A Non-Aldol Preparation of Enantiopure Propionate-Derived Motifs with the Assistance of Chiral Sulfoxides: Application to a Convergent Synthesis of the Lactone Core of Octalactins

Article abstract of DOI:10.1002/ejoc.201500527

Propionate-derived fragments were prepared by a non-aldol method using chiral sulfoxide chemistry. A methacrylate ester, assisted by a chiral sulfoxide as an auxiliary agent, was easily transformed into an optically pure allylic alcohol, which was then su

Full text of DOI:10.1002/ejoc.201500527

FULL PAPER
DOI: 10.1002/ejoc.201500527
A Non-Aldol Preparation of Enantiopure Propionate-Derived Motifs with the
Assistance of Chiral Sulfoxides: Application to a Convergent Synthesis of the
Lactone Core of Octalactins
Claude Bauder*[a]
Keywords: Natural products / Asymmetric synthesis / Synthesis design / Chiral auxiliaries / Macrocycles
Propionate-derived fragments were prepared by a non-aldol
method using chiral sulfoxide chemistry. A methacrylate
ester, assisted by a chiral sulfoxide as an auxiliary agent, was
easily transformed into an optically pure allylic alcohol,
Houk, taking into account of the various A(1,2) allylic strains.
Thus, the the two adjacent stereocentres in the enantiopure
allylic alcohol were installed with an anti configuration. As
an application of this work, we have described an enantiose-
which was then subjected to diastereoselective hydrobor- lective synthesis of the unusual eight-membered lactone ring
ation with the bulky dialkylborane 9-BBN. The diastereofa- of the octalactins. Two propionate-derived fragments were
cial selectivity was governed by a preferred spatial arrange- coupled to give precursor 18, which was subjected to Yamag-
ment of a staggered conformation model, as suggested by
uchi’s macrolactonisation to give the required lactone ring.
ration was determined by a first total synthesis[2a] by
Buszek et al.; Clardy et al.[2b] confirmed the absolute con-
figuration through a total synthesis of the enantiomers of
the natural octalactins A and B. Since then, six other total
syntheses of octalactin A and/or B have been reported,
using different approaches,[3] and many other formal syn-
theses of the octalactins have been described, mainly focus-
sing on the lactone ring.[4] The fascinating synthesis of me-
dium-ring lactones, which are found in many natural prod-
ucts, has proved to be a challenge.[5]
The highly functionalised framework of the octalactins
prompted us to explore a new approach for the synthesis of
this peculiar structure through sulfoxide chemistry. As a
part of our studies on the development of sulfoxide chemis-
try, we report in this paper a straightforward synthesis of
enantiopure diol 4 (as well as its enantiomer) in a two-step
reduction reaction from unsaturated β-keto sulfoxide 2
(Figure 2). These two successive reductions allowed control
of the newly formed stereocentres, leading to an anti config-
uration between the alcohol functionality and the adjacent
methyl group.
Introduction
Octalactins A and B (Figure 1) are marine metabolites
isolated from a Streptomyces sp.,[1a] and both compounds
contain an unusual eight-membered lactone ring. Octalac-
tin A showed significant cytotoxicity in tests towards B-16-
F10 murine melanoma and HCT-116 human colon tumor
cell lines, whereas octalactin B showed no activity in the
same bioassays.[1a–1c] The complex structure of octalactin
A, as well as its therapeutic potential, makes it an attractive
target for organic synthesis. The relative configuration of
octalactones A and B were determined by X-ray analysis
by Fenical and Clardy.[1a] Thereafter, their absolute configu-
Figure 1. Targeted enantiopure lactone 19 of octalactins; TBDMS
= tert-butyldimethylsilyl; PMB = para-methoxybenzyl.
[a] Université de Strasbourg, Institut de Chimie,
Laboratoire de Chimie Inorganique Moléculaire et Catalyse,
UMR 7177-CNRS,
4 rue Blaise Pascal, 67070 Strasbourg CEDEX, France
E-mail: cbauder@unistra.fr
Figure 2. Synthesis of the two enantiomers 4 and ent-4; DiBAL-H
= diisobutylaluminium hydride; 9-BBN = 9-borabicyclo[3.3.1]-
nonane.
https://www.unistra.fr/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500527.
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Eur. J. Org. Chem. 2015, 5402–5413

Convergent Synthesis of the Lactone Core of Octalactins
These diols (4 and ent-4) could be regarded as a propion-
ate derivatives after desulfination, and consequently can be
viewed as building blocks for the synthesis of natural prod-
ucts. We have applied this process in the synthesis of the
lactone moiety (i.e., 19) of octalactin (Figure 1).
Scheme 1. Reagents and conditions: (a) LDA (lithium diisoprop-
ylamide), THF, ethyl methacrylate, –75 °C, 2 (91%); (b) DiBAL-H,
THF, –78 °C, 3 (67.7%); (c) 9-BBN, THF, 0 °C to room temp., 4 h,
then H2O2/NaOH, 0 °C to room temp., 3 h, 4 and other isomers
(86%), see text and experimental section for the purification of 4.
Results and Discussion
From a synthetic point of view, the lactone unit of the
octalactins could come from the connection of two prop-
ionate-derived structures followed by a ring closure. Thus,
as shown in Figure 3, we envisaged a Yamaguchi macrolac-
tonisation[6] from seco-acid 18. Thus, we planned the syn-
thesis of propionate-derived precursors 14 and ent-7 that
would be coupled by a Wittig reaction to give (Z)-olefin 18.
The hydroboration of substituted olefins with the bulky
dialkylborane 9-BBN has the advantage of being regioselec-
tive, with the boron atom being installed on the less substi-
tuted carbon of the olefin. Furthermore, considering
Houk’s model for a preferred staggered conformation in
acyclic allylic alcohol systems,[12] the selective diastereofa-
cial approach of boranes is controlled both by steric effects
[A(1,2) and (A1,3) allylic strain][13] and by the allylic ste-
reocentre. For chiral olefin 3, we have two possible repulsive
A(1,2) allylic strains, depending on the orientation of the
substituents on the allylic stereocentre. Consequently, two
favourable conformational transition states TS1 and TS2
can be proposed to minimise repulsive interactions (Fig-
ure 4), with the OH group adopting an outside or inside
position, respectively.
Figure 3. Route for the synthesis of lactone 19 via seco-acid 18;
PMP = para-methoxyphenyl.
For the stereoselective synthesis of propionate-derived
units 14 and ent-7, we aimed to use a chiral auxiliary[7] ap-
proach based on sulfoxide chemistry, which has been exten-
sively developed in our laboratory. By using such a non-
aldol approach, enolate species would be avoided. It is
known that the diastereoselective hydroboration[8] of op-
tically active allylic alcohols gives convenient access to en-
antiomerically pure propionic derivatives. To this end, we
prepared nonracemic β-keto sulfoxide 2 from the lithium
anion of methyl sulfoxide 1[9] and ethyl methacrylate.[10]
Compound 2 was then subjected to stereoselective re-
duction[11] with DiBAL-H to cleanly give pure alcohol 3 in
Figure 4. Illustration of the staggered transition states TS1 and TS2
in hydroboration with 9-BBN of enantiopure allylic alcohol 3.
68% yield as a single diastereomer (Scheme 1). This result
As has been previously proposed,[8c,8d,12] the antiperi-
1
was confirmed by H NMR spectroscopic analysis. Com- planar hydroboration will then occur on the face opposite
pound 3 was then subjected to hydroboration with 9-BBN to the largest group on the adjacent chiral centre. It follows
(9-borabicyclo[3.3.1]nonane) in THF, followed by oxidation that TS1 is more favourable than TS2, as the latter transi-
with H2O2/NaOH to give predominantly diol 4, among tion state is strongly destabilised by a nonbonding interac-
other isomers (86.5%, dr = 90:10), with an anti configura- tion between the large substituents of the alkylborane 9-
tion for the propionate-derived moiety. The anti relation- BBN and the OH group. This implies that the hydrobor-
ship was determined by full NMR spectroscopic analysis ation of 3 should lead to 4 with good stereoselectivity for
(more specifically an nOe experiment) of the corresponding an anti configuration, bearing in mind the already fixed
purified acetonide (i.e., 4a). Moreover, the absolute configu- stereochemistry of the alcohol group.
ration of compounds 3 and 4 was confirmed by single-
Unfortunately, at this stage, diol 4 could not easily be
crystal X-ray analysis of the recrystallised products (see separated from the other possible isomeric products by
Supporting Information).
chromatography, due to their close Rf values. To avoid this
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C. Bauder
FULL PAPER
problematic purification, it was necessary to subject the
crude diol to acetonide-formation conditions [DMP (2,2-
dimethoxypropane), Me2CO, pTsOH]. The major product
(i.e., 4a; the acetonide derivative of 4) could then be readily
separated from the other possible isomers. The required
pure diol (i.e., 4) was then obtained smoothly upon depro-
tection of 4a with Amberlyst 15 in MeOH (69% over three
steps starting from allylic alcohol 3). When the hydrobor-
ation of allylic alcohol 3 was carried out on a large (grams)
scale, a simple crystallisation (from EtOAc) of the crude 4
could be carried out to avoid the formation of acetonide
4a. But this resulted in a lower yield of the final product.
Thereafter, diol 4 was sequentially subjected to a regiose-
lective silylation and acetylation to give protected sulfoxide
6 (Scheme 2). Compound 6 in turn was transformed into
aldehyde 7 by a mild one-pot Pummerer reaction, using
TFAA (trifluoroacetic acid ahydride) as activating agent,
followed by treatment with aqueous NaHCO3.[14] Sub-
sequently, aldehyde 7 was subjected to a Wittig reaction
with triphenylphosphonium bromide to give olefin 8 in
good yield (91%). Saponification gave allylic alcohol 9, and
a subsequent classical hydroboration with 9-BBN followed
by treatment with sodium hydroxide and H2O2 gave diol 10
in a nearly quantitative yield.
Scheme 3. Reagents and conditions: (a) 9-BBN, THF, NaOAc,
H2O2, A and B (41%, when treatment with NaOAc for 4 h), or
only A (38%, when treatment with NaOAc for 1.5 h); (b) MeOH,
K2CO3, 10 (47.5%).
The next reactions to accomplish the synthesis of the de-
sired phosphonium salt (i.e., 14) are shown in Scheme 4.
Diol 10 was converted in good yield (91%) into the benzyl-
idene acetal 11, whose absolute configuration was fully de-
termined on the basis of nOe experiments. Alcohol 12[16]
was synthesised by TBAF (tetrabutylammonium fluoride)-
mediated desilylation of 11 in THF at 0 °C. Compound 12
was halogenated by standard methods to give the corre-
sponding iodide (i.e., 13), which, under standard condi-
tions, was then converted into triphenylphosphonium salt
14 as a white solid.
Scheme 4. Reagents and conditions: (a) MeOC6H4CH(OMe)2,
CH2Cl2, CSA (camphorsulfonic acid), room temp., 3 h, 11 (91%);
(b) TBAF, THF, 0 °C to room temp., 3 h, 12 (92%); (c) I2, THF,
PPh3, Imd, 0 °C to room temp., 1 h 45, 13 (91%); (d) MeCN, PPh3,
80 °C for 20 h, 14 (85%).
Next, we had to synthesise enantiopure aldehyde ent-7,
which was isolated after several reaction steps. As shown in
Scheme 5, the synthesis of ent-7 began with methyl p-tolyl
sulfoxide ent-1, following reaction conditions similar to
those described for the synthesis of compound 4 in
Scheme 1.
Scheme 2. Reagents and conditions: (a) TBDMSCl, Imd (imid-
azole), Na2SO4, DMF, room temp., 5 (99%); (b) Ac2O, Et3N, cat.
DMAP (4-dimethylaminopyridine), CH2Cl2, room temp., 6 (92%);
(c) Et3N, TFAA, CH2Cl2, 0 °C for 25 min, then NaHCO3 aq., room
temp., 2 h, 7 (99%); (d) KHMDS (potassium hexamethyldisilaz-
ide), Ph3PMe-Br, THF, 0 °C for 20 min, then aldehyde, room temp.,
2 h, 8 (91%); (e) K2CO3, MeOH, room temp., 50 min, 9 (88%);
(f) 9-BBN, THF, 0 °C to room temp., 6 h, then H2O2/NaOH, 0 °C
to room temp., 2 h, 10 (99%).
Initially, we also attempted to directly convert allylic
acetate 8 into diol 10 by hydroboration under different con-
ditions, using NaOAc[15] as a less drastic base than NaOH.
But each attempt gave a low yield (38–41%) of a mixture
of regioisomers (A and B), resulting from partial migration
of the acetyl group, and also from incomplete conversion
of the starting material (Scheme 3). This mixture was also
deacylated (K2CO3 in MeOH) in low yield (47.5%). Be-
cause of these difficulties, the saponification of 8 was car-
ried out before the hydroboration as described above for a
better overall yield.
Scheme 5. Reagents and conditions: (a) LDA, THF, ethyl meth-
acrylate, –70 °C, ent-2 (99%); (b) DiBAL-H, THF, –78 °C, ent-3
(76 %); (c) 9-BBN, THF, 0 °C to room temp., 3 h, then H2O2/
NaOH, 0 °C to room temp., 4 h, ent-4 and other isomers (71.7%);
(d) TBDMSCl, Imd, Na2SO4, DMF, room temp., ent-5 (92%);
(e) Ac2O, Et3N, cat. DMAP, CH2Cl2, room temp., ent-6 (90%);
(f) Et3N, TFAA, CH2Cl2, 0 °C for 25 min, then NaHCO3 aq., room
temp., 2 h, ent-7 (80%).
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Eur. J. Org. Chem. 2015, 5402–5413

Convergent Synthesis of the Lactone Core of Octalactins
Thus, compound ent-1 was converted into sulfinyl ester respectively, even after 44 h at ambient temperature. The
ent-2, which was then transformed into allylic alcohol ent- secondary alcohol was not affected during this oxidation.
3 by stereoselective reduction (DiBAL-H; de Ͼ 98% ac- It seems that under these oxidation conditions, the over-
cording 1H NMR spectroscopy). Compound ent-3 was oxidation to the carboxylic acid is more complicated in our
1
transformed into pure diol ent-4 (dr = 90:10 according H case.
NMR spectroscopy) by a diastereofacially selective re-
duction (9-BBN). Successive protections of diol ent-4, in-
cluding an initial regioselective silylation (TBDMSCl) of
the primary alcohol and then an acylation, gave ent-6. The
target aldehyde (i.e., ent-7) was formed in 80% yield from
ent-6 by a mild one-pot Pummerer reaction at 0 °C in
dichloromethane in the presence of TFAA, followed by
treatment with aqueous NaHCO3.[14]
Having achieved, using a convenient sulfur chemistry ap-
proach, the synthesis of the two enantiopure propionate-
derived precursors, phosphonium 14 and aldehyde ent-7, we
next planned to use these two precursors in an olefination
coupling reaction with a view to synthesising the lactone
Scheme 7. Reagents and conditions: (a) CH2Cl2, BAIB, TEMPO,
moiety of the octalactins. A Wittig reaction between ylide
derivative 14 and aldehyde ent-7 (Scheme 6) gave, in moder-
ate yield (38%), the desired (Z)-olefin (i.e., 15) after purifi-
cation by silica gel column chromatography. The Z configu-
ration should facilitate the subsequent intramolecular
cyclisation. Although the (E)-olefin was not observed in the
crude product, the side-products could not be identified by
NMR spectroscopic analysis. Despite this, this reaction was
not further optimised.
H2O, room temp. for 44 h, 17 (35%) and 18 (31%); (b) CH2Cl2,
BAIB, TEMPO, room temp. for 48 h, 17 (43.8 %); (c) NaClO2,
NaH2PO4, H2O, tBuOH, amylene, then aldehyde 17, room temp.
for 1 h, 18 (49%); (d) 2,4,6-Cl3PhCOCl, Et3N, PhMe, room temp.
for 5 h, then DMAP cat., PhMe, room temp. for 17 h, 19 (52%).
Based on previous investigations, we also attempted a di-
rect lactonisation of 16 under anhydrous conditions in the
presence of TEMPO/BAIB.[19] It was described that the ini-
tial oxidation of the primary hydroxy group to an aldehyde
would lead to the corresponding hemiacetal. This, in turn,
would lead to the formation of the lactone after prolonged
oxidation. Unfortunately, in our case, we observed only the
formation of aldehyde 17 instead of the expected lactone.
To avoid the formation of a mixture of aldehyde and
acid, it was more successful to adopt a two-step oxidation
sequence followed by Yamaguchi macrolactonisation under
high-dilution conditions (Scheme 7). Consequently, diol 16
was first oxidised under anhydrous TEMPO-mediated con-
ditions to give the corresponding aldehyde (i.e., 17), which
was then oxidised into carboxylic acid 18 under Pinnick’s
conditions.[20] Thereafter, the desired eight-membered ring
(i.e., 19) was obtained in 53% yield from seco-acid 18 by
means of the macrolactonisation procedure described by
Yamaguchi[6,22] using 2,4,6-trichlorobenzoyl chloride and
DMAP. The reduction of the olefin bond of 19 can be en-
visaged according to protocols previously described in the
literature[3a,3b,21] to give the saturated medium ring of natu-
ral octalatins A and B.
Scheme 6. Reagents and conditions: (a) KHMDS, THF, phosphon-
ium 14, 0 °C to room temp., then aldehyde ent-7, –65 °C to room
temp., 15 (38%); (b) DiBAL-H, CH2Cl2, 0 °C for 2 h, 16 (58%).
Olefin 15 was subjected to a regioselective cleavage with
a large excess of DiBAL-H in CH2Cl2, following a slight
modification of Takano’s procedure,[17] to give polyol 16.
An excess of the reducing agent was used in order to reduce
the acetate functionality, but also to cleave the benzylidene
acetal regioselectively at the less hindered site, and in this
way free the primary alcohol while at the same time install-
ing PMB protection onto the secondary alcohol.
Conclusions
As a key intermediate in our synthetic strategy, com-
In summary, we have successfully demonstrated a conve-
pound 16 had to be transformed into seco-acid 18 before nient non-aldol approach for the synthesis of enantiopure
the final macrolactonisation (Scheme 7). We attempted to propionate-derived building blocks using a non-racemic
regioselectively oxidise the terminal alcohol group of 16 to sulfoxide as a chiral auxiliary, and using two successive dia-
give a carboxylic group with TEMPO (2,2,6,6-tetrameth- stereoselective reductions. The stereocontrolled reduction of
ylpiperidinyloxy)/BAIB [(diacetoxyiodo)benzene] in the the prochiral carbonyl group of a methacrylate ester, cou-
presence of water;[18] this led to the isolation of aldehyde pled to a chiral sulfoxide, gave rise to the key intermediate,
17 and the required acid (i.e., 18) in 35 and 31% yields, an enantiopure allylic alcohol (3 or ent-3). This intermedi-
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C. Bauder
FULL PAPER
with diethyl ether (2ϫ 150 mL), and the combined organic layers
were washed with brine (50 mL), dried (MgSO4), filtered, and evap-
orated under reduced pressure to give a yellow liquid. While the
liquid was still hot, hexane (150 to 200 mL) was added until a white
precipitate formed. Crystallisation was carried out at –20 °C. The
solid (containing both menthol and methyl sulfoxide) was collected
by filtration, and then it was dissolved in hot diethyl ether (200 mL)
and hexane (ca. 150 mL). After a few hours at ambient temperature
(20 h), two crops of crystals (17.9 g and 7.3 g) were collected by
filtration. This material was washed with hexane, and dried under
ate was further converted into the corresponding propion-
ate-derived unit by stereoselective hydroboration with 9-
BBN. The efficiency of this approach was well demon-
strated: all of the stereocentres could be easily controlled,
using the chiral sulfoxide as the source of chirality. We
aimed to support our results by the application to the syn-
thesis of a natural product. In this context, we were able to
synthesise polyfunctionalised precursors that could be used
for a convergent synthesis of the medium-ring lactone core
of the octalactins. After connection of the appropriate frag- vacuum to give (+)-(R)-methyl p-tolyl sulfoxide (1; 25.2 g, 68.5%)
as white crystals, m.p. 75 °C. [α]2D0 = +192 (c = 1.02, CHCl3);
ments, a final macrolactonisation of seco-acid 24 was ac-
complished using Yamaguchi’s convenient method. The ap-
[α]2D0 = +149 (c = 0.11, acetone). Pure (+)-(R)-methyl p-tolyl sulfox-
ide could also be obtained by chromatographic purification of the
proach described in this paper could be useful for the syn-
crude yellow oil on silica gel (diethyl ether was used as eluent to
thesis of many other natural products.
remove the menthol, and then EtOAc to isolate the desired product
1
as a white solid). H NMR (300 MHz, CDCl3): δ = 7.54 and 7.33
(AAЈBBЈ, J = 8.1 Hz, Δν = 62.2 Hz, 4 H, pTol), 2.70 (s, 3 H, Me),
2.41 (s, 3 H, Me of pTs) ppm. 13C NMR (75 MHz, CDCl3): δ =
142.4 (Cq arom), 141.5 (Cq arom), 130.0 (CH arom), 123.5 (CH
arom), 43.9 (Me), 21.4 (Me of pTs) ppm.
Experimental Section
General Information: All starting materials and reagents were ob-
tained from commercial suppliers and used as received. All solvents
were purified according to standard methods: THF and diethyl
ether were distilled from Na/benzophenone; toluene was distilled
from Na; CH2Cl2, Et3N, and DMSO were distilled from calcium
hydride. Anhydrous MeCN and DMF were used as obtained from
commercial suppliers. Air- and moisture-sensitive reactions were
carried out in heatgun-dried glassware under argon. Reactions were
monitored by thin-layer chromatography (TLC) with 0.25 mm
Merck precoated silica gel plates (60F-254). Spots were detected
under UV irradiation (254 nm) and/or by staining with acidic ceric
ammonium molybdate, unless otherwise noted. Flash column
chromatography was carried out using silica gel 60 (particle size
0.040–0.063 mm), supplied by Merck, Geduran, packed into a glass
column, yields refer to chromatographically and spectroscopically
pure compounds, unless otherwise stated. All the NMR spectra
(1H, 13C, COSY, NOESY, HMQC, and HSQC) were recorded with
Bruker AV300, AV400, or AV500 spectrometers using an internal
deuterium lock at ambient temperature. Unless otherwise noted,
CDCl3 was used as solvent for all NMR experiments. Multiplicities
are described using the following abbreviations: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br. = broad, and
ABX = ABX system. Chemical shifts are given in ppm, and cou-
pling constants are presented in Hz. 13C NMR spectra were cal-
The preparation of ent-1 followed the same procedure, starting
from (+)-(R)-menthyl p-toluenesulfinate, m.p. 75 °C. [α]2D0 = –187
(c = 1, CHCl3).
(R)-3-Methyl-1-(p-tolylsulfinyl)but-3-en-2-one (2): A solution of
(+)-(R)-methyl p-tolyl sulfoxide (1; 2.90 g, 0.0188 mol) in dry THF
(25 mL) was added by cannula to a stirred solution of LDA
(1.15 equiv.) [freshly prepared from diisopropylamine (3.5 mL,
1.32 equiv.) and nBuLi (in THF; 50 mL, 1.15 equiv.)] at –75 °C.
The mixture was stirred for 45 min at the same temperature, then
a solution of ethyl methacrylate (1.2 mL, 0.51 equiv.) in dry THF
(5 mL) was added to the yellow solution of methyl p-tolyl sulfoxide
anion. The reaction mixture was stirred for 1 h, during which time
the temperature was allowed to reach –40 °C. Then it was carefully
quenched with saturated aqueous NH4Cl solution (20 mL), and di-
luted with water (10 mL) and EtOAc (30 mL). HCl (20% aq.;
20 mL) was added at room temperature until the mixture reached
pH 4, and then the mixture was vigorously stirred for 1 h. The
aqueous layer was extracted with EtOAc (15 mL), and the com-
bined organic extracts were washed with water (3ϫ 40 mL), dried
with Na2SO4, filtered, and concentrated under reduced pressure.
The crude yellow oil was purified by silica gel column chromatog-
raphy (EtOAc/cyclohexane, 7:3) to remove the excess methyl p-tolyl
sulfoxide, and give keto sulfoxide 2 (1.93 g, 91%) as a viscous le-
mon-yellow oil. [α]2D0 = +182.8 (c = 1.4, CHCl3). C12H14O2Si
(222.303): calcd. C 64.83, H 6.35; found C 64.96, H 6.22. 1H NMR
(300 MHz, CDCl3): δ = 7.49 and 7.26 (AAЈBBЈ, J = 8.3 Hz, Δν =
69.7 Hz, 4 H, pTol), 5.90 (q, J4c,Me = 0.9 Hz, 1 H, 4c-H), 5.88 (q,
1
ibrated using the central triplet peak of CDCl3 (δ = 77.0 ppm); H
NMR spectra were calibrated using the residual CHCl3 peak (δ =
7.26 ppm). For NMR assignments, please refer to the atom num-
bering in the schemes. Optical rotations ([α]D) were recorded with
a Polarimeter Model 341 (Perkin–Elmer) at a wavelength of 589 nm
in a 10 cm quartz cuvette, and are reported as follows: [α]2D0, con-
centration (c in g/100 mL), and solvent. Mass spectra (ESI) were
obtained with a microTOF instrument (Bruker Daltonics, Bremen,
Germany). Elemental analyses were measured at the Service de
Microanalyse of the Université de Strasbourg (France).
J4t,Me = 1.5 Hz, 1 H, 4t-H), 4.24 and 3.95 (AB system, JAB
=
13.8 Hz, Δν = 83.5 Hz, 2 H, 1-H), 2.35 (s, 3 H, Me of pTol), 1.76
(br. s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 192.5 (CO),
144.3 (Cq-3), 141.9 (Cq arom), 139.8 (Cq arom), 129.8 (CH arom),
128.5 (CH2-4), 124.0 (CH arom), 64.9 (CH2-1), 21.2 (Me of pTol),
17.0 (Me) ppm.
(+)-(R)-Methyl p-Tolyl Sulfoxide 1 and (–)-(S)-Methyl p-Tolyl Sulf-
oxide (ent-1):[9b,9d] A solution of methylmagnesium iodide in diethyl
ether [prepared from methyl iodide (19.7 mL, 0.315 mol) and mag-
nesium (7.72 g, 0.317 mol) in anhydrous diethyl ether (120 mL)]
was slowly added over 2 h to a chilled (0 °C) solution of (–)-men-
thyl p-toluenesulfinate[9c] (70.3 g, 0.238 mol) in benzene (or toluene;
200 mL). The resulting homogeneous orange solution was stirred
for 2 h at 0 °C, and then for 1 h at room temperature. The reaction
was then quenched very carefully with saturated aqueous ammo-
nium chloride solution (200 mL). The aqueous layer was extracted
(S)-3-Methyl-1-[(R)-p-tolylsulfinyl]but-3-en-2-ol (3): Keto sulfoxide
2 (2.41 g, 0.0108 mol) was dissolved in dry THF (55 mL), and the
solution was cooled to –78 °C. DiBAL-H (1 m in hexane; 13 mL,
1.2 equiv.) was added dropwise. The reaction mixture was stirred
for 1 h 20 min, and the progress of the reaction was monitored by
TLC analysis (diethyl ether/CH2Cl2, 1:1). After this time, the reac-
tion was quenched slowly at –40 °C with MeOH (4 mL) and an
aqueous disodium tartaric acid salt solution (1 m; 10 mL), then the
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Eur. J. Org. Chem. 2015, 5402–5413

Convergent Synthesis of the Lactone Core of Octalactins
mixture was diluted with EtOAc (50 mL) and water (20 mL). After
0.5 h at ambient temperature, the aqueous phase became cloudy,
and HCl (20% aq.; 15 mL) was added until the mixture reached
pH 2. The mixture was stirred vigorously for 1 h, and then the two
clear layers were separated. The aqueous layer was extracted with
EtOAc (2ϫ 15 mL), and the combined organic layers were washed
with water (3ϫ 40 mL) and brine (10 mL), dried with Na2SO4, and
filtered. The solvents were evaporated in vacuo to leave a yellow
oil. This crude product was purified by silica gel column
chromatography (diethyl ether) to give alcohol 3 (1.64 g, 67.7%),
of acetonnide), 21.3 (Me of pTol), 19.1 (Me ax of acetonnide), 12.2
(Me-3) ppm.
Deprotection of Acetonide 4a: Amberlyst 15 (350 mg) was added to
a solution of acetonide 4a (313 mg, 1.10 mmol) in MeOH (8 mL).
The mixture was stirred at room temperature for 6 h, and then it
was filtered through a short pad of Celite, which was rinsed with
EtOAc (3ϫ 10 mL). The filtrate was concentrated in vacuo. The
crude product which was purified by silica gel column chromatog-
raphy (EtOAc) to give free diol 4 (252 mg, 95%) as a white solid,
m.p. 126 °C. [α]2D0 = +303.5 (c = 1.06, CHCl3). C12H15O3S
(242.334): calcd. C 59.47, H 7.49; found C 59.56, H 7.55. 1H NMR
(400 MHz, CDCl3): δ = 7.52 and 7.35 (AAЈBBЈ, J = 11 Hz, Δν =
70 Hz, 4 H, pTol), 4.16 (m, X part of ABX system, 1 H, 2-H), 3.83
(br. s, 2 H, 2 OH), 3.68 (AB part of an ABX system, J4a,4b = 14.8,
J4a,3 = 8.8, J4b,3 = 4.6 Hz, Δν = 56.5 Hz, 2 H, 4-H), 2.95 (AB part
of an ABX system, J1a,1b = 17.6, J1a,2 = 13.6, J1b,2 = 2.6 Hz, Δν =
71.6 Hz, 2 H, 1-H), 2.42 (s, 3 H, Me of pTol), 1.79 (m, X part of
ABX system, 1 H, 3-H), 0.82 (d, J = 7.0 Hz, 3 H, Me-3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 141.8 (Cq arom), 139.1 (Cq arom),
130.1 (CH arom), 124.0 (CH arom), 70.6 (CH-2), 66.1 (CH2-4),
60.7 (CH2-1), 40.4 (CH-3), 21.4 (Me of pTol), 13.4 (Me-3) ppm.
which crystallised on standing as a white solid, m.p. 90 °C. [α]2D0
=
+292 (c = 1.0, CHCl3). C12H14O2Si (222.303): calcd. C 64.25, H
7.19; found C 64.28, H 7.51. 1H NMR (300 MHz, CDCl3): δ =
7.52 and 7.32 (AAЈBBЈ, J = 8.3 Hz, Δν = 60.3 Hz, 4 H, pTol), 5.06
(br. s, 1 H, 4t-H), 4.88 (br. s, 1 H, 4c-H), 4.60 (m, X part of ABX
system, 1 H, 2-H), 4.22 (d, JOH,2 = 3.8 Hz, 1 H, OH), 2.88 (AB
part of an ABX system, J1a,1b = 13.5, J1a,2 = 10.5, J1b,2 = 2.2 Hz,
Δν = 48 Hz, 2 H, 1-H), 2.41 (s, 3 H, Me of pTol), 1.68 (br. s, 3 H,
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.9 (Cq-3), 141.6
(Cq arom), 139.7 (Cq arom), 130.0 (CH arom), 124.0 (CH arom),
112.1 (CH2-4), 69.8 (CH-2), 61.1 (CH2-1), 21.4 (Me of pTol), 18.1
(Me) ppm.
(2S,3S)-4-(tert-Butyldimethylsilyloxy)-3-methyl-1-[(R)-p-tolylsulfin-
yl]butan-2-ol (5): tert-Butyldimethylsilyl chloride (142 mg,
1.18 equiv.) was added to a solution of sulfoxide 4 (192 mg,
0.792 mmol), anhydrous Na2SO4 (ca. 183 mg, ca. 1.6 equiv.), and
imidazole (174 mg, 2.70 equiv.) in dry DMF (3.5 mL). The mixture
was stirred for 1 h at ambient temperature until TLC indicated that
all of the starting material had been monosilylated. Diethyl ether
(15 mL) and water (15 mL) were added, and the mixture was stirred
for 1 h at room temperature. The aqueous phase was extracted with
diethyl ether (10 mL). The combined organic extracts were washed
with water (2ϫ 10 mL) and brine (5 mL), dried with Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (EtOAc) to give
monosilyl ether 5 (280 mg, 99%) as a colourless oil. [α]2D0 = +197.4
(c = 3.7, CHCl3). C18H32O3SSi (356.595): calcd. C 60.63, H 9.05;
(2S,3S)-2-Methyl-4-[(R)-p-tolylsulfinyl]butane-1,3-diol (4): 9-BBN
(0.5 m solution in THF; 23 mL, 2.55 equiv.) was added dropwise
to a cold (0 °C) solution of sulfoxide 3 (1.0112 g, 4.50 mmol) in
anhydrous THF (28 mL). The ice bath was removed after 10 min,
and the mixture was stirred at ambient temperature for 4 h. The
mixture was then cooled to 0 °C, and NaOH (3 m aq.; 10 mL) and
H2O2 (30% aq.; 10 mL), and a saturated aqueous solution of NaCl
(5 mL) were added slowly in sequence. The reaction mixture was
stirred at room temperature for 3 h, and then it was diluted with
EtOAc (20 mL). An aqueous solution of Na2S2O3·5H2O (1 m;
2 mL) was carefully added. The organic layer was washed with
brine (5 mL), dried with MgSO4, filtered, and concentrated under
reduced pressure. The resulting viscous oil was purified by silica
gel column chromatography (diethyl ether, then EtOAc, and then
EtOAc/acetone, 3:1) to give a translucent oil that solidified as a
white solid. This material (941 mg, 86%) contained 4 and other
isomers. At this stage, due to the close Rf values, we failed to isolate
diastereomerically pure 4. However, it was separated from the other
isomers by conversion into dioxane derivative 4a (see below).
1
found C 62.98, H 9.44. H NMR (300 MHz, CDCl3): δ = 7.53 and
7.32 (AAЈBBЈ, J = 8.1 Hz, Δν = 62.7 Hz, 4 H, pTol), 4.45 (d, J =
1.8 Hz, 1 H, OH), 4.16 (m, 1 H, 2-H), 3.64 (AB part of an ABX
system, J4a,4b = 10.2, J4a,3 = 7.5, J4b,3 = 4.0 Hz, Δν = 27.3 Hz, 2
H, 4-H), 2.87 (AB part of an ABX system, J1a,1b = 13.0, J1a,2
=
The mixture of sulfoxides (840 mg, 3.46 mmol) was dissolved in
acetone (5 mL) and 2,2-dimethoxypropane (DMP; 10 mL), and a
catalytic amount of of p-toluenesulfonic acid (pTsOH; 22 mg,
10 mol-%) was added. The mixture was stirred at room temperature
for 5 h. The solvents were evaporated in vacuo, and the residue was
diluted with EtOAc (30 mL). The organic extract was washed with
water (3ϫ 15 mL), dried with Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by silica
gel column chromatography (diethyl ether) to give pure acetonide
4a (825 mg, 84%) as a colourless oil. [α]2D0 = +247 (c = 0.84,
10.0, J1b,2 = 2.2 Hz, Δν = 24.1 Hz, 2 H, 1-H), 2.41 (s, 3 H, Me of
pTol), 1.78 (m, 1 H, 3-H), 0.86 (s, 9 H, tBu-Si), 0.82 (d, J = 6.9 Hz,
3 H, Me-3), 0.05 (s, 3 H, Me-Si), 0.04 (s, 3 H, Me-Si) ppm. 13C
NMR (75 MHz, CDCl3): δ = 141.3 (Cq arom), 140.7 (Cq arom),
130.0 (CH arom), 123.9 (CH arom), 70.5 (CH-2), 67.1 (CH2-4),
62.4 (CH2-1), 40.1 (CH-3), 25.8 [C(CH3)3Si], 21.4 (Me of pTol),
18.1 [C(Me)3Si], 13.0 (Me-3), –5.6 (2 MeSi) ppm.
(2S,3S)-4-(tert-Butyldimethylsilyloxy)-3-methyl-1-[(R)-p-tolylsulfin-
yl]butan-2-yl Acetate (6): Sulfoxide 5 (308.0 mg, 0.863 mmol) was
dissolved in dry CH2Cl2 (10 mL), and a catalytic amount of DMAP
(27 mg, 0.25 equiv.), anhydride acetic (225 μL, 2.7 equiv.), and tri-
ethylamine (0.38 mL, 3.1 equiv.) were added in sequence. The reac-
CHCl3). HRMS (ESI): calcd. for C15H22O3SNa [m
+
Na]+
1
305.1182; found 305.1171. H NMR (300 MHz, CDCl3): δ = 7.53
and 7.30 (AAЈBBЈ, J = 8.1 Hz, Δν = 67.3 Hz, 4 H, pTol), 4.11 (ddd,
J = 10.4, J = 10.4, J = 2.1 Hz, 1 H, 2-H), 3.64 (AB part of an tion mixture was stirred for 3 h at ambient temperature, and then
ABX system, J4a,4b = 11.9, J4a,3 = 11.4, J4b,3 = 5.2 Hz, Δν = 46 Hz, CH2Cl2 (5 mL) and water (10 mL) were added. The organic layer
2 H, 4-H), 2.78 (AB part of an ABX system, J1a,1b = 12.9, J1a,2
=
was washed with water (2ϫ 5 mL), dried with Na2SO4, filtered and
concentrated under reduced pressure. The oily residue was purified
by silica gel column chromatography (EtOAc/cyclohexane, 1:1) to
give 6 (318 mg, 92%) as a colourless viscous oil, which crystallised
10.6, J1b,2 = 2.0 Hz, Δν = 67.2 Hz, 2 H, 1-H), 2.39 (s, 3 H, Me of
pTol), 1.77–1.61 (m, 1 H, 3-H), 1.52 (s, 3 H, Me ax of acetonide),
1.43 (s, 3 H, Me eq of acetonide), 0.75 (d, J = 6.6 Hz, 3 H, Me-3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 141.7 (Cq arom), 141.2 (Cq on standing to give a white solid, m.p. 56 °C. [α]2D0 = +133.1 (c =
arom), 129.9 (CH arom), 123.7 (CH arom), 98.8 (Cq, acetonide),
69.4 (CH-2), 65.8 (CH2-4), 63.0 (CH2-1), 33.9 (CH-3), 29.5 (Me eq found C 60.02, H 8.57. H NMR (300 MHz, CDCl3): δ = 7.52 and
1.42, CHCl3). C20H34O4SSi (398.632): calcd. C 60.26, H 8.60;
1
Eur. J. Org. Chem. 2015, 5402–5413
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5407

C. Bauder
FULL PAPER
7.31 (AAЈBBЈ, J = 8.1 Hz, Δν = 63.0 Hz, 4 H, pTol), 5.39 (m, 1 H, solvents were evaporated, and the crude product was purified by
2-H), 3.53 (m, 2 H, 4-H), 3.02 (AB part of an ABX system, J1a,1b silica gel column chromatography (CH2Cl2) to give alcohol 9
= 13.8, J1a,2 = 9.9, J1b,2 = 2.8 Hz, Δν = 33.4 Hz, 2 H, 1-H), 2.40 (57 mg, 88%) as a colourless liquid. [α]2D0 = +22.9 (c = 0.70,
(s, 3 H, Me of pTol), 2.09 (m, 1 H, 3-H), 2.05 (s, 3 H, AcO), 0.88
CHCl3). HRMS (ESI): calcd. for C12H28O2SiNa [M + Na]+
1
(d, J = 6.9 Hz, 3 H, Me-3), 0.81 (s, 9 H, tBu-Si), –0.003 (s, 6 H, 2 253.1594; found 253.1620. H NMR (500 MHz, CDCl3): δ = 5.85
Me-Si) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.9 (CO), 141.5 (m, 1 H, 2-H), 5.27 (dd, J1,2 = 17.1, J1t,1c = 1.9 Hz, 1 H, 1-H trans),
(Cq arom), 141.2 (Cq arom), 129.9 (CH arom), 124.0 (CH arom), 5.15 (dd, J1,2 = 10.4, J1c,1t = 1.9 Hz, 1 H, 1-H cis), 4.02 (m, 1 H,
70.0 (CH-2), 64.2 (CH2-4), 60.8 (CH2-1), 38.9 (CH-3), 25.8 3-H), 3.73 (d, J = 2.7 Hz, 1 H, OH), 3.69 (AB part of an ABX
[C(CH3)3Si], 21.4 (Me of pTol), 20.9 (MeCO), 18.0 [C(Me)3Si], 12.3
(Me-3), –5.5 (MeSi), –5.6 (MeSi) ppm.
system, J5a,5b = 10.0, J5a,4 = 7.5, J5b,4 = 3.7 Hz, Δν = 85.6 Hz, 2
H, 5-H), 1.75 (m, 1 H, 4-H), 0.90 (s, 9 H, tBu-Si), 0.88 (d, J =
7.0 Hz, 3 H, Me), 0.08 (s, 3 H, Me-Si), 0.07 (s, 3 H, Me-Si) ppm.
13C NMR (125 MHz, CDCl3): δ = 139.7 (CH-2), 115.5 (CH2-1),
78.2 (CH-3), 67.9 (CH2-5), 39.6 (CH-4), 25.8 [C(CH3)3Si], 18.1
[C(Me)3Si], 13.5 (Me), –5.6 (MeSi), –5.7 (MeSi) ppm.
(2S,3S)-4-(tert-Butyldimethylsilyloxy)-3-methyl-1-oxobutan-2-yl
Acetate (7): Triethylamine (450 μL, 3.36 equiv.) and trifluoroacetic
anhydride (420 μL, 3.1 equiv.) were successively added to a solution
of sulfoxide 6 (383.2 mg, 0.961 mmol) in CH2Cl2 (8.5 mL) at 0 °C.
The mixture was stirred at the same temperature for 25 min, then
an aqueous solution of NaHCO3 (0.5 m; 11 mL, 5.72 equiv.) was
added. The mixture was left at ambient temperature for 2 h, and
then it was diluted with water (10 mL) and CH2Cl2 (10 mL). The
organic layer was washed with water (3 ϫ 15 mL), and brine
(5 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude yellow oil was purified by column chromatog-
raphy on silica gel (CH2Cl2) to give aldehyde 7 (263 mg, 99%) as
a colourless oil. [α]2D0 = +7.8 (c = 0.81, CHCl3). HRMS (ESI): calcd.
for C13H26O4SiNa [M + Na]+ 297.1493; found 297.1482. 1H NMR
(400 MHz, CDCl3): δ = 9.49 (s, 1 H, CHO), 4.97 (d, J = 2.9 Hz, 1
H, 2-H), 3.56 (AB of a degenerated ABX system, 2 H, 4-H), 2.49
(m, 1 H, 3-H), 2.19 (s, 3 H, AcO), 0.97 (d, J = 7.0 Hz, 3 H, Me-
3), 0.87 (s, 9 H, tBu-Si), 0.03 (s, 6 H, 2 Me-Si) ppm. 13C NMR
(75 MHz, CDCl3): δ = 197.7 (CHO), 170.7 (COOMe), 79.9 (CH-
2), 63.6 (CH2-4), 38.2 (CH-3), 25.8 [C(CH3)3Si], 20.6 (MeCO), 18.3
[C(Me)3Si], 13.2 (Me-3), –5.7 (2 MeSi) ppm.
(3R,4S)-5-(tert-Butyldimethylsilyloxy)-4-methylpentane-1,3-diol
(10) from 8: 9-BBN (0.5 m solution in THF; 0.85 mL, 2.4 equiv.)
was added dropwise at 0 °C to a solution of olefin 8 (47.7 mg,
0.175 mmol) in anhydrous THF (1 mL). The mixture was stirred
for 20 h at ambient temperature, and for 6.5 h at 50 °C, then it was
cooled to 0 °C, and hydrolysed by the sequential addition of EtOH
(0.3 mL), a saturated aqueous solution of NaOAc (1.4 mL), and
H2O2 (30% aq.; 0.4 mL). The mixture was stirred for 1.5 h at room
temperature, then the organic layer was washed with water (5 mL).
An aqueous solution of Na2S2O3·5H2O (1 m; 2 mL) was carefully
added, followed by brine (4 mL). The organic layer was dried
(MgSO4), filtered, and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography
(EtOAc/cyclohexane, 2:8) to give product A (19 mg, 38%), as well
as starting material (11 mg).
Following a similar procedure, but carrying out the hydroboration
at room temperature for 19 h, and then treating with NaOAc for
4 h, we obtained, after purification, two inseparable regioisomers
A and B (41%) as well as starting material (33%).
(3R,4S)-5-(tert-Butyldimethylsilyloxy)-4-methylpent-1-en-3-yl Acet-
ate (8): KHMDS (0.5 m solution in toluene; 1.8 mL, 1.44 equiv.)
was added dropwise to a stirred suspension of dry methyltri-
phenylphosphonium bromide (340.5 mg, 1.52 equiv.) in dry THF
(5 mL) at 0 °C. The resulting yellow mixture was stirred for 20 min
at 0 °C, then a solution of aldehyde 7 (171.9 mg, 0.626 mmol) in
dry THF (3 mL) was added. The mixture was stirred for 2 h at
ambient temperature, then the reaction was quenched with satu-
rated aqueous NH4Cl solution (4 mL), water (5 mL), and HCl
(10% aq.; 0.6 mL) until the pH reached 1. The mixture was diluted
with EtOAc (10 mL), and the aqueous layer was washed with water
(2 ϫ 10 mL), and brine (5 mL). The organic extract was dried
(MgSO4), filtered, and evaporated under reduced pressure. The
crude product was purified by column chromatography on silica
gel (CH2Cl2) to give pure olefin 8 (154 mg, 91%) as a slightly yel-
low liquid. [α]2D0 = +2.8 (c = 1.07, CHCl3). HRMS (ESI): calcd. for
C14H28O3SiNa+ [M + Na]+ 295.1700; found 295.1719. 1H NMR
(500 MHz, CDCl3): δ = 5.76 (m, 1 H, 2-H), 5.26 (m, 1 H, 3-H),
5.21 (m, 2 H, 1-H), 3.51 (AB part of an ABX system, J5a,5b = 10.0,
J5a,4 = 6.5, J5b,4 = 5.5 Hz, Δν = 20.8 Hz, 2 H, 5-H), 2.05 (s, 3 H,
AcO), 1.93 (m, 1 H, 4-H), 0.90 (d, J = 7.2 Hz, 3 H, Me), 0.89 (s,
9 H, tBu-Si), 0.03 (s, 6 H, 2 Me-Si) ppm. 13C NMR (125 MHz,
CDCl3): δ = 170.0 (CO), 134.4 (CH-2), 117.7 (=CH2-1), 76.0 (CH-
3), 64.3 (CH2-5), 39.4 (CH-4), 25.9 [C(CH3)3Si], 21.2 (Ac), 18.2
[C(Me)3Si], 12.5 (Me), –5.5 (MeSi) ppm.
1
NMR spectroscopic data for A: H NMR (500 MHz, CDCl3): δ =
5.05 (m, 1 H, 3-H), 3.68–3.62 (m, 1 H, 1a-H), 3.53–3.47 (m, 1 H,
1b-H), 3.53 (AB part of an ABX system, J5a –5b = 9.7, J5a –4 = 6.0,
J5b –4 = 5.0 Hz, Δν = 25.3 Hz, 2 H, 5-H), 2.49 (br. s, 1 H, OH),
2.08 (s, 3 H, AcO), 1.94–1.87 (m, 2 H, 4-H and 2a-H), 1.67–1.61
(m, 1 H, 2b-H), 0.94 (d, J = 7.0 Hz, 3 H, Me), 0.88 (s, 9 H, tBu-
Si), 0.034 (s, 3 H, Me-Si), 0.030 (s, 3 H, Me-Si) ppm. 13C NMR
(125 MHz, CDCl3): δ = 171.9 (CO), 72.6 (CH-3), 64.4 (CH2-5),
58.6 (CH2-1), 39.5 (CH-4), 34.3 (CH2-2), 25.8 [C(CH3)3Si], 21.0
(AcO), 18.2 [C(Me)3Si], 13.2 (Me), –5.5 (2 MeSi) ppm.
The mixture of the alcohol regioisomers A and B (25 mg,
0.087 mmol) was stirred with anhydrous K2CO3 (50.5 mg,
4.2 equiv.) in dry MeOH/THF (1 mL/0.5 mL). After 2 h at room
temperature, the solution was filtered, the filter residue was rinsed
with EtOAc, and the combined filtrates were concentrated under
reduced pressure. The crude product was purified by silica gel col-
umn chromatography (EtOAc/cyclohexane, 1:1) to give diol 10
(10 mg, 47%). Analysis of this compound is given in the next sec-
tion.
(3R,4S)-5-(tert-Butyldimethylsilyloxy)-4-methylpentane-1,3-diol
(10) from 9: 9-BBN (0.5 m solution in THF; 4.6 mL, 3.49 equiv.)
was added dropwise to a solution of allylic alcohol 9 (133.0 mg,
0.577 mmol) in anhydrous THF (5.5 mL) at 0 °C. The mixture was
stirred for 6 h at ambient temperature, then it was hydrolysed at
0 °C with NaOH (3 m aq.; 2.4 mL) and H2O2 (30% aq.; 2.4 mL).
The mixture was stirred at room temperature until complete con-
sumption of starting material occurred (2 h, as monitored by TLC).
Brine (3 mL) was added. The organic layer was diluted with EtOAc
(10 mL), and washed with water (5 mL), and an aqueous solution
(3R,4S)-5-(tert-Butyldimethylsilyloxy)-4-methylpent-1-en-3-ol (9):
K2CO3 (200 mg, 5.1 equiv.) was added to a solution of acetate 8
(76.3 mg, 0.28 mmol) in MeOH (5 mL). The mixture was stirred at
room temperature for 50 min. After this time, TLC indicated that
all of the starting material had been consumed. The mixture was
filtered through Celite, which was then rinsed with EtOAc. The
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Eur. J. Org. Chem. 2015, 5402–5413

Convergent Synthesis of the Lactone Core of Octalactins
of Na2S2O3·5H2O (1 m; 1 mL). The organic phase was washed with
brine (5 mL), dried (MgSO4), and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography (EtOAc/cyclohexane, 2:8, then 1:1) to give diol 10
(142 mg, 99%) as a colourless oil. [α]2D0 = +20.15 (c = 1.29, CHCl3).
HRMS (ESI): calcd. for C12H28O3SiNa [M + Na]+ 271.1700; found
271.1724. 1H NMR (500 MHz, CDCl3): δ = 3.85 (m, 2 H, 1-H),
(S)-3-Methyl-1-(p-tolylsulfinyl)but-3-en-2-one (ent-2): A solution of
(–)-methyl p-tolyl sulfoxide (ent-1; 4.1777 g, 0.0270 mol) in dry
THF (15 mL) was added by cannula to a stirred solution of LDA
(1.2 equiv.) [freshly prepared from diisopropylamine (5 mL,
1.32 equiv.) and nBuLi (in THF; 38 mL, 1.24 equiv.)] at –70 °C.
The mixture was stirred for 55 min at the same temperature, then
neat ethyl methacrylate (1.8 mL, 0.53 equiv.) was added dropwise
3.79 (m, 1 H, 3-H), 3.69 (AB part of an ABX system, J5a,5b = 10.0, to the resulting lithium anion of methyl p-tolyl sulfoxide. The mix-
J5a,4 = 8.5, J5b,4 = 4.0 Hz, Δν = 86.3 Hz, 2 H, 5-H), 1.78 (m, 1 H, ture was stirred for 1.5 h, during which time the temperature was
4-H), 1.72 (m, 2 H, 2-H), 0.90 (s, 9 H, tBu-Si), 0.82 (d, J = 7.0 Hz, allowed to rise to –25 °C. The resulting milky solution was then
3 H, Me), 0.08 (s, 6 H, Me-Si) ppm. 13C NMR (125 MHz, CDCl3): quenched with saturated aqueous NH4Cl solution (10 mL), and the
δ = 78.0 (CH-3), 68.9 (CH2-5), 61.7 (CH2-1), 39.7 (CH-4), 36.2 aqueous phase was acidified at room temperature with HCl (20%
(CH2-2), 25.8 [C(CH3)3Si], 18.1 [C(Me)3Si], 13.3 (Me), –5.6 (MeSi),
–5.7 (MeSi) ppm.
aq.; 30 mL) to pH 2. The organic layer was diluted with EtOAc
(20 mL), washed with water (3ϫ 50 mL) and brine (20 mL), dried
with Na2SO4, filtered, and concentrated under reduced pressure to
leave a pale yellow oil. The crude product was purified by silica
gel column chromatography (EtOAc/cyclohexane, 7:3) to give keto
sulfoxide ent-2 (3.14 g, 99%) as a pale yellow oil. [α]2D0 = –213 (c =
3.3, CHCl3). C12H14O2Si (222.303): calcd. C 64.83, H 6.35; found
tert-Butyl{(2S)-2-[(4R)-2-(4-methoxyphenyl)-1,3-dioxan-4-
yl]propoxy}dimethylsilane (11): Camphorsulfonic acid (6.3 mg,
0.06 equiv.) and p-methoxybenzaldehyde dimethyl acetal (90 μL,
1.17 equiv.) were added to a solution of diol 10 (104.9 mg,
0.422 mmol) in CH2Cl2 (5 mL) containing anhydrous Na2SO4
(175 mg). The mixture was stirred for 3 h at room temperature, then
it was diluted with CH2Cl2 (5 mL), and quenched with saturated
aqueous NaHCO3 (1 mL) and water (5 mL). The organic layer was
washed with water (2ϫ 5 mL), brine (4 mL), dried (MgSO4), fil-
tered, and concentrated in vacuo. The residue was purified by silica
gel column chromatography (EtOAc/cyclohexane, 2:8) to give 11
(130 mg, 91%) as a colourless oil. [α]2D0 = –31.4 (c = 1.05, CHCl3).
HRMS (ESI): calcd. for C20H34O4SiNa [M + Na]+ 389.2119; found
1
C 64.96, H 6.31. H NMR (300 MHz, CDCl3): δ = 7.52 and 7.29
(AAЈBBЈ, J = 7.9 Hz, Δν = 69.4 Hz, 4 H, pTol), 5.93 (q, J4c,Me
=
0.5 Hz, 1 H, 4c-H), 5.91 (q, J4t,Me = 1.5 Hz, 1 H, 4t-H), 4.26 and
3.97 (AB system, JAB = 13.9 Hz, Δν = 86.1 Hz, 2 H, 1-H), 2.38 (s,
3 H, Me of pTol), 1.80 (br. s, 3 H, Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 192.6 (CO), 144.5 (Cq-3), 142.0 (Cq arom), 139.9 (Cq
arom), 129.9 (CH arom), 128.6 (CH2-4), 124.1 (CH arom), 65.0
(CH2-1), 21.3 (Me of pTol), 17.1 (Me) ppm.
389.2092. 1H NMR (400 MHz, CDCl3): δ = 7.41 and 6.88 (R)-3-Methyl-1-[(S)-p-tolylsulfinyl]but-3-en-2-ol (ent-3): DiBAL-H
(AAЈBBЈ, J = 8.8 Hz, Δν = 210.3 Hz, 4 H, PMP), 5.44 (s, 1 H, H
acetal), 4.27 (ddd, J1eq,1ax = 11.4, J1eq,2ax = 5.0, J1eq,2eq = 1.4 Hz,
(1 m solution in PhMe; 9.3 mL, 1.23 equiv.) was added dropwise to
a solution of keto sulfoxide ent-2 (1.685 g, 0.00757 mol) in THF
(35 mL) at –78 °C. The reaction mixture was stirred for 1 h, during
which time the temperature was allowed to reach –45 °C, then it
was quenched carefully with MeOH (2 mL), and diluted with
1 H, 1eq-H), 3.92 (ddd, J1ax,2ax = 12.4, J1ax,1eq = 11.5, J1ax,2eq
=
2.6 Hz, 1 H, 1ax-H), 3.80 (s, 3 H, OMe), 3.79 (m, 1 H, 3-H), 3.66
(AB part of an ABX system, J5a,5b = 9.8, J5a,4 = 5.4, J5b,4 = 4.6 Hz,
Δν = 19.4 Hz, 2 H, 5-H), 1.85 (m, 1 H, 4-H), 1.80 (m, 1 H, 2ax- EtOAc (25 mL). The gelatinous mixture was acidified at ambient
H), 1.52 (m, 1 H, 2eq-H), 0.95 (d, J = 6.9 Hz, 3 H, Me-4), 0.90 (s,
9 H, tBu-Si), 0.03 (s, 6 H, Me-Si) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.7 (Cq arom), 131.6 (Cq arom), 127.3 (CH arom),
temperature with HCl (20% aq.; 10 mL) to pH 2–3. The aqueous
layer was extracted with EtOAc (15 mL). The combined organic
extracts were washed with water (3ϫ 40 mL), and brine (5 mL),
113.5 (CH arom), 101.0 (CH acetal), 77.8 (CH-3), 67.1 (CH2-1), dried with Na2SO4, filtered, and concentrated under reduced pres-
63.9 (CH2-5), 55.3 (OMe), 40.5 (CH-4), 28.2 (CH2-2), 25.9 sure to give a lemon-yellow viscous oil. The crude product was
[C(CH3)3Si], 18.3 [C(Me)3Si], 12.3 (Me-4), –5.4 (2 MeSi) ppm.
purified by silica gel column chromatography (diethyl ether/
CH2Cl2, 1:1) to give alcohol ent-3 (1.30 g, 76%), which crystallised
on standing as a white solid, m.p. 80–81 °C. [α]2D0 = –278.7 (c =
1.08, CHCl3). C12H14O2Si (222.303): calcd. C 64.25, H 7.19; found
(2S)-2-[(4R)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]propan-1-ol
(12):[16] A solution of TBAF (tetrabutylammonium fluoride; 1 m
THF solution; 0.31 mL, 1.13 equiv.) was added dropwise to a
stirred solution of silylated alcohol 11 (100.1 mg, 0.273 mmol) in
dry THF (4 mL) at 0 °C. The mixture was stirred at room temp.
for 3 h, then it was quenched by the successive addition of water
(5 mL) and saturated aqueous NaHCO3 (1 mL), and diluted with
EtOAc (5 mL). The phases were separated, the aqueous layer was
extracted with EtOAc (5 mL), and the combined organic extracts
were washed with water (2 ϫ 10 mL), and brine (4 mL), dried
(MgSO4), filtered, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (EtOAc) to give
1
C 64.02, H 7.13. H NMR (300 MHz, CDCl3): δ = 7.53 and 7.33
(AAЈBBЈ, J = 8.1 Hz, Δν = 59.7 Hz, 4 H, pTol), 5.06 (br. s, 1 H,
4t-H), 4.87 (br. s, 1 H, 4c-H), 4.60 (m, X part of ABX system, 1
H, 2-H), 4.17 (d, JOH,2 = 1.5 Hz, 1 H, OH), 2.89 (AB part of an
ABX system, J1a,1b = 13.2, J1a,2 = 10.2, J1b,2 = 2.1 Hz, Δν =
49.1 Hz, 2 H, 1-H), 2.40 (s, 3 H, Me of pTol), 1.68 (br. s, 3 H, Me)
ppm. 13C NMR (75 MHz, CDCl3): δ = 144.9 (Cq-3), 141.6 (Cq
arom), 139.7 (Cq arom), 130.0 (CH arom), 123.9 (CH arom), 112.0
(CH2-4), 69.7 (CH-2), 61.4 (CH2-1), 21.3 (Me of pTol), 18.1 (Me)
ppm.
1
alcohol 12 (63 mg, 92%) as a colourless oil. H NMR (500 MHz,
CDCl3): δ = 7.38 and 6.89 (AAЈBBЈ, J = 8.7 Hz, Δν = 253.5 Hz, 4
(2R,3R)-2-Methyl-4-[(S)-p-tolylsulfinyl]butane-1,3-diol (ent-4): 9-
H, PMP), 5.47 (s, 1 H, acetal), 4.28 (ddd, J = 11.5, J = 5.0, J = BBN (0.5 m solution in THF; 3.3 mL, 2.45 equiv.) was added drop-
1.4 Hz, 1 H, 1eq-H), 3.95 (ddd, J = 12.4, J = 11.5, J = 2.6 Hz, 1 wise to a cold (0 °C) solution of sulfoxide ent-3 (151 mg,
H, 1ax-H), 3.80 (s, 3 H, OMe), 3.79 (m, 1 H, 3-H), 3.68 (dd, J =
0.673 mmol) in anhydrous THF (4 mL). The ice bath was removed
5.8, J = 5.0 Hz, 2 H, 5-H), 2.53 (dd, J = 6.2, J = 5.4 Hz, 1 H, OH), after 10 min, and the mixture was stirred at ambient temperature
1.92 (m, 1 H, 4-H), 1.88 (m, 1 H, 2eq-H), 1.59 (m, 1 H, 2ax-H), 0.93
for 3 h. The reaction mixture was then treated sequentially at 0 °C
(d, J = 7.0 Hz, 3 H, Me-4) ppm. 13C NMR (125 MHz, CDCl3): δ with the dropwise addition of NaOH (3 m aq.; 2 mL), H2O2 (30%
= 160.0 (Cq arom), 130.9 (Cq arom), 127.3 (CH arom), 113.7 (CH aq.; 2 mL), and saturated aqueous NaCl (2 mL). The mixture was
arom), 101.2 (CH acetal), 82.0 (CH-3), 67.0 (CH2-5), 66.8 (CH2- stirred at room temperature for 4 h, and then it was diluted with
1), 55.3 (OMe), 40.4 (CH-4), 29.4 (CH2-2), 12.8 (Me-4) ppm.
EtOAc (10 mL). An aqueous solution of Na2S2O3·5H2O (2 m;
Eur. J. Org. Chem. 2015, 5402–5413
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5409

C. Bauder
FULL PAPER
1 mL) was carefully added, and the organic layer was washed with
brine (4 mL), dried with Na2SO4, filtered, and concentrated under
reduced pressure. The resulting viscous oil was purified by silica
gel column chromatography (diethyl ether, then EtOAc, and then
EtOAc/acetone, 3:1) to give ent-4 and other isomers (117 mg,
71.7%) as a translucent oil that solidified as a white solid. At this
stage, due to the close Rf values, we failed to isolate the pure dia-
stereomer ent-4. However, it was separated from the other isomers
as its dioxane derivative ent-4a (see below).
the combined organic layers were washed with water (2ϫ 10 mL),
and brine (5 mL), dried with Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel col-
umn chromatography (EtOAc) to give ent-5 (186 mg, 92%) as a
colourless liquid. [α]2D0 = –199.8 (c = 1.93, CHCl3). C18H32O3SSi
(356.595): calcd. C 60.63, H 9.05; found C 60.58, H 9.01. 1H NMR
(400 MHz, CDCl3): δ = 7.54 and 7.32 (AAЈBBЈ, J = 8.1 Hz, Δν =
62.8 Hz, 4 H, pTol), 4.44 (d, J = 2.6 Hz, 1 H, OH), 4.16 (m, 1 H,
2-H), 3.64 (AB part of an ABX system, J4a,4b = 10.3, J4a,3 = 7.3,
J4b,3 = 4.2 Hz, Δν = 25.1 Hz, 2 H, 4-H), 2.87 (AB part of an ABX
system, J1a,1b = 13.2, J1a,2 = 10.0, J1b,2 = 2.2 Hz, Δν = 25.2 Hz, 2
H, 1-H), 2.40 (s, 3 H, Me of pTol), 1.78 (m, 1 H, 3-H), 0.86 (s, 9
H, tBu-Si), 0.82 (d, J = 7.0 Hz, 3 H, Me-3), 0.04 (s, 3 H, Me-Si),
0.03 (s, 3 H, Me-Si) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.3
(Cq arom), 140.7 (Cq arom), 129.9 (CH arom), 123.9 (CH arom),
70.5 (CH-2), 67.1 (CH2-4), 62.4 (CH2-1), 40.1 (CH-3), 25.8
[C(CH3)3Si], 21.4 (Me of pTol), 18.1 [C(Me)3Si], 13.0 (Me-3), –5.6
(2 MeSi) ppm.
The mixture of sulfoxides (605 mg, 0.00249 mmol) was dissolved in
acetone (3 mL) and 2,2-dimethoxypropane (DMP; 7 mL), and a
catalytic amount of of p-toluenesulfonic acid (10.6 mg; pTsOH)
was added. The mixture was stirred at room temperature for 3 h.
The solvents were evaporated in vacuo, and the residue was diluted
with EtOAc (20 mL). The organic extract was washed with water
(3ϫ 5 mL), dried with Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by silica gel col-
umn chromatography (diethyl ether) to give pure acetonide ent-4a
(613 mg, 87%) as a colourless oil. [α]2D0 = –192.2 (c = 1.5, CHCl3).
HRMS (ESI): calcd. for C15H22O3SNa [M + Na]+ 305.1182; found
305.1172. 1H NMR (300 MHz, CDCl3): δ = 7.54 and 7.31
(AAЈBBЈ, J = 8.1 Hz, Δν = 67.0 Hz, 4 H, pTol), 4.11 (ddd, J =
10.4, J = 10.4, J = 2.1 Hz, 1 H, 2-H), 3.65 (AB part of an ABX
system, J4a,4b = 11.7, J4a,3 = 11.1, J4b,3 = 5.1 Hz, Δν = 35.8 Hz, 2
(2R,3R)-4-(tert-Butyldimethylsilyloxy)-3-methyl-1-[(S)-p-tolylsulfin-
yl]butan-2-yl Acetate (ent-6): A catalytic amount of DMAP (8 mg)
and then acetic anhydride (130 μL, 2.78 equiv.) and triethylamine
(250 μL, 3.64 equiv.) were added successively to a solution of sulf-
oxide ent-5 (176 mg, 0.493 mmol) in CH2Cl2 (6.5 mL). The reaction
mixture was stirred at room temp. for 15 h, then it was diluted with
CH2Cl2 (10 mL) and water (10 mL), and the mixture was stirred
for 15 min at room temperature. The organic layer was washed with
water (2ϫ 10 mL), dried with Na2SO4, filtered, and concentrated
under reduced pressure. The oily residue was purified by silica gel
column chromatography (EtOAc/cyclohexane, 1:1) to give ent-6
(178 mg, 90%) as a white solid, m.p. 58 °C. [α]2D0 = –133.3 (c = 1.55,
CHCl3). C20H34O4SSi (398.632): calcd. C 60.26, H 8.60; found C
60.13, H 8.47. 1H NMR (400 MHz, CDCl3): δ = 7.51 and 7.30
(AAЈBBЈ, J = 8.2 Hz, Δν = 63.4 Hz, 4 H, pTol), 5.39 (m, 1 H, 2-
H, 4-H), 2.79 (AB part of an ABX system, J1a,1b = 12.9, J1a,2
=
10.6, J1b,2 = 2.1 Hz, Δν = 67.3 Hz, 2 H, 1-H), 2.40 (s, 3 H, Me of
pTol), 1.77–1.62 (m, 1 H, 3-H), 1.53 (s, 3 H, Me ax of acetonide),
1.44 (s, 3 H, Me eq of acetonide), 0.75 (d, J = 6.9 Hz, 3 H, Me-3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 141.7 (Cq arom), 141.2 (Cq
arom), 129.9 (CH arom), 123.8 (CH arom), 98.9 (Cq, acetonide),
69.4 (CH-2), 65.8 (CH2-4), 63.0 (CH2-1), 34.0 (CH-3), 29.5 (Me eq
of acetonide), 21.3 (Me of pTol), 19.1 (Me ax of acetonide), 12.2
(Me-3) ppm.
H), 3.53 (m, 2 H, 4-H), 3.02 (AB part of an ABX system, J1a,1b
=
Deprotection of Acetonide ent-4a: Amberlyst 15 (718 mg) was added
to a solution of acetonide ent-4a (598.9 mg, 2.12 mmol) in MeOH
(15 mL). The mixture was stirred at room temperature for 14 h. It
was filtered through a short pad of Celite, which was then rinsed
with EtOAc (3ϫ 10 mL). The filtrate was concentrated in vacuo.
The crude product was purified by silica gel column chromatog-
raphy (EtOAc) to give free diol ent-4 (421 mg, 82%) as a white
solid, m.p. 124 °C. [α]2D0 = –307.1 (c = 1.04, CHCl3). C12H15O3S
(242.334): calcd. C 59.47, H 7.49; found C 58.23, H 7.43. 1H NMR
(300 MHz, CDCl3): δ = 7.52 and 7.35 (AAЈBBЈ, J = 8.2 Hz, Δν =
50.3 Hz, 4 H, pTol), 4.85 (d, J = 3.4 Hz, 1 H, 2-OH), 4.14 (m, X
part of ABX system, 1 H, 2-H), 3.76 (m, 1 H, 4a-H), 3.59 (m, 1
H, 4b-H), 3.22 (m, 1 H, 4-OH), 2.94 (AB part of an ABX system,
J1a,1b = 13.3, J1a,2 = 10.2, J1b,2 = 2.0 Hz, Δν = 62.0 Hz, 2 H, 1-H),
2.43 (s, 3 H, Me of pTol), 1.79 (m, 1 H, 3-H), 0.81 (d, J = 7.0 Hz,
3 H, Me-3) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.7 (Cq
arom), 139.2 (Cq arom), 130.1 (CH arom), 124.0 (CH arom), 70.8
(CH-2), 66.2 (CH2-4), 60.4 (CH2-1), 40.4 (CH-3), 21.4 (Me of
pTol), 13.4 (Me-3) ppm.
13.8, J1a,2 = 9.6, J1b,2 = 2.7 Hz, Δν = 32.8 Hz, 2 H, 1-H), 2.40 (s,
3 H, Me of pTol), 2.08 (m, 1 H, 3-H), 2.04 (s, 3 H, AcO), 0.88 (d,
J = 7.0 Hz, 3 H, Me-3), 0.81 (s, 9 H, tBu-Si), –0.002 (s, 6 H, 2 Me-
Si) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.9 (CO), 141.5 (Cq
arom), 141.2 (Cq arom), 129.9 (CH arom), 124.0 (CH arom), 70.0
(CH-2), 64.2 (CH2-4), 60.8 (CH2-1), 39.0 (CH-3), 25.8 [C(CH3)3Si],
21.4 (Me of pTol), 20.9 (Me, AcO), 18.1 [C(Me)3Si], 12.3 (Me-3),
–5.5 (MeSi), –5.6 (MeSi) ppm.
(2R,3R)-4-(tert-Butyldimethylsilyloxy)-3-methyl-1-oxobutan-2-yl
Acetate (ent-7): Triethylamine (140 μL, 3.2 equiv.) and trifluoro-
acetic anhydride (140 μL, 3.1 equiv.) were successively added to a
solution of sulfoxide ent-6 (125.8 mg, 0.315 mmol) in CH2Cl2
(3.2 mL) at 0 °C. The mixture was stirred at the same temperature
for 25 min, then it was treated with NaHCO3 (0.5 m aq.; 3.2 mL,
5 equiv.). The mixture was left at ambient temperature for 2 h, and
then it was diluted with water (10 mL) and CH2Cl2 (5 mL). The
organic layer was washed with water (3 ϫ 15 mL), and brine
(4 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude yellow oil was purified by column chromatog-
raphy on silica gel (CH2Cl2) to give aldehyde ent-7 (69 mg, 80%)
as a colourless oil. [α]2D0 = –8.8 (c = 1.17, CHCl3). HRMS (ESI):
calcd. for C13H26O4SiNa [M + Na]+ 297.1493; found 297.1528. 1H
NMR (500 MHz, CDCl3): δ = 9.49 (s, 1 H, CHO), 4.97 (d, J =
3.2 Hz, 1 H, 2-H), 3.56 (AB of a degenerated ABX system, 2 H, 4-
H), 2.48 (m, 1 H, 3-H), 2.19 (s, 3 H, AcO), 0.97 (d, J = 7.0 Hz, 3
H, Me-3), 0.87 (s, 9 H, tBu-Si), 0.03 (s, 6 H, 2 Me-Si) ppm. 13C
NMR (125 MHz, CDCl3): δ = 197.7 (CHO), 170.6 (AcO), 79.9
(2R,3R)-4-(tert-Butyldimethylsilyloxy)-3-methyl-1-[(S)-p-tolylsulfin-
yl]butan-2-ol (ent-5): Imidazole (107 mg, 2.78 equiv.) and tert-butyl-
dimethylsilyl chloride (104 mg, 1.22 equiv.) were added successively
to a solution of diol ent-4 (137 mg, 0.565 mmol) and anhydrous
sodium sulfate (ca. 132 mg) in dry DMF (2.5 mL). The reaction
mixture was stirred for 1 h, after which time TLC indicated that
no starting material was remaining. The mixture was diluted with
diethyl ether (10 mL) and water (10 mL). The mixture was stirred
at ambient temperature for 1 h, then the two layers were separated. (CH-2), 63.6 (CH2-4), 38.2 (CH-3), 25.7 [C(CH3)3Si], 20.5 (MeCO),
The aqueous phase was extracted with diethyl ether (10 mL), and 18.3 [C(Me)3Si], 13.2 (Me-3), –5.6 (MeSi), –5.7 (MeSi) ppm.
5410
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5402–5413

Convergent Synthesis of the Lactone Core of Octalactins
(4R)-4-[(R)-1-Iodopropan-2-yl]-2-(4-methoxyphenyl)-1,3-dioxane at room temperature for 20 min. The reaction mixture was cooled
(13): A solution of iodine (113.3 mg, 1.33 equiv.) in THF (1.5 mL) to –65 °C, and a solution of aldehyde ent-7 (60.2 mg, 1 equiv.) in
was added dropwise to a chilled (0 °C) solution of alcohol 12
THF (2 mL) was added slowly. The mixture was stirred 45 min at
(84.3 mg, 0.335 mmol), containing imidazole (68.2 mg, 2.98 equiv.) this temperature, and then for 5 h at ambient temperature, during
and triphenylphosphine (120.6 mg, 1.37 equiv.) in dry THF (5 mL).
After 10 min, the slightly yellow mixture removed from the cooling
bath. The mixture was stirred for 1 h 45 min at ambient tempera-
ture, during which time a white precipitate formed. The reaction
was quenched by the addition of Na2S2O3·5H2O (1 m aq.; 1 mL),
followed saturated aqueous NaHCO3 (2 mL). The mixture was di-
luted with water (5 mL) and EtOAc (10 mL). The aqueous layer
was extracted with EtOAc (5 mL), and the combined organic layers
were washed with water (2 ϫ 5 mL), and brine (5 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography
(EtOAc/cyclohexane, 1:1) to give 13 (111 mg, 91%) as a viscous
colourless oil. [α]2D0 = –67.01 (c = 1.54, CHCl3). HRMS (ESI):
which time a white precipitate was formed. The reaction was then
quenched with a saturated solution of NH4Cl (4 mL), and the mix-
ture was diluted with water (8 mL) and EtOAc (15 mL), and acidi-
fied with HCl (10% aq.; 0.2 mL) to pH 5. The organic layer was
washed with water (3ϫ 8 mL), and brine (5 mL), dried (MgSO4),
filtered, and evaporated under reduced pressure. The crude orange
oil was purified by silica gel column chromatography (diethyl ether/
cyclohexane, 1:5) to give exclusively (Z)-olefin 15 (41 mg, 38%) as
a colourless oil. [α]2D0 = +12.02 (c = 2.03, CHCl3). HRMS (ESI):
calcd. for C27H44O6SiNa [M + Na]+ 515.2799; found 515.2740. 1H
NMR (400 MHz, CDCl3): δ = 7.41 and 6.87 (AAЈBBЈ, J = 8.6 Hz,
Δν = 213 Hz, 4 H, PMP), 5.68 (t app, 1 H, J = 10.8 Hz, 5-H vinyl),
5.55 (dd, J = 9.7, J = 7.4 Hz, 1 H, 7-H), 5.44 (s, 1 H, acetal), 5.35
(t app, J = 10.4 Hz, 1 H, 6-H vinyl), 4.21 (m, 1 H, 1a-H), 3.90 (m,
1 H, 1b-H), 3.80 (m, 4 H, 3-H, MeO), 3.49 (AB part of an ABX
1
calcd. for C14H19IO3Na [M + Na]+ 385.0271; found 385.0263. H
NMR (500 MHz, CDCl3): δ = 7.41 and 6.89 (AAЈBBЈ, J = 9.0 Hz,
Δν = 260 Hz, 4 H, PMP), 5.47 (s, 1 H, acetal), 4.29 (ddd, J = 11.5, system, J9a,9b = 10.0, J9a,8 = 6.0, J9b,8 = 5.2 Hz, Δν = 19.7 Hz, 2
J = 5.0, J = 1.4 Hz, 1 H, 1a-H), 3.96 (ddd, J = 12.3, J = 11.5, J =
2.7 Hz, 1 H, 1b-H), 3.80 (s, 3 H, OMe), 3.63 (ddd, J = 11.2, J =
8.4, J = 2.4 Hz, 1 H, 3-H), 3.44 (AB part of an ABX system, J5a,5b
H, 9-H), 2.91 (m, 1 H, 4-H), 2.00 (s, 3 H, AcO), 1.89 (m, 1 H, 8-
H), 1.81 (m, 1 H, 2a-H), 1.39 (m, 1 H, 2b-H), 1.09 (d, J = 7.0 Hz,
3 H, Me-4), 0.89 (br. s, 12 H, tBu-Si, Me-8), 0.03 (s, 6 H, Me-Si)
= 9.5, J5a,4 = 5.5, J5b,4 = 3.0 Hz, Δν = 68.2 Hz, 2 H, 5-H), 1.81 (m, ppm. 13C NMR (100 MHz, CDCl3): δ = 169.8 (CO), 159.7 (Cq
1 H, 2a-H), 1.61 (m, 1 H, 2b-H), 1.51 (m, 1 H, 4-H), 0.99 (d, J = arom, PMP), 135.9 (CH-5 vinyl), 131.7 (Cq arom, PMP), 127.3
6.7 Hz, 3 H, Me-4) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.8 (CH arom, PMP), 126.5 (CH-6 vinyl), 113.4 (CH arom, PMP),
(Cq arom), 131.1 (Cq arom), 127.2 (CH arom), 113.5 (CH arom), 101.0 (CH acetal), 79.9 (CH-3), 71.2 (CH-7), 67.0 (CH2-2), 64.2
100.9 (CH acetal), 79.6 (CH-3), 66.8 (CH2-1), 55.3 (OMe), 38.7 (CH2-9), 55.3 (OMe), 39.8 (CH-8), 36.8 (CH-4), 28.4 (CH2-2), 25.8
(CH-4), 28.5 (CH2-2), 16.4 (Me-4), 14.7 (CH2-5) ppm.
[C(CH3)3Si], 21.2 (OAc), 18.2 [C(Me)3Si], 17.1 (Me-4), 12.7 (Me-
8), –5.4 (MeSi), –5.5 (MeSi) ppm.
{(R)-2-[(2R,4R)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]propyl}-
triphenylphosphonium Iodide (14): Iodide 13 (51.1 mg, 0.141 mmol),
triphenylphosphine (251.2 mg, 6.8 equiv.), and solid NaHCO3
(34.7 mg, 2.9 equiv.) were dissolved in dry MeCN (3 mL). The mix-
ture was heated at 80 °C for 20 h, after which time the solvent was
evaporated. CH2Cl2 (2 mL) was added, and the inorganics were
removed by filtration through cotton wool. The solvent was evapo-
rated again, and the residue was triturated with diethyl ether, the
solvent was decanted (3ϫ 4 mL), and the solid was collected by
filtration. The resulting solid was purified by silica gel column
(2R,3S,6S,7R,Z)-1-(tert-Butyldimethylsilyloxy)-9-hydroxy-7-(4-
methoxybenzyloxy)-2,6-dimethylnon-4-en-3-yl Acetate (16): DiBAL-
H (1 m in cyclohexane; 0.9 mL, 11.0 equiv.) was added dropwise to
a chilled (0 °C) solution of compound 15 (40.5 mg, 0.0821 mmol)
in dry CH2Cl2 (3 mL). The reaction mixture was stirred at 0 °C for
2 h, and after this time it was carefully quenched with MeOH
(0.2 mL) and saturated aqueous K,Na tartrate (Rochelle salt;
3 mL). The mixture was stirred for 1 h at ambient temperature, and
then it was diluted with water (10 mL), CH2Cl2 (8 mL), and HCl
chromatography (CH2Cl2 to CH2Cl2/MeOH, 20:1) to give phos- (10% aq.; 0.6 mL) to reach pH 5–6. The organic phase was sepa-
phonium salt 14 (74 mg, 85%) as a white solid, m.p. 114 °C. [α]2D0
= +25.0 (c = 1.02, CHCl3). HRMS (ESI): calcd. for C32H34IO3 [M
rated, and concentrated to remove the MeOH. The residue was
diluted with diethyl ether (10 mL), and this solution was washed
+ Na]+ 497.2240; found 497.2194. 31P NMR (121 MHz, CDCl3): δ with water (3ϫ 5 mL), and brine (4 mL), dried (MgSO4), filtered
1
= 23.1 ppm. H NMR (500 MHz, CDCl3): δ = 7.83 (m, 6 H, Ph), and evaporated under reduced pressure. The crude oil was purified
7.74 (m, 3 H, Ph), 7.58 (m, 6 H, Ph), 7.45 and 6.90 (AAЈBBЈ, J = by silica gel column chromatography (EtOAc/cyclohexane, 1:1) to
8.7 Hz, Δν = 271 Hz, 4 H, PMP), 5.60 (s, 1 H, acetal), 4.22 (m, 1 give diol 16 (21 mg, 58%) as a colourless oil. [α]2D0 = +13.86 (c =
H, 1a-H), 4.19 (m, 1 H, m, 1 H, 3-H), 3.98 (m, 1 H, 5a-H), 3.96 2.14, CHCl3). HRMS (ESI): calcd. for C25H44O5SiNa [M + Na]+
1
(m, 1 H, 1b-H), 3.84 (m, 1 H, 5b-H), 3.80 (s, 3 H, OMe), 2.06 (m,
475.2850; found 475.2799. H NMR (400 MHz, CDCl3): δ = 7.28
1 H, 4-H), 1.72 (m, 1 H, 2a-H), 1.57 (m, 1 H, 2b-H), 0.72 (d, J = and 6.87 (AAЈBBЈ, J = 8.8 Hz, Δν = 162 Hz, 4 H, PMB), 5.44 (m,
6.9 Hz, 3 H, Me-4) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.9 2 H, 5-H and 6-H vinyl), 4.56 and 4.47 (AB system, J = 11.2 Hz,
(Cq arom), 134.9 (d, JC,P = 2.5 Hz, CH arom, P-Ph), 133.7 (d, JC,P Δν = 29.6 Hz, 2 H, CH2-PMB), 4.29 (t app, J = 7.9 Hz, 1 H, 7-H),
= 10.0 Hz, CH arom, P-Ph), 131.1 (Cq arom, P-Ph), 130.3 (d, JC,P
= 12.5 Hz, CH arom, P-Ph), 127.8 (Cq arom, PMP), 118.6 (d, JC,P (m, 1 H, 9b-H), 3.53 (m, 1 H, 3-H), 2.94 (m, 1 H, 4-H), 1.76 (m,
= 85.8 Hz, Cq arom, P-Ph), 113.5 (Cq arom, PMP), 101.3 (CH 3 H, 2-H and 8-H), 1.00 (d, J = 6.7 Hz, 3 H, Me-4), 0.89 (s, 9 H,
3.80 (s, 3 H, MeO), 3.74 (m, 1 H, 9a-H), 3.71 (m, 2 H, 1-H), 3.62
acetal), 79.8 (d, JC,P = 12.4 Hz, CH-3), 66.5 (CH2-1), 55.3 (OMe), tBu-Si), 0.80 (d, J = 7.0 Hz, 3 H, Me-8), 0.08 (s, 6 H, Me-Si) ppm.
34.2 (d, JC,P = 2.9 Hz, CH-4), 28.9 (CH2-2), 24.9 (d, JC,P = 51.0 Hz, 13C NMR (100 MHz, CDCl3): δ = 159.3 (Cq arom, PMB), 134.8
CH2-5), 16.0 (Me-4) ppm.
(CH-5 vinyl), 131.8 (CH-6 vinyl), 130.4 (Cq arom, PMB), 129.6
(CH arom, PMB), 113.8 (CH arom, PMB), 81.6 (CH-3), 71.8 (CH-
7), 71.7 (CH2-PMP), 67.7 (CH2-9), 60.8 (CH2-1), 55.2 (OMe), 40.3
(CH-8), 35.2 (CH-4), 33.0 (CH2-2), 25.8 [C(CH3)3Si], 18.1 [C(Me)
3Si], 16.0 (Me-4), 13.1 (Me-8), –5.5 (MeSi), –5.6 (MeSi) ppm.
(2R,3S,6S,Z)-1-(tert-Butyldimethylsilyloxy)-6-[(2R,4R)-2-(4-meth-
oxyphenyl)-1,3-dioxan-4-yl]-2-methylhept-4-en-3-yl Acetate (15):
KHMDS (0.5 m solution in PhMe; 0.46 mL, 1.01 equiv.) was added
dropwise to a solution of phosphonium salt 14 (141.6 mg,
0.226 mmol, 1.03 equiv.) in THF (4 mL) at 0 °C. The resulting (3R,4S,7S,8R,Z)-9-(tert-Butyldimethylsilyloxy)-7-hydroxy-3-(4-
homogeneous yellow solution was stirred at 0 °C for 0.5 h, and then methoxybenzyloxy)-4,8-dimethylnon-5-enal (17) and (3R,4S,7S,
Eur. J. Org. Chem. 2015, 5402–5413
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5411

C. Bauder
FULL PAPER
8R,Z)-9-(tert-Butyldimethylsilyloxy)-7-hydroxy-3-(4-methoxybenz- 25.8 [C(CH3)3Si], 18.0 [C(Me)3Si], 17.3 (Me-4), 12.9 (Me-8), –5.6
yloxy)-4,8-dimethylnon-5-enoic Acid (18): BAIB (42.1 mg, (MeSi) ppm.
7.4 equiv.), TEMPO (5.4 mg, 1.9 equiv.), and water (0.5 mL) were
added successively to a solution of diol 16 (8 mg, 0.0176 mmol) in
CH2Cl2 (1 mL). The mixture was stirred vigorously for 44 h at
room temperature. The reaction was then quenched with aqueous
Na2S2O3·5H2O (1 m; 0.3 mL), and the mixture was diluted with
water (2 mL) and diethyl ether (5 mL). The organic layer was
(4R,5S,8S,Z)-8-[(R)-1-(tert-Butyldimethylsilyloxy)propan-2-yl]-4-
(4-methoxybenzyloxy)-5-methyl-3,4,5,8-tetrahydro-2H-oxocin-2-one
(19): Et3N (8 μL, 10.4 equiv.) and 2,4,6-trichlorobenzoyl chloride
(9 μL, 10.4 equiv.) were added to a stirred solution of acid 18
(2.6 mg, 0.0055 mmol) in dry toluene (0.5 mL). The mixture was
stirred at ambient temperature for 5 h, during which time the solu-
washed with a mixture of saturated aqueous NaHCO3 (0.3 mL)
tion became cloudy. Dry toluene (2 mL) was added, followed by a
and water (3 mL), then with water (2ϫ 3 mL), and brine (4 mL).
solution of DMAP (8.7 mg, 12.9 equiv.) in dry toluene (1 mL). The
mixture was stirred for 17 h at room temperature. EtOAc (10 mL),
It was dried with MgSO4, filtered, and concentrated under reduced
pressure. The resulting orange liquid was purified by preparative
saturated aqueous NaHCO3 (2 mL), and water (5 mL) were se-
thin-layer chromatography (EtOAc/cyclohexane, 1:3) to give alde-
quentially added to the resulting milky reaction mixture. The or-
hyde 17 (2.8 mg, 35%), and acid 18 (2.6 mg, 31%). Compound 18
ganic layer was washed with water (2ϫ 5 mL), and brine (4 mL),
dried with MgSO4, filtered, and concentrated under reduced pres-
sure to leave a yellow solid. The residue was purified by thin-layer
chromatography (EtOAc/cyclohexane, 1:3) to give lactone 19
is described in the next section. Data for aldehyde 17: [α]2D0 = +15.67
(c = 0.37, CHCl3). HRMS (ESI): calcd. for C25H42O5SiNa [M +
1
Na]+ 473.2694; found 473.2651. H NMR (500 MHz, CDCl3): δ =
9.75 (t, J = 1.9 Hz, 1 H, CHO), 7.25 and 6.86 (AAЈBBЈ, J = 8.8 Hz,
(1.3 mg, 52%). [α]2D0 = –31.9 (c = 0.13, CHCl3). HRMS (ESI): calcd.
Δν = 192 Hz, 4 H, PMB), 5.49 (dd, J = 11.1, J = 6.9 Hz, 1 H, 6-
for C25H40O5SiNa [M + Na]+ 471.2537; found 471.2532. 1H NMR
H vinyl), 5.40 (dd, J = 10.7, J = 10.3 Hz, 1 H, 5-H vinyl), 4.50 (s,
(500 MHz, CDCl3): δ = 7.29 and 6.87 (AAЈBBЈ, J = 8.5 Hz, Δν =
2 H, CH2-PMB), 4.21 (t app, J = 8.5 Hz, 1 H, 7-H), 3.89 (m, 1 H,
210 Hz, 4 H, PMB), 4.95 (t app, J = 10.5 Hz, 1 H, 6-H), 5.54 (dd,
3-H), 3.80 (s, 3 H, MeO), 3.67 (AB part of an ABX system, J9a,9b
J = 10.6, J = 6.4 Hz, 1 H, 5-H), 4.95 (t app, J = 9.2 Hz, 1 H, 7-
= 10.2, J9a,8 = 8.0, J9b,8 = 4.7 Hz, Δν = 58.7 Hz, 2 H, 9-H), 2.84
H), 4.83 and 4.41 (AB system, J = 11.5 Hz, Δν = 207 Hz, 2 H,
(m, 1 H, 4-H), 2.63 (m, 2 H, 2-H), 1.74 (m, 1 H, 8-H), 1.01 (d, J
CH2-PMB), 3.81–3.78 (m, 1 H, 9a-H), 3.80 (s, 3 H, MeO), 3.64 (d,
J = 7.3 Hz, 1 H, 3-H), 3.47 (dd, J = 9.8, J = 3.8 Hz, 1 H, 9b-H),
3.26 (dd, J = 13.4, J = 7.4 Hz, 1 H, 2a-H), 2.75 (d, J = 13.4 Hz, 1
= 6.7 Hz, 3 H, Me-4), 0.90 (s, 9 H, tBu-Si), 0.77 (d, J = 6.9 Hz, 3
H, Me-8), 0.08 (s, 6 H, Me-Si) ppm. 13C NMR (125 MHz, CDCl3):
δ = 201.9 (CHO), 159.2 (Cq arom, PMB), 133.3 (CH-5 vinyl), 132.6
H, 2b-H), 269 (m, 1 H, 4-H), 2.07 (m, 1 H, 8-H), 1.17 (d, J =
(CH-6 vinyl), 130.2 (Cq arom, PMB), 129.5 (CH arom, PMB),
7.0 Hz, 3 H, Me-4), 0.93 (d, J = 7.0 Hz, 3 H, Me-8), 0.88 (s, 9 H,
113.7 (CH arom, PMB), 77.1 (CH-3), 71.9 (CH2-PMB), 71.8 (CH-
7), 67.8 (CH2-9), 55.2 (OMe), 45.9 (CH2-2), 40.1 (CH-8), 35.7 (CH-
4), 25.8 [C(CH3)3Si], 18.1 [C(Me)3Si], 16.5 (Me-4), 13.1 (Me-8),
–5.5 (MeSi), –5.6 (MeSi) ppm.
tBu-Si), 0.03 (s, 3 H, Me-Si), 0.02 (s, 3 H, Me-Si) ppm. 13C NMR
(125 MHz, CDCl3): δ = 172.0 (CO ester), 159.2 (Cq arom, PMB),
138.7 (CH-5 vinyl), 129.9 (CH arom, PMB), 129.6 (CH-6 vinyl),
113.6 (CH arom, PMB), 75.9 (CH-3), 74.7 (CH-7), 70.3 (CH2-
PMB), 63.3 (CH2-9), 55.2 (OMe), 38.7 (CH-8), 38.1 (CH-4), 37.7
(3R,4S,7S,8R,Z)-9-(tert-Butyldimethylsilyloxy)-7-hydroxy-3-(4-
(CH2-2), 25.9 [C(CH3)3Si], 19.9 (Me-4), 18.2 [C(Me)3Si], 12.6 (Me-
methoxybenzyloxy)-4,8-dimethylnon-5-enoic Acid (18): A premixed
8), –5.5 (MeSi), –5.6 (MeSi) ppm.
solution of NaClO2 (41.2 mg, 29 equiv.) and NaH2PO4·H2O
(28.5 mg, 13 equiv.) in distilled water (0.9 mL) was added to a vig-
orously stirred solution of tBuOH (3.2 mL) and amylene (1.3 mL).
The mixture was stirred for 15 min at ambient temperature, and
then it was added to neat aldehyde 17 (7.1 mg, 0.0157 mmol). The
reaction was run for 1 h at room temperature, after which time
TLC indicated the disappearance of the aldehyde. Water (2 mL)
and EtOAc (5 mL) were added, and the aqueous layer was ex-
tracted with EtOAc (5 mL). The combined organic layers were
evaporated to remove the tBuOH. The residue was diluted with
EtOAc (6 mL), and the organic phase was washed with water
(4 mL), and brine (4 mL), dried with MgSO4, filtered, and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (EtOAc/cyclohexane, 1:1) to give acid
CCDC-1039716 (for 3) and -1039717 (for 4) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Full NMR spectroscopic data and crystallographic data.
Acknowledgments
C. B. is grateful to Dr. D. Matt for his constant support and en-
couragement.
1
18 (3.6 mg, 49%). H NMR (500 MHz, CDCl3): δ = 7.27 and 6.87
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J2a,2b = 14.2, J2a,3 = 7.5, J2b,3 = 5.5 Hz, Δν = 28.7 Hz, 2 H, 2-H),
1.81 (m, 1 H, 8-H), 1.03 (d, J = 6.7 Hz, 3 H, Me-4), 0.89 (s, 9 H,
tBu-Si), 0.76 (d, J = 7.0 Hz, 3 H, Me-8), 0.09 (s, 6 H, Me-Si) ppm.
13C NMR (125 MHz, CDCl3): δ = 173.5 (COOH), 159.2 (Cq arom,
PMB), 134.2 (CH-5 or CH-6 vinyl), 131.7 (CH-5 or CH-6 vinyl),
130.0 (Cq arom, PMB), 129.5 (CH arom, PMB), 113.7 (CH arom,
PMB), 79.6 (CH-3), 72.4 (CH-7), 71.9 (CH2-PMB), 68.4 (CH2-9),
55.2 (OMe), 39.6 (CH-8), 37.8 (CH2-2), 36.1 (CH-4), 29.7 (grease),
5412
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5402–5413

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[22] A ring-closing metathesis reaction (RCM) from bis-terminal
olefin 24 was not observed in our specific case; see the Support-
ing Information for the synthesis of 24.
Received: April 24, 2015
Published Online: July 17, 2015
Eur. J. Org. Chem. 2015, 5402–5413
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5413