J = 3.6 Hz, 6 H, –Si(CH3)2C(CH3)3] ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.1, 158.9, 153.3, 135.4, 131.0, 129.4,
129.0, 128.9, 127.3, 113.7, 81.7, 71.2, 71.1, 65.9, 55.3, 55.2, 42.1,
38.4, 37.8, 25.7, 25.6, 23.8, 9.5, 9.0, –3.6, –4.6, –4.8 ppm. [α]2D8.1
=
–62.44 (c = 1.27, CHCl3). MS (EI): m/z (%) = 569 [M+], 374, 362,
301, 276, 252, 241, 218, 185, 121 (100), 91, 73, 59. HRMS: m/z
calcd. for C32H47NO6Si: 569.3173, found 569.3171.
18a: IR (film): ν = 3453, 3058, 2930, 1781, 1700, 1613, 1514, 1455,
˜
1390 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.27–7.12 (m, 7 H,
PhCH2CHN–, –OCH2ArOCH3), 6.78 (d, J = 8.6 Hz, 2 H, OCH2-
ArOCH3), 4.62 (ddt, J = 10.4, 7.0, 3.3 Hz, 1 H, PhCH2CHN–),
4.46 (dd, J = 17.6, 10.4 Hz, 2 H, –OCH2ArOCH3), 4.10 (m, 3 H,
–CHOH, PhCH2CHCH2O–), 3.80 (d, J = 3.6 Hz, 1 H, –CHOCH2-
ArOCH3), 3.70 (s, 3 H, –OCH2ArOCH3), 3.52 (m, 1 H, –CHOH),
3.21 (dd, J = 13.4, 3.2 Hz, 1 H, PhCH2CHCH2O–), 3.04 (dd, J =
6.2, 3.5 Hz, 2 H, –COCH2CH), 2.69 (dd, J = 13.4, 9.6 Hz, 1 H,
PhCH2CHCH2O–), 1.84 (quintet of d, J = 7.1, 2.6 Hz, 1 H,
OHCHCHCH3), 1.66 (m, 1 H, –CH2CH3), 1.45 (m, 1 H,
–CH2CH3), 0.86 (m, 6 H, –CH2CH3, –CHCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.1, 159.1, 153.5, 135.2, 130.4, 129.4,
129.4, 128.9, 127.2, 113.7, 82.5, 71.4, 70.6, 66.2, 55.2, 41.3, 39.3,
37.8, 23.0, 11.6, 10.7 ppm. [α]2D8.0 = –76.5 (c = 1.92, CHCl3). MS
(EI): m/z (%) = 455 [M+], 302, 249, 219, 178, 137, 121 (100), 86,
69. HRMS: m/z calcd. for C26H33NO6: 455.2308, found 455.2308.
To a solution of the TBS-protected compound (381 mg, 0.65 mmol)
as described above in diethyl ether (10 mL) was added distilled
water (21 µL, 1.21 mmol). After the solution was cooled to 0 °C,
lithium borohydride (810 µL of a 2.0  solution in THF,
1.62 mmol) was added slowly with stirring. After 10 min, the tem-
perature of the solution was raised to room temperature, and the
resulting solution was stirred for additional 1 h. The reaction was
terminated with addition of aqueous NaOH solution (1.0 ,
15 mL) and extracted with diethyl ether (3ϫ10 mL). After the or-
ganic layer was washed with saturated sodium chloride solution
(15 mL), the ethereal solution was dried (MgSO4) and concen-
trated. Purification of the residue by flash chromatography (hex-
ane/EtOAc, 7:1) provided the desired alcohol compound as a color-
less liquid (250 mg, 94%). IR (film): ν = 3429, 2955, 1612, 1514,
˜
1
1461, 1249, 1060 cm–1. H NMR (300 MHz, CDCl3): δ = 7.15 (m.
2 H, ArH), 6.77 (m, 2 H, ArH), 4.42 (d, J = 11.1 Hz, 1 H, –CO-
CH2Ar), 4.26 (d, J = 11.1 Hz, 1 H, –COCH2Ar), 3.76 (q, J =
5.8 Hz, 1 H, –CH2CHCHCH3), 3.70 (s, 3 H, –ArOCH3), 3.63–3.57
(m, 2 H, HOCH2–), 3.29 (m, 1 H, –HCCHCH2), 1.91 (s, 1 H,
–OH), 1.72 (m, 2 H, OHCH2 CH2 –), 1.68–1.42 (m, 3 H,
–CH2CH3, –CHCHCH3), 0.84 (d, J = 7.1 Hz, 3 H, –CHCHCH3),
0.81 (t, J = 7.2 Hz, 3 H, –CH2CH3), 0.81 [s, 9 H, –Si(CH3)2C-
(CH3)3], 0.00 [d, J = 9.5 Hz, 6 H, Si(CH3)2C(CH3)3] ppm. 13C
NMR (75 MHz, CDCl3): δ = 159.7, 131.9, 129.9, 114.4, 80.6, 73.6,
71.7, 61.0, 56.0, 40.8, 36.3, 26.6, 24.7, 18.7, 11.3, 10.8, –3.7, –3.7
ppm. [α]2D3.4 = –23.5 (c = 1.75, CHCl3). MS (EI): m/z (%) = 396
[M+], 260, 201, 189, 145, 137, 122 (100), 89, 75, 57. HRMS: m/z
calcd. for C22H40O4Si: 396.2696, found 396.2693.
18b: IR (film): ν = 3459, 3054, 2926, 2852, 1782, 1695, 1612, 1514,
˜
1
1457, 1384 cm–1. H NMR (300 MHz, CDCl3): δ = 7.29–7.12 (m,
7 H, PhCH2CHN–, –OCH2ArOCH3), 6.78 (d, J = 8.6 Hz, 2 H,
–OCH2 ArOCH3 ), 4.60 (ddt, J = 10.6, 6.8, 3.2 Hz, 1 H,
PhCH2CHN–), 4.49 (d, J = 11.1 Hz, 1 H, –OCH2ArOCH3) 4.31
(d, J = 11.1 Hz, 1 H, –OCH2ArOCH3), 4.21 (br. t, J = 4.3 Hz, 1
H, –CHOH), 4.11 (m, 2 H, PhCH2CHCH2O –), 3.71 (s, 3 H,
–OCH2ArOCH3), 3.42 (m, 1 H, –CHOCH2ArOCH3), 3.32 (s, 1
H, –CHOH), 3.23 (dd, J = 13.4, 3.2 Hz, 1 H, –PhCH2CHCH2-
O–), 3.10 (dd, J = 16.8, 9.2 Hz, 1 H, COCH2CH), 2.84 (dd, J =
16.7, 3.3 Hz, 1 H, –COCH2CH), 2.68 (dd, J = 13.4, 9.6 Hz, 1 H,
PhCH2CHCH2O–), 1.73 (m, 2 H, –OHCHCHCH3, –CH2CH3),
1.50 (m, 1 H, –CH2CH3), 0.95 (d, J = 7.1 Hz, 3 H, –CH CH3), 0.8
(t, J = 7.5 Hz, 3 H, –CH2CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 172.4, 159.1, 153.4, 135.2, 130.6, 129.4, 128.9, 127.3, 113.8,
83.5, 70.7, 70.6, 66.2, 55.2, 55.1, 41.0, 39.1, 37.7, 23.1, 10.0, 7.4
ppm. [α]2D0.9 = –54.1 (c = 1.23, CHCl3). MS (EI): m/z (%) = 455
[M+], 301, 248, 219, 178, 137, 121 (100), 86, 77, 65. HRMS: m/z
calcd. for C26H33NO6: 455.2308, found 455.2304.
The alcohol (250 mg, 0.63 mmol) obtained as described above was
dissolved in DMF (5 mL). To this solution was added a solution of
imidazole (61 mg, 0.90 mmol) and tert-butyldimethylsilyl chloride
(118 mg, 0.78 mmol) in DMF (2 mL) at 0 °C under nitrogen. After
it was stirred for 10 min at 0 °C, the solution was warmed to room
temperature and stirred for additional 2 h at room temperature.
After the reaction was completed, aqueous saturated NH4Cl
(3S,4S,5R)-1,3-Bis(tert-butyldimethylsilyloxy)-4-methylheptan-5-ol (10 mL) was added and the mixture was extracted with CH2Cl2
(19a): 2,6-Lutidine (19 µL, 0.17 mmol) and TBSOTf (38 µL,
0.17 mmol) was added to a solution of 18a (50.0 mg, 0.11 mmol)
in CH2Cl2 (5 mL) at 0 °C. The resulting solution was stirred at 0 °C
for 1 h. The reaction was terminated by addition of NaHNO3
(5 mL) and extracted with CH2Cl2 (3ϫ10 mL). The organic layer
was separated, dried (MgSO4), and concentrated. Purification of
the residue by flash chromatography (hexane/EtOAc, 7:1) offered
the desired TBS-protected compound (51 mg, 82%) as a colorless
(3ϫ20 mL). The organic layer was separated, dried (MgSO4), and
concentrated. Purification of the residue by flash chromatography
(hexane/EtOAc, 20:1) offered the desired compound (305 mg, 95%)
as a colorless oil. IR (film): ν = 2954, 1614, 1587, 1513, 1462, 1388,
˜
1
1360 cm–1. H NMR (300 MHz, CDCl3): δ = 7.30 (m, 2 H, ArH),
6.88 (m, 2 H, ArH), 4.53 (d, J = 10.9 Hz, 1 H, –COCH2Ar), 4.26
( d , J = 1 0 . 9 H z , 1 H , – C O C H 2 A r ) , 3 . 9 0 ( m , 1 H ,
–CH2CHCHCH3), 3.81 (s, 3 H, –ArOCH3), 3.66 (m, 2 H,
TBSOCH2CH2–), 3.45 (q, J = 5.7 Hz, 1 H, –HCCHCH2–), 1.86–
liquid. IR (film): ν = 2958, 1784, 1699, 1513, 1462, 1384, 1248,
˜
1198 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.20 (m, 5 H, 1.60 (m, 5 H, –CH2CH3, –CHCHCH3 TBSOCH2CH2CH2–), 0.98
PhCH2CHN–), 7.11 (d, J = 7.9 Hz, 2 H, –OCH2ArOCH3), 6.78 (d,
(d, J = 6.9 Hz, 3 H, –CHCHCH3), 0.95 (t, J = 7.3 Hz, 3 H,
Eur. J. Org. Chem. 2007, 3369–3379
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3377

H.-Y. Kang et al.
–CH2CH3), 0.94 [s, 9 H, –Si(CH3)2C(CH3)3], 0.93 [s, 9 H, –Si- BrCHCH3), 1.65 (m, 3 H, CH2CH3, CHCH3), 0.98 (d, J = 6.9 Hz,
FULL PAPER
(CH3)2C(CH3)3], 0.07 [s, 6 H, –Si(CH3)2C(CH3)3], 0.06 [s, 6 H,
–Si(CH3)2C(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ = 159.0,
131.3, 129.2, 129.0, 128.9, 113.6, 80.3, 71.2, 70.5, 60.0, 55.1, 40.6,
3 H, CHCH3), 0.90 [m, 12 H, CH2CH3, SiC(CH3)3], 0.09 (s, 3 H,
SiCH3), 0.07 (s, 3 H, SiCH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 170.4, 72.3, 60.1, 41.3, 41.1, 36.2, 26.5, 26.2, 22.2, 18.6, 10.9,
37.5, 25.9, 25.9, 25.7, 24.0, 18.2, 18.1, 10.1, 9.6, –3.0, –4.2, –4.4, 10.5, –3.75, –3.85 ppm. [α]2D4.4 = –0.80 (c = 1.08, CHCl3). MS (EI):
–5.3 ppm. [α]2D3.9 = –21.85 (c = 1.33, CHCl3). MS (EI): m/z (%) =
510 [M+], 331, 321, 303, 242, 218, 185, 173, 147, 133, 121 (100),
101, 89, 73, 57. HRMS: m/z calcd. for C28H54O4Si2: 510.3561,
found 510.3578.
m/z (%) = 410 [M+], 213, 201, 189, 173, 145, 127 (100), 109, 89, 75,
55. HRMS: m/z calcd. for C17H35BrO4Si: 410.1488, found
410.1500.
The alcohol (145 mg, 0.35 mmol) obtained above was dissolved in
CH2Cl2 (2 mL). To this solution was added Dess–Martin
periodinane (DMP) (179 mg, 0.42 mmol) and stirred for 30 min at
room temperature. After the reaction was completed, aqueous satu-
rated NaHCO3 (5 mL) was added and mixture was extracted with
CH2Cl2 (3 ϫ 10 mL). The organic layer was separated, dried
(MgSO4), and concentrated. Purification by flash chromatography
(hexane/EtOAc, 7:1) offered the desired aldehyde 20a (131 mg,
91%) as a yellow liquid. 1H NMR (300 MHz, CDCl3): δ = 9.77 [m,
1 H, C(=O)H], 5.02 (m, 1 H, CHCH2CH3), 4.36 [m, 1 H, C(=O)
The compound (305 mg, 0.60 mmol) obtained was dissolved in a
solution of CH2Cl2 and pH 7 buffer solution (10:1)(11 mL). To this
solution dichlorodicyanoquinone (DDQ) (198 mg, 0.87 mmol) was
added at 0 °C. The resulting solution was stirred at 0 °C for 1 h.
After filtration through the pad of Celite with CH2Cl2 (3ϫ10 mL),
the solution was concentrated. Purification by flash chromatog-
raphy (hexane/EtOAc, 9:1) gave the desired alcohol 19a (173 mg,
74%) as a colorless liquid. IR (film): ν = 3438, 2955, 1471, 1389,
˜
1360, 1256 cm–1. 1H NMR (300 MHz, CDCl3): δ = 4.00 (td, J =
6.0, 3.0 Hz, 1 H, CHOH), 3.64 (m, 2 H, CH2OSi) ppm. 3.58 (td, 1 CHBr], 4.15 (m, 1 H, CHOSi), 2.59 (m, 2 H, CH2CHOSi), 1.86
H, J = 5.9, 3.0 Hz, CHOSi), 2.66 (br., 1 H, CHOH), 1.72 (q, 2 H, (m, 1 H, CHCH3), 1.80 (dd, J = 6.9, 1.3 Hz, 3 H, BrCHCH3), 1.64
J = 6.3 Hz, CH2CH2OSi), 1.59 (m, 1 H, CHCH3), 1.38–1.52 (m, 2 (m, 2 H, CH2CH3), 0.95 (d, J = 7.0 Hz, 3 H, BrCHCH3), 0.85–
H, CH2CH3), 0.90 (t, 3 H, J = 7.4 Hz, CHCH3), 0.86 [s, 21 H,
SiC(CH3)3, SiC(CH3)3, CHCH3], 0.06 [s, 6 H, Si(CH3)2], 0.00 [s, 6
H, Si(CH3)2]. 13C NMR (75 MHz, CDCl3): δ = 76.9, 75.4, 60.7,
40.2, 38.0, 28.6, 26.5, 18.8, 18.6, 11.1, 6.93, –3.20, –3.97, –4.82 ppm.
[α]2D5.5 = –12.94 (c = 1.48, CHCl3). MS (EI): m/z (%) = 390 [M+],
333, 303, 263, 241, 201, 189, 171, 147, 133, 109, 89, 73, 59. HRMS:
m/z calcd. for C20H46O3Si2: 390.2986, found 390.2987.
0.89 [m, 12 H, CH2CH3, SiC(CH3)3], 0.06 (s, 3 H, SiCH3), 0.02 (s,
3 H, SiCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 202, 170, 77.1,
69.7, 48.8, 42.5, 41.0, 26.4, 26.2, 22.2, 18.6, 10.9, 10.5, –3.82, –3.92
ppm.
(6S,7S,8R)-6-(tert-Butyldimethylsilyloxy)-8-ethyl-4-hydroxy-3,7-di-
methyl-1-oxacyclooctan-2-one (21a): Diiodomethane (51 µL,
0.64 mmol) was added to a mixture of samarium (powder, 105 mg,
0.70 mmol) in THF (3 mL) at room temperature under nitrogen.
Samarium(II) iodide was obtained as a blue-colored solution which
was used after stirring for 2 h. After the solution was cooled to
–78 °C, a solution of the aldehyde 20a (130 mg, 0.32 mmol) in THF
(2 mL) was added under nitrogen. After the solution was stirred
for 1 h at –78 °C, it was warmed to room temperature and 0.1 
HCl (5 mL) was added. The mixture was extracted with diethyl
ether (3ϫ20 mL). After the organic layer was washed with satu-
rated sodium thiosulfate solution (15 mL) and saturated sodium
chloride solution (15 mL), the ethereal solution was dried (MgSO4)
and concentrated. Purification of the residue by flash chromatog-
raphy (hexane/EtOAc, 3:1) provided the desired lactone 21a as a
(1R,2S,3S)-3-(tert-Butyldimethylsilyloxy)-1-ethyl-2-methyl-5-oxo-
pentyl 2-Bromopropanoate (20a): 2-bromopropionic acid (111 µL,
1.23 mmol) and DMAP (40 mg, 0.33 mmol) was added to a solu-
tion of 19a (160 mg, 0.41 mmol) in CH2Cl2 (5 mL) at room tem-
perature. After the solution was cooled to 0 °C, N,N-dicyclohex-
ylcarbodiimide (93 mg, 0.45 mmol) was added. The resulting solu-
tion was stirred for 5 min at 0 °C before it was warmed to room
temperature. After additional stirring for 30 min at room tempera-
ture, the precipitate was filtered. The filtrate was concentrated and
purified by flash chromatography (hexane/EtOAc, 10:1). The de-
sired bromoester was obtained as a colorless liquid (210 mg, 97%).
IR (film): ν = 2928, 2857, 1737, 1471, 1387, 1256, 1222 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 5.04 [m, 1 H, CHOC(=O)], 4.33 (m, yellow liquid [a 7:1 mixture of diastereomers; major compound: Rf
1 H, BrCHCH3), 3.82 (m, 1 H, CHOSi), 3.60 (m, 2 H, CH2OSi), = 0.24 (hexane/EtOAc, 1:1; 66 mg, 63%), minor compound: Rf =
1.84 (m, 1 H, CHCH3), 1.79 (d, J = 6.9 Hz, 3 H, BrCHCH3), 1.62 0.15 (hexane/EtOAc, 1:1; 9.4 mg, 9.0%)]. The following data were
(m, 4 H, CH2CH3, CH2CHOSi), 0.86–0.91 [m, 24 H, CHCH3,
obtained from the major compound. 1H NMR (500 MHz, CDCl3):
CH2CH3, SiC(CH3)3, SiC(CH3)3], 0.03 (s, 3 H, SiCH3), 0.01 (s, 3 δ = 4.87 [dd, J = 8.4, 5.3 Hz, 1 H, CHOC(=O)], 4.04 (dd, J = 9.1,
H, SiCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.0, 78.3, 70.6, 4.7 Hz, 1 H, CHOSi), 3.57 (m, 1 H, CHOH), 3.44 (br., 1 H,
59.9, 41.3, 41.1, 26.2, 25.9, 22.1, 18.5, 10.6, 10.0, –4.02, –4.99 ppm.
[α]2D4.3 = –7.13 (c = 1.73, CHCl3). MS (EI): m/z (%) = 524 [M+],
337, 315, 303, 287, 253, 241, 211, 189, 171, 145, 109, 89, 75 (100),
CHOH), 3.15 [dq, J = 9.4, 6.3 Hz, 1 H, C(=O)CHCH3], 2.15 (ddd,
J = 15.9, 9.2, 3.5 Hz, 1 H, SiOCHCHCH3), 1.89 (m, 1 H, one of
CH2CH3), 1.84 (m, 2 H, CH2CHOH), 1.49 (m, 1 H, one of
59. HRMS: m/z calcd. for C23H49BrO4Si2: 524.2353, found CH2CH3), 1.34 [d, J = 6.3 Hz, 3 H, C(=O)CHCH3], 0.96 (m, 3 H,
524.2334.
SiOCHCHCH3), 0.92 [s, 9 H, SiC(CH3)3], 0.89 (m, 3 H, CH2CH3),
0.12 (s, 3 H, SiCH3), 0.10 (s, 3 H, SiCH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 176.0, 78.8, 76.9, 76.0, 44.5, 42.6, 27.4, 26.4, 18.5,
16.1, 11.5, 10.8, –4.1, –4.3 ppm. MS (EI): m/z (%) = 330 [M+], 287,
257, 213, 201, 173, 159, 139, 115 (100), 99, 85, 75, 57. HRMS: m/z
calcd. for C17H34O4Si: 330.2226, found 330.2244.
The bromoester (210 mg, 0.40 mmol) obtained was dissolved in
MeOH (2 mL). To this solution -10-Camphorsulfonic acid
(19 mg, 0.08 mmol) was added. The resulting solution was stirred
at 0 °C for 1 h. The reaction was terminated by addition of Et3N
(56 µL, 0.42 mmol). After the solution was concentrated, purifica-
tion of the residue by flash chromatography (hexane/EtOAc, 5:1)
gave the desired primary alcohol (145 mg, 88%) as a colorless li-
(6S,7S,8R)-6-(tert-Butyldimethylsilyloxy)-8-ethyl-3,7-dimethyl-1-ox-
acyclooctane-2,4-dione (22a): Lactone 21a (55 mg, 0.17 mmol) ob-
tained as described in the previous procedure (a 7:1 mixture of
quid. IR (film): ν = 3431, 2928, 1737, 1257, 1163, 1060 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 5.02 [m, 1 H, CHOC(=O)], 4.36 (m, diastereomers) was dissolved in CH2Cl2 (2 mL). To this solution
1 H, BrCHCH3), 3.82 (m, 1 H, CHOSi), 3.73 (m, 2 H, CH2OH),
1.93 (m, 2 H, CH2CH2CHOSi), 1.82 (dd, J = 7.0, 1.9 Hz, 3 H,
was added Dess–Martin periodinane (DMP) (141 mg, 0.33 mmol).
The resulting solution was stirred for 30 min at room temperature.
3378
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3369–3379

Synthesis of the Tetraketide Lactones
FULL PAPER
A. L. Cutter, P. F. Leadlay, J. Chem. Soc., Chem. Commun.
1995, 1517–1518; b) K. E. H. Wiesmann, J. Cortés, M. J. B.
Brown, A. L. Cutter, J. Staunton, P. F. Leadlay, Chem. Biol.
1995, 2, 583–589; c) R. Piper, S. Ebert-Khosla, D. E. Cane, C.
Khosla, Biochemistry 1996, 35, 2054–2060; d) G. Luo, R.
Pieper, A. Rosa, C. Khosla, D. E. Cane, Bioorg. Med. Chem.
1996, 4, 995–999; e) . A. L. Wilkinson, U. Hanefeld, B. Wilkin-
son, P. F. Leadlay, J. Staunton, Tetrahedron Lett. 1998, 39,
9827–9830.
B. J. Beck, Y. J. Yoon, K. A. Reynolds, D. H. Sherman, Chem.
Biol. 2002, 9, 575–583.
S.-J. Kim, H.-Y. Kang, D. H. Sherman, Synthesis 2001, 1790–
1793.
After the reaction was completed, aqueous saturated NaHCO3
(5 mL) was added and mixture was extracted with CH2Cl2
(3ϫ10 mL). The organic layer was separated, dried (MgSO4), and
concentrated. Purification of the residue by flash chromatography
(hexane/EtOAc, 7:1) offered the desired compound 22a (48 mg,
88%) as a yellow liquid (an 8:1 mixture of diastereomers). The
1
major compound showed the following spectroscopic behavior. H
NMR (300 MHz, CDCl3): δ = 5.04 [ddd, J = 8.6, 4.6, 4.4 Hz, 1 H,
CHOC(=O)], 4.05 (m, 1 H, CHOSi), 3.49 [q, J = 6.7 Hz, 1 H, C(O)-
CHCH3], 3.23 [d, J = 11.8 Hz, 1 H, one of CH2C(=O)], 2.71 [t, J
= 11.2 Hz, 1 H, one of CH2C(=O)], 1.89 (m, 1 H, SiOCHCHCH3),
1.55–1.72 (m, 2 H, CH2CH3), 1.19 [d, J = 6.7 Hz, 3 H, C(=O)-
CHCH3], 1.02 (t, J = 7.4 Hz, 3 H, CH2CH3), 0.94 (d, J = 4.9 Hz,
3 H, SiOCCHCH3), 0.81 [s, 9 H, SiC(CH3)3], 0.03 (s, 3 H, SiCH3),
0.00 (s, 3 H, SiCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 202,
172. 80.5, 71.7, 57.8, 45.5, 42.4, 26.2, 25.1, 18.6, 11.5, 11.1, 10.1,
–4.58, –4.64 ppm.
[8]
[9]
[10]
[11]
[12]
H.-H. Yang, E.-S. Kim, Y. J. Yoon, H.-Y. Kang, Bull. Korean
Chem. Soc. 2006, 27, 473–474.
B. J. Beck, C. C. Aldrich, R. A. Fecik, K. A. Reynolds, D. H.
Sherman, J. Am. Chem. Soc. 2003, 125, 12551–12557.
a) G. A. Molander, J. B. Etter, L. S. Harring, P. Thorel, J. Am.
Chem. Soc. 1991, 113, 8036–8045; b) H. B. Kagan, J. L. Namy,
P. Girard, Tetrahedron 1981, 37, 175–180; c) T. Mukaiyama, I.
Shina, H. Iwadare, M. Saitoh, T. Nishimura, N. Ohkawa, H.
Satoh, K. Nishimura, Y. Tani, M. Hasegawa, K. Yamada, K.
Saitoh, Chem. Eur. J. 1999, 5, 121–161; d) S. Inoue, Y. Iwabu-
chi, H. Irie, S. Hatakeyama, Synlett 1998, 735–736; e) T. Take-
mura, Y. Nishii, S. Takahashi, J. Kobayashi, T. Nakata, Tetra-
hedron 2002, 58, 6359–6365; f) P. P. Reddy, K. F. Yen, B. J.
Uang, J. Org. Chem. 2002, 67, 1034–1035; g) M. Inoue, M.
Sasaki, K. Tachibana, J. Org. Chem. 1999, 64, 9416–9429; h)
M. Inoue, M. Sasaki, K. Tachibana, Tetrahedron 1999, 55,
10949–10970; i) M. Inoue, M. Sasaki, K. Tachibana, Tetrahe-
dron Lett. 1997, 38, 1611–1614; j) S. Ichikawa, S. Shuto, N.
Minakawa, A. Matsuda, J. Org. Chem. 1997, 62, 1368–1375; k)
M. Inoue, M. Sasaki, K. Tachibana, Angew. Chem. Int. Ed.
Engl. 1998, 37, 965–969; l) M. Inoue, M. Tachibana, K. Sasaki,
J. Org. Chem. 1999, 64, 9416–9429.
(6S)-4-Hydroxy-6-[(1S,2R)-2-hydroxy-1-methylbutyl]-3-methyl-5,6-
dihydro-2H-pyran-2-one (2a): A solution of lactone 22a (41 mg,
0.12 mmol) as obtained previously (an 8:1 mixture of dia-
stereomers) in HF/CH3CN [48% HF/CH3CN, 1:19 (v/v)] (1 mL)
was stirred for 1 h at room temperature. The reaction was termin-
ated by addition of solid CaCO3 (30 mg). After the mixture was
filtered with aid of Celite and washed by ether (3ϫ10 mL), the
filtrate was concentrated. Purification by flash chromatography
(hexane/EtOAc, 1:1 to 1:2) provided the desired lactone 2a
(15.5 mg, 58%) as a white solid. Spectroscopic data were matched
with those obtained previously.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedure for compounds 15b–17b, 23a,
19b–26b, 28–34.
[13] a) S.-i. Fukuzawa, H. Matsuzawa, S.-i. Yoshimitsu, J. Org.
Chem. 2000, 65, 1702–1706; b) S.-i. Fukuzawa, M. Tatsuzawa,
K. Hirano, Tetrahedron Lett. 1998, 39, 6899–6900.
[14] We first tried the protection of the free hydroxy group of 14a.
However, we were not able to protect the free secondary hy-
droxy group with the PMB group. Therefore, we have decided
to use the aldehyde 13b for the asymmetric Reformatsky reac-
tion to prepare 3.
[15] For reported examples for translactonization by deprotection
of the silyl groups, see: a) P. T. O’Sullivan, W. Buhr, M. A. M.
Fuhry, J. R. Harrison, J. E. Davies, N. Feeder, D. R. Marshall,
J. W. Burton, A. B. Holmes, J. Am. Chem. Soc. 2004, 126,
2194–2207; b) M. S. Congreve, A. B. Holmes, A. B. Hughes,
M. G. Looney, J. Am. Chem. Soc. 1993, 115, 5815–5816.
[16] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–
2925.
Acknowledgments
This work is supported by the Korea Research Foundation Grant
(KRF-2004-015-C00267).
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Received: March 22, 2007
Published Online: May 11, 2007
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