Total synthesis of mycestericin A and its 14-epimer

Article abstract of DOI:10.1016/j.tet.2009.09.012

The total synthesis of mycestericin A (1) and its 14-epimer 34 is described herein. The Overman rearrangement of an allylic trichloroacetimidate derived from l-tartrate generated a tetra-substituted carbon with nitrogen and subsequent stereoselective transformations afforded the highly functionalized left-half segment, vinyl iodide. Cross-coupling of the vinyl iodide with a chiral organometallic species synthesized from d-tartrate under the Negishi or Suzuki-Miyaura coupling conditions, followed by deprotection, completed the total synthesis of 1. The 14-epimer of mycestericin A was also synthesized, and a comparison of [α]_D values of peracetyl γ-lactone derivatives of mycestericin A and its 14-epimer as well as degradation studies of 1 and 34 fully confirmed the proposed absolute structure of mycestericin A.

Full text of DOI:10.1016/j.tet.2009.09.012

Tetrahedron 65 (2009) 9188–9201
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of mycestericin A and its 14-epimer
,
Hiroyoshi Yamanaka a, Kazuya Sato a, Hideyuki Sato a, Masatoshi Iida a, Takeshi Oishi b, Noritaka Chida a
*
a Department of Applied Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
b School of Medicine, Keio University, 4-1-1 Hiyoshi, Kohoku-ku, Yokohama 223-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of mycestericin A (1) and its 14-epimer 34 is described herein. The Overman re-
arrangement of an allylic trichloroacetimidate derived from -tartrate generated a tetra-substituted
carbon with nitrogen and subsequent stereoselective transformations afforded the highly functionalized
left-half segment, vinyl iodide. Cross-coupling of the vinyl iodide with a chiral organometallic species
Received 21 August 2009
Accepted 4 September 2009
Available online 9 September 2009
L
synthesized from
protection, completed the total synthesis of 1. The 14-epimer of mycestericin A was also synthesized, and
a comparison of [ D values of peracetyl -lactone derivatives of mycestericin A and its 14-epimer as well
as degradation studies of 1 and 34 fully confirmed the proposed absolute structure of mycestericin A.
Ó 2009 Elsevier Ltd. All rights reserved.
D-tartrate under the Negishi or Suzuki–Miyaura coupling conditions, followed by de-
Keywords:
Mycestericin A
Total synthesis
Overman rearrangement
Negishi coupling
Suzuki–Miyaura coupling
a]
g
1. Introduction
generate natural products possessing
structures.7–11
a-substituted a-amino acid
Mycestericin A (1) is a member of mycestericins produced by
Mycelia sterilia and has been reported to have a potent immuno-
suppressive activity.1 A structural elucidation study revealed that
the structure of mycestericin A is similar to that of myriocin, a well-
known immunosuppressant and serine palmitoyltransferase (SPT)
To date, however, there has been no reported study of the
synthesis of mycestericin A, which possesses the most complicated
structure in the mycestericin family. In this paper, we present the
first report of the total synthesis of mycestericin A and its 14-epi-
mer from tartrates, and the confirmation of the proposed absolute
structure of the natural product.12
inhibitor, possessing an intriguing
a-substituted a-amino acid
structure,2 although mycestericin A has another E-olefin between
C-12 and C-13 and one distal (R)-allylic alcohol function at C-14
(Fig. 1).1a The stereochemistry at C-14 was determined using the
benzoate CD chirality method of an N-acetyl-14-O-benzoyl de-
2. Results and discussion
2.1. Retrosynthesis
rivative of mycestericin A
g-lactone, which was prepared from
natural 1.1a Mycestericin A and its congeners have been reported to
have comparable IC50 values to that of myriocin in the nanomolar
range in the mouse allogeneic mixed lymphocyte reaction.1 Due to
their potent biological properties such as immunosuppressive,
antifungal, and SPT inhibitory activities,3 naturally occurring mol-
ecules of this type, including myriocin,2 sphingofungins,4 sulfa-
misterins,5 and mycestericins,1 as well as their derivatives are
expected to be promising lead compounds for novel therapeutic
agents based on their ability to modulate sphingolipid bio-
synthesis.6 These interesting biological findings as well as archi-
tecturally novel structures have stimulated a number of synthetic
efforts, including total syntheses and synthetic approaches to
Our previous success with the total synthesis of myriocin,9e,10h
sphingofungin E,10h and lactacystin,13 from aldohexoses suggested
that the Overman rearrangement14,15 on chiral scaffolds would ef-
fectively generate the tetra-substituted carbon with nitrogen. This
idea involves disconnection of the carbon framework in 1 into the
highly functionalized left-half segment, vinyl iodide 2 or 3, and the
hydrophobic right-half segment, organometallic species 4, pos-
sessing an (E,R)-allylic alcohol function (Fig. 2). The well-established
Pd-catalyzed coupling reaction of 2 or 3 with 4 was expected to
stereoselectively construct the carbon backbone with two E-olefins
in 1. We planned to prepare the left-half segment 2 or 3 from
homoallyl alcohol 6, which was thought to arise by the stereo-
selective allylation of aldehyde 7. The Overman rearrangement of
chiral allylic trichloroacetimidate 8 would install a tetra-substituted
carbon with nitrogen in 7, generating a precursor of
a-substituted a-
* Corresponding author. Tel.: þ81 45 566 1573; fax: þ81 45 566 1551.
E-mail address: chida@applc.keio.ac.jp (N. Chida).
amino acid. For the preparation of imidate 8, -tartrate was chosen
L
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.012

H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
9189
2.2. Preparation of the highly functionalized left half,
vinyl iodide 2
The synthesis of 2 commenced with the known acetonide 916
prepared from dimethyl
-tartrate in a three-step reactions11e with
L
a 31% overall yield (Scheme 1). After protection of the primary
hydroxy group in 9, the O-benzyl group in 10 was removed to give
11 with a 94% yield from 9. PCC oxidation of 11, followed by the
Wittig reaction generated 12 as the single isomer (93% for two
steps). The E-geometry of 12 was confirmed by the observed NOE
between a vinyl proton and H-4. The reduction of 12 with DIBAL
generated allyl alcohol 13 with a yield of 97%. The treatment of 13
with trichloroacetonitrile and DBU produced trichloroacetimidate
8, which, without purification, was heated in xylene in the presence
17
of K2CO3 in a sealed tube at 140 ꢀC for 48 h. Due to Overman
rearrangement, this reaction provided 1418 and its epimer, epi-14,
with isolated yields of 62% and 33%, respectively. Although the
observed stereoselectivity in the Overman rearrangement of 8 was
moderate (14:epi-14¼1.9:1), the relatively short-step synthesis of
14 from 9 with acceptable overall yields led us to employ this ap-
proach for the total synthesis. At this stage, the structure of 14 could
not be fully determined but was later confirmed by X-ray analysis of
the more advanced compound 6 (vide infra).
Figure 1. Structures of mycestericin A and related natural products.
as a homochiral starting material. On the other hand, the counter-
part 4, which would be generated from alkyl iodide 5, was planned
to be synthesized from
gation reaction.
D-tartrate by the E-selective carbon-elon-
Scheme 1. Bn¼–CH2Ph, PCC¼pyridinium chlorochromate, MS4A¼molecular sieves
4 Å, DIBAL¼[(CH3)2CHCH2]2AlH.
The transformation of rearranged product 14 to generate 2 was
next examined (Scheme 2). Ozonolysis of 14, followed by further
oxidation and esterification produced 15 with a 97% yield. Removal
of the O-silyl protecting group resulted in 16 (100% yield). Pfitzner–
Moffatt oxidation of 16 gave aldehyde 7, which, without purifica-
tion, was reacted with allyl tributyltin in the presence of MgBr2 in
19
CH2Cl2 to stereoselectively generate an allylated product, homo-
allyl alcohol 6, as the sole product in 75% yield from 16.
The chelation control (between an aldehyde-carbonyl and an
a-ether oxygen) was expected to favor the formation of 6, the
structure of which has been unambiguously assigned by a single
crystal X-ray analysis.20 The hydroxy group in 6 was protected as
a methoxymethyl ether to give 17 (80% yield). Ozonolysis of 17,
Figure 2. Retrosynthetic route to mycestericin A. MOM¼–CH2OMe, TBDPS¼–SiPh2(t-Bu).

9190
H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
Scheme 3. 9-BBN¼9-borabicyclo[3.3.1]nonane, Ms¼–SO2Me.
hydroxy group in 22a was transformed into O-mesylate, which was
then reacted with allylmagnesium chloride24 to provide 23a in 81%
yield. Hydroboration of 23a with excess 9-BBN (8 equiv to 23a)
followed by oxidation provided primary alcohol 24a, whose hydroxy
function was replaced with iodide, to give 5a,18 a precursor for the
coupling reaction, with a 75% yield.
Scheme 2. DCC¼N,N0-dicyclohexylcarbodiimide, TFA¼CF3CO2H.
followed by the Takai reaction21 with CHI3 in the presence of CrCl2
in THF/1,4-dioxane provided (E)-vinyl iodide (2) with a 60% yield as
a geometrically pure compound after chromatographic purification.
2.3. Synthesis of the hydrophobic right-half segment
2.4. Attempted synthesis of 1 via the Negishi coupling
reaction
The counterpart for the coupling reaction, a precursor of or-
ganometallic species, iodide 5a, was synthesized from
(Scheme 3). The known di-O-tosylate22 18, prepared from diiso-
propyl -tartrate with an 86% overall yield, was treated with n-
D
-tartrate
Having established the procedure for the preparation of both
counterparts for the coupling reaction, we subsequently explored
the conditions of the Negishi cross-coupling reaction,25 which has
been utilized for the total synthesis of myriocin and sphingofungin
F by Ham et al.9f,10i The reaction of iodide 5a with t-BuLi at ꢁ78 ꢀC
followed by treatment with ZnCl2 generated an alkyl zinc species.
This was then reacted with vinyl iodide 2 in the presence of
Pd(PPh3)4 to generate the coupling product, fully protected
mycestericin A (25), in 86% yield (Scheme 4). The treatment of 25
with aqueous HCl at 60 ꢀC removed all the protecting groups,
however, the concomitant elimination of a methoxymethyloxy or
hydroxy function at C-14 (mycestericin A numbering) also occurred
D
pentylmagnesium bromide in the presence of CuBr to afford 19 in
53% yield. After deprotection of the acetonide group, the product
was converted into epoxide 20 (93% yield), whose hydroxy group
was protected as an MOM ether to give 21a (96% yield).
23
Oxidative cleavage of the epoxide group in 21a with HIO4
generated the corresponding aldehyde, which was then reacted with
the stabilized Wittig reagent to afford an inseparable mixture of
E-olefin and its Z-isomer (E:Z¼6.5:1). DIBAL reduction of the mixture
followed by chromatographic separation gave geometrically pure
E-allyl alcohol 22a in 55% isolated yield from 21a. The primary
and, after acetylation, g
-lactone-diene 2726 was obtained. On the
Scheme 4.

H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
9191
cation intermediate 26. The attempted deprotection of 25 with
TMSBr, which was reported to be effective for the clean depro-
tection of an allylic MOM ethers,27 also resulted in the formation of
a mixture of 28a,b and 29a,b. These results clearly showed that the
allylic alcohol moiety in 25 is unexpectedly labile under the acidic
conditions used, prompting us to devise an improved route to 1.
2.5. The alternative approach to 1: completion of the total
synthesis
To avoid the formation of the allyl cation 26, a coupling reaction
of substrates possessing protecting groups that could be removed
under basic conditions was next explored (Scheme 5). For this
purpose, compound 6 was converted into g-lactone 30 (98% yield)
by treatment with aqueous acetic acid at 70 ꢀC followed by acety-
lation. Ozonolysis of 30 and subsequent Takai reaction generated
a new left-half segment, vinyl iodide 3, as a single E-isomer after
chromatographic purification with a yield of 73%. On the other
hand, for the preparation of the right-half segment, the alcohol
function in epoxide 20 was protected as a 2-(trimethylsilyl)ethoxy-
methyl (SEM) group to give 21b (100% yield). Then, the same re-
action sequence as employed for the conversion of 21a to 5a was
applied to 21b to provide 5b18 with a 28% overall yield from 21b.
Another right-half segment 23c, possessing a TBDPS protecting
group, was also synthesized from 20 (56% overall for six steps)
following the same reaction sequence. Although epoxide 20 could
also be transformed into its OTBS and OTES derivatives, it was
found that the periodate oxidation of the epoxides possessing OTBS
and OTES groups resulted in the decomposition of the substrates.
The Negishi coupling of 5b-derived alkyl zinc with g-lactone 3,
followed by acetylation, successfully provided 31 (44% yield;
Scheme 6). Compound 31 was treated with anhydrous Bu4NF and
MS4A in N,N-dimethyl propylene urea (DMPU)28 at 80 ꢀC and then
acetylated. Under these reaction conditions, the SEM protecting
group was successfully removed without formation of an allyl
cation to generate tetraacetyl mycestericin A
a single isomer (38% yield). The spectral data (1H and 13C NMR) as
well as the [ D value of the synthetic 28b were identical with those
reported for
-lactone obtained from natural mycestericin A.1a Fi-
g-lactone (28b) as
Scheme 5. SEM¼–CH2OCH2CH2SiMe3.
a
g
]
other hand, the reaction of 25 with aqueous acetic acid followed by
nally, alkaline hydrolysis of 28b followed by ion-exchange resin
(IRC-76) treatment furnished mycestericin A (1) in 93% yield. The
acetylation afforded a
g-lactone, which is expected to possess the
structure of 28b (49% yield). The 1H NMR data of the synthetic
21
25
[a
]
value {[
a
]
ꢁ8.6 (c 0.45, MeOH); lit.1a
[
a]
D
ꢁ8.5 (c 0.50,
D
D
g
-lactone were very similar to those reported for the lactone 28b
derived from natural mycestericin A1a and the FABMS data also
MeOH)} and spectroscopic data showed good concordance with
those reported for the natural product.1a Thus, the first total syn-
thesis of mycestericin (1) has been achieved.
supported its structure. However, in the 13C NMR of the synthetic
g-lactone, in addition to a set of four signals (d 123.2, 128.6, 134.0,
and 135.0 ppm) due to olefinic carbons whose chemical shifts are in
good agreement with those of the authentic 28b, an extra four
signals (d 123.1, 128.1, 134.4, and 134.6 ppm) of olefinic carbons,
2.6. The second-generation total synthesis via the Suzuki–
Miyaura coupling
whose intensities were almost same as those of the former four
signals, were observed. These results revealed that the synthetic
As described in the previous section, mycestericin A (1) was
successfully synthesized using Negishi coupling as the key reaction.
However, the yield of the coupling reaction (44%) was not satis-
factory and, furthermore, the final deprotection also resulted in
g-lactone is an inseparable mixture of diastereomers. The most
plausible products of the acid hydrolysis of 25, followed by acety-
lation, are 28a,b and 29a,b, which would be formed via the allyl
Scheme 6. DMPU¼N,N-dimethyl propylene urea.

9192
H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
a poor yield (38%). The low yield of the Negishi coupling may be due
to the presence of base-sensitive functionalities ( -lactone and
g
acetyl groups) in the left-half segment (3), which might have un-
dergone attack by an excess of organozinc or organolithium re-
agents. The harsh basic reaction conditions for the deprotection of
the OSEM group would have induced the decomposition of the
substrate and/or product.29 To improve these crucial steps, the
Suzuki–Miyaura method30 of coupling
g-lactone 3 with an orga-
noborane derived from the alkene 23c possessing OTBDPS group
was next investigated. The B-alkyl Suzuki–Miyaura coupling pro-
cedure has been successfully employed in the total synthesis of
sphingofungins E and F by Trost,10d and sphingofungin E by Naka-
mura and Shiozaki.10g
Hydroboration of 23c with excess 9-BBN followed by H2O
quench produced the corresponding organoborane, which was
then reacted with 3 in the presence of PdCl2$dppf, Ph3As, and
K2CO3 in DMF (Scheme 7). To our delight, under these reaction
conditions, coupling product 32 was obtained with a yield of 87%.
The use of Ph3As was found to be essential for a higher yield; the
similar reaction in the absence of Ph3As gave 32 in 58% yield.31
Although the treatment of 32 with Bu4NF in THF at room temper-
ature resulted in recovery of the starting material, the reaction
performed at 65 ꢀC generated 28b in 63% yield after acetylation. By
use of the Suzuki–Miyaura coupling reaction, the overall yield of
mycestericin A was much improved (4.3% yield from 9 using the
Negishi coupling approach compared to 14.0% yield from 9 with the
Suzuki–Miyaura approach).
Scheme 8.
The 1H and 13C NMR spectra of 28a and 34 were quite similar to
those of 28b and 1, respectively, and we were unable to detect any
notable differences between the NMR spectra of 28a and 28b and
those between 34 and 1. Fortunately, it was found that the [
values of these compounds displayed some differences as shown in
Table 1. The relatively large differences in [ D values between 28b
a]
D
a
]
and 28a (Table 1, entries 1–3) allowed us to clearly distinguish
these two compounds, assigning the stereochemistry at C-14 in
natural mycestericin A as R.
Table 1
[a] values of compounds 28b, 28a, 1, and 34
D
Scheme 7.
Entry Compound Source
[
a
]
D
Measurement conditions
1
2
3
4
5
6
28b
28b
28a
1
1
34
From natural product þ58.4a 25 ꢀC, c 0.5, CHCl3
Synthetic
þ58.2 21 ꢀC, c 0.41, CHCl3
þ30.0 21 ꢀC, c 0.22, CHCl3
ꢁ8.5a 25 ꢀC, c 0.5, MeOH
ꢁ8.6 21 ꢀC, c 0.45, MeOH
ꢁ5.0 20 ꢀC, c 0.15, MeOH
2.7. Total synthesis of 14-epi-mycestricin A (34): confirmation
of the stereochemistry at C-14 of the natural product
Synthetic
Natural product
Synthetic
Synthetic
As described in the Introduction, the C-14 stereochemistry of
mycestericin A had been determined by way of the benzoate CD
chirality method for the N-acetyl-14-O-benzoyl derivative of
a
Ref. 1a.
mycestericin A g
-lactone.1a To confirm the stereochemistry at C-14
by the synthetic method, synthesis of 14-epimer of mycestericin A
was next investigated. For this purpose, the enantiomer of diene
2.8. Degradation studies of mycestericin A (1) and its
14-epimer (34)
23c (ent-23c) was synthesized starting from dimethyl
a similar reaction sequence to that employed for the conversion of
diisopropyl
-tartrate to 23c (Scheme 8).32 The B-alkyl Suzuki–
Miyaura coupling of an organoborane generated from ent-23c with
vinyl iodide 3 afforded the coupling product 33 in 77% yield.
Deprotection of the OTBDPS group and subsequent acetylation
L-tartrate by
It is a possible that the allylic hydroxy functions at C-14 in
compounds 1 and 34 might undergo partial epimerization during
the synthetic or purification process via an allyl cation intermediate
and it is now understood that such epimerization cannot be
detected by 1H nor 13C NMR analyses. To confirm the stereo-
chemical purities at C-14 in final compounds 1 and 34, studies of
their degradation were conducted (Scheme 9). In the preparation of
reference compounds (36 and ent-36) for HPLC analyses, com-
pound 22b was converted into diacetate 35 (77% yield). Ozonolysis
D
provided 14-epi-tetraacetyl mycestericin A g-lactone (28a) in 26%
yield. Alkaline hydrolysis of 28a, followed by ion-exchange resin
(IRC-76) treatment, resulted in an 81% yield of 14-epi-mycestericin
A (34).

H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
9193
of 35 (reductive workup with NaBH4), followed by the removal of
4. Experimental
4.1. General
O-acetyl groups and subsequent O-benzoylation, produced au-
thentic 36 in 49% yield. A similar reaction sequence was applied to
ent-22b to give ent-36. The chiral HPLC analyses (DAICEL CHIR-
ALCEL OJ-H, 4.6 mm IDꢂ250 mm, i-PrOH/hexane¼1:300, flow
rate¼0.8 mL/min) of 36 (retention time: 21.9 min) and ent-36 (re-
tention time: 19.0 min) revealed that the optical purities of both
compounds were >99% ee. Next, the degradation reactions of
synthetic mycestericin A (1) and its 14-epimer (34) were per-
Melting points were determined on a Mitamura-Riken micro
hot stage and were not corrected. Optical rotations were recorded
using a sodium lamp (589 nm) with a JASCO DIP-370 instrument
with 1 dm tube and values of [
a
]
are recorded in units of
D
10ꢁ1 deg cm2 gꢁ1. Infrared (IR) spectra were measured with a JASCO
FT/IR-200 spectrometer. 1H NMR spectra were recorded at 300 MHz
on a JEOL Lambda 300 or on a Varian MVX-300 spectrometers for
solutions in CDCl3, unless otherwise noted. Chemical shifts are
formed. Treatment of
1 with Ac2O/pyridine gave tetraacetyl
mycestericin -lactone (28b), whose ozonolysis (reductive
A
g
workup with NaBH4) followed by basic methanolysis and sub-
sequent benzoylation provided a dibenzoate in 50% overall yield
after chromatographic separation. The same reaction sequence was
applied to 14-epi-mycestericin A (34) to afford a dibenzoate via 28a
in 38% overall yield. The 1H NMR spectra of these dibenzoates were
totally identical to those of 36. The chiral HPLC analyses of degra-
dation products clearly showed that the dibenzoate derived from
mycestericin A (1) is 36 with >99% ee, whereas the dibenzoate
obtained from 14-epi-mycestericin A (34) is ent-36 with >99% ee.
From these experiments it was confirmed that no epimerization at
C-14 had occurred during the synthetic and purification processes
for the preparation of 1 and 34, and our final products (1 and 34)
were both diastereomerically homogeneous.
reported as
d values in parts per million. Abbreviations used are:
b (broad peak), s (singlet), d (doublet), t (triplet), q (quartet) and m
(complex multiplet). 13C NMR spectra were recorded at 75 MHz on
a JEOL Lambda 300 spectrometer for solutions in CDCl3, unless
otherwise noted. Chemical shifts are reported as
d values in parts
per million. Mass spectra are measured by a JEOL GC Mate spec-
trometer with EI (70 eV) or FAB mode. Organic extracts were dried
over solid anhydrous Na2SO4 and concentrated below 40 ꢀC under
reduced pressure. Column chromatography was carried out with
silica gel (Merck Kieselgel 60 F254; 230–400 mesh) for purification.
Preparative TLC (PLC) was performed with Merck PLC plate (Kie-
selgel 60 F254, 0.5 mm thickness).
4.2. Synthesis of the left-half segment
4.2.1. {[(4S,5S)-5-(Benzyloxy)-2,2-dimethyl-1,3-dioxan-4-yl]methoxy}-
(tert-butyl)-diphenylsilane (10). To a solution of [(4S,5S)-5-(benzyl-
oxy)-2,2-dimethyl-1,3-dioxan-4-yl]methanol16,11e
(9)
(1.34 g,
5.31 mmol) in DMF (18 mL) at room temperature were added im-
idazole (545 mg, 8.01 mmol) and TBDPSCl (1.90 mL, 7.31 mmol).
After being stirred at room temperature for 20 h, the reaction mix-
ture was diluted with brine, and products were extracted with EtOAc.
The organic layer was washed with brine, and dried. Removal of the
solvent left a residue, which was purified by column chromatogra-
phy (100 g silica gel, 1:20–1:10 EtOAc/hexane as an eluent) to afford
25
10 (2.61 g, 100%) as a colorless syrup: [
a
]
þ15.3 (c 0.89, CHCl3); IR
D
(neat) 3450, 2990, 2940, 2875, 1455, 1385, 1200, 1120, 1080, 1055,
1025 cmꢁ1; 1H NMR
d
1.06 (9H, s), 1.39, 1.40 (each 3H, 2s), 3.43 (1H,
ddd, J¼1.4, 2.0, 3.9 Hz), 3.71 (1H, ddd, J¼3.9, 9.0, 9.0 Hz), 3.89 (1H, dd,
J¼2.0, 12.9 Hz), 3.94–4.02 (3H, m), 4.56 and 4.72 (each 1H, 2d,
J¼11.9 Hz), 7.25–7.46 (11H, m), 7.63–7.68 (4H, m); 13C NMR
d 19.1,
19.4, 27.1, 29.2, 62.2, 63.0, 69.7, 71.6, 72.3, 98.7, 127.7, 127.9, 128.0,
128.5, 129.8, 129.9, 133.7, 133.8, 135.8, 135.8, 138.6; HRMS (FAB) m/z
calcd for C30H38O4SiNa (MþNa)þ 513.2437, found: m/z 513.2452.
4.2.2. (4S,5S)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,2-dimethyl-
1,3-dioxan-5-ol (11). To
a solution of naphthalene (1.02 g,
7.96 mmol) in THF at ꢁ10 ꢀC was added Li (37 mg, 5.3 mmol), and
the mixture was stirred at ꢁ10 ꢀC for 30 min. To this mixture
ꢁ10 ꢀC under Ar was added a solution of 10 (261 mg, 0.532 mmol)
in THF (5.6 mL). After being stirred at ꢁ10 ꢀC for 3.5 h, the reaction
mixture was quenched by addition of EtOH (2 mL) and then diluted
with EtOAc. The organic layer was washed with brine, and dried.
Removal of the solvent left a residue, which was purified by column
Scheme 9. Bz¼–C(O)Ph.
3. Conclusion
In summary, the first total synthesis of mycestericin A (1) from
chromatography (50 g silica gel, 1:40–1:3 EtOAc/hexane as an el-
22
dimethyl
steps and 4.3% overall yield). The synthesis of 14-epi-mycestericin A
(34), comparison of the [ values of their -lactone derivatives
L-tartrate has been achieved via an efficient route (24
uent) to afford 11 (200 mg, 94%) as a colorless syrup: [
a
]
þ15.6 (c
D
1.52, CHCl3); IR nmax (neat) 3480, 2995, 2960, 2930, 2860, 1470,
a
]
g
1425, 1365, 1275, 1230, 1200, 1130, 1110, 1065 cmꢁ1; 1H NMR
d
1.06
D
(28b and 28a), and the degradation studies of 1 and 34 fully con-
firmed the proposed absolute structure of the natural product, in-
cluding the stereochemistry at the distal C-14 hydroxy group. This
work has also provided a new synthetic pathway for the synthesis
(9H, s), 1.40 and 1.43 (each 3H, 2s), 2.76 (1H, d, J¼10.2 Hz), 3.63 (1H,
dddd, J¼1.5, 1.5, 2.7, 10.2 Hz), 3.68 (1H, dd, J¼5.1, 9.8 Hz), 3.85 (1H,
dd, J¼2.7, 12.2 Hz), 3.87 (1H, dd, J¼7.1, 9.8 Hz), 3.95 (1H, ddd, J¼1.5,
5.1, 7.1 Hz), 4.05 (1H, dd, J¼1.5, 12.2 Hz), 7.34–7.46 (6H, m), 7.65–
of highly oxygenated
a
-substituted
a
-amino acid derivatives with
7.74 (4H, m); 13C NMR
d 18.6, 19.4, 27.0, 29.6, 63.7, 66.2, 72.4, 99.1,
potent biological activities utilizing readily available tartrates.
127.9, 129.9, 133.4, 133.7, 135.8, 135.9; HRMS (FAB) m/z calcd for

9194
H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
C23H33O4Si, (MþH)þ 401.2148, found: 401.2145. Anal. Calcd for
epi-14 (327 mg, 33% from 12) as a crystalline residue. Data for 14:
21
C23H32O4Si: C, 68.83; H, 8.05. Found: C, 68.83; H, 7.98.
[a
]
þ12.6 (c 1.20, CHCl3); IR nmax (neat) 3400, 2930, 2860, 1720,
D
1515,1505,1425,1380,1200,1140, 1115 cmꢁ1; 1H NMR
d 1.08 (9H, s),
4.2.3. (2E)-Ethyl 2-{(4R)-4-[(tert-butyldiphenylsilyloxy)methyl]-2,2-
dimethyl-1,3-dioxan-5-ylidene}acetate (12). To the mixture of 11
(1.04 g, 2.60 mmol) and MS 4 Å (800 mg) in CH2Cl2 (40 mL) was
added a suspension of PCC (1.96 g, 9.10 mmol), NaOAc (1.49 g,
18.2 mmol), and MS 4 Å (800 mg) in CH2Cl2 (40 mL), and the mix-
ture was stirred at room temperature for 2 h. The reaction mixture
was partially concentrated and then diluted with Et2O. The in-
soluble material was removed by filtration through a pad of Celite.
The filtrate was concentrated to give a crude ketone (929 mg) as
a yellow syrup, which was used for next reaction without further
purification. To a solution of the crude ketone (929 mg) in toluene
(27 mL) was added Ph3P]CHCO2Et (2.70 g, 7.80 mmol), and the
mixture was stirred at 100 ꢀC for 12 h. The mixture was concen-
trated to give a residue, which was purified by column chroma-
1.47 and 1.48 (each 3H, 2s), 3.80 (1H, d, J¼11.9 Hz), 3.80–3.91 (2H,
m), 3.94 (1H, dd, J¼2.2, 10.2 Hz), 4.31 (1H, d, J¼11.9 Hz), 5.16 (1H, d,
J¼17.5 Hz), 5.28 (1H, d, J¼11.2 Hz), 5.78 (1H, dd, J¼11.2, 17.5 Hz),
7.32–7.48 (6H, m), 7.64–7.74 (5H, m); 13C NMR
d 18.5, 19.4, 27.0,
29.2, 58.3, 63.0, 64.2, 75.8, 92.9, 99.5, 116.9, 127.7, 127.7, 129.8, 133.1,
133.3, 135.7, 135.8, 161.2; HRMS (FAB) m/z calcd for C27H35Cl3NO4Si,
(MþH)þ 570.1401, found: 570.1398. Anal. Calcd for C27H34NO4Cl3Si:
C, 56.79; H, 6.00; N, 2.45. Found: C, 56.61; H, 6.29; N, 2.45. Data for
25
epi-14: mp 77.6–79.0 ꢀC; [
a
]
D
þ1.8 (c 0.47, CHCl3); IR (neat) 3340,
2915, 1860, 1730, 1510, 1430, 1240, 1200, 1100, 1055 cmꢁ1; 1H NMR
d
1.11 (9H, s), 1.38 and 1.51 (each 3H, 2s), 3.66 (1H, dd, J¼3.9,
10.2 Hz), 3.88 (1H, dd, J¼8.3, 10.2 Hz), 4.12 (1H, d, J¼11.7 Hz), 4.19
(1H, dd, J¼3.9, 8.3 Hz), 4.61 (1H, d, J¼11.7 Hz), 5.36 (1H, d,
J¼17.6 Hz), 5.41 (1H, d, J¼11.0 Hz), 6.25 (1H, dd, J¼11.0, 17.6 Hz),
tography (50 g silica gel, 1:20 EtOAc/toluene as an eluent) to afford
7.34–7.48 (6H, m), 7.58–7.66 (4H, m), 7.70 (1H, br s); 13C NMR
d 18.9,
22
12 (1.14 g, 93% for two steps) as a colorless syrup: [
a
]
ꢁ52.4 (c 0.70,
19.5, 27.3, 28.6, 58.5, 65.3, 66.1, 72.8, 99.3, 115.9, 127.9, 130.1, 132.7,
132.7, 132.8, 135.5, 161.3; HRMS (FAB) m/z calcd for C27H35Cl3NO4Si,
(MþH)þ 570.1401, found: 570.1392. Anal. Calcd for C27H34NO4Cl3Si:
C, 56.79; H, 6.00; N, 2.45. Found: C, 56.99; H, 6.12; N, 2.30.
D
CHCl3); IR nmax (neat) 2990, 2935, 2860, 1715, 1415, 1370, 1210, 1150,
1115 cmꢁ1; 1H NMR
d
1.06 (9H, s),1.27 (3H, t, J¼7.3 Hz),1.35 and 1.36
(each 3H, 2s), 3.83 (1H, dd, J¼5.9, 10.5 Hz), 3.90 (1H, dd, J¼5.6,
10.5 Hz), 4.15 (2H, q, J¼7.3 Hz), 4.41 (1H, ddd, J¼2.0, 5.6, 5.9 Hz), 4.61
(1H, ddd, J¼2.0, 3.9, 17.8 Hz), 5.02 (1H, dd, J¼2.0, 17.8 Hz), 5.78 (1H,
dd, 1H, J¼2.0, 3.9 Hz) 7.34–7.46 (6H, m), 7.64–7.71 (4H, m); 13C NMR
Starting from diisopropyl
14) was synthesized by the similar procedures as described for the
preparation of 14 from dimethyl -tartrate. Optical purities of 14
D-tartrate, an enantiomer of 14 (ent-
L
d
14.4, 19.4, 24.4, 25.3, 27.0, 60.3, 61.9, 65.0, 71.7, 100.3, 112.6, 127.9,
and ent-14 were determined to be >99% ee by chiral HPLC analyses
[DAICEL CHIRALCEL OD-H, 4.6 mm IDꢂ250 mm, i-PrOH/
hexane¼1:15, flow rate¼0.8 mL/min, UV (254 nm) detection]: re-
tention time for 14, 6.0 min; for ent-14, 7.2 min.
127.9, 129.9, 133.5, 135.8, 135.8, 158.9, 166.1; HRMS (FAB) m/z calcd
for C27H37O5Si, (MþH)þ 469.2410, found: 469.2407. Anal. Calcd for
C27H36O5Si: C, 69.20; H, 7.74. Found: C, 69.19; H, 7.54.
4.2.4. (2E)-2-{(4R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,2-di-
4.2.6. Methyl (4R,5S)-4-[(tert-butyldiphenylsilyloxy)methyl]-2,2-di-
methyl-5-(2,2,2-trichloroacetamido)-1,3-dioxane-5-carboxylate
(15). Ozonewas introduced intoa solution 14 (375 mg, 0.657 mmol)
in EtOH (6.6 mL) at ꢁ78 ꢀC for 25 min. Afterconfirming the complete
consumption of the starting material (TLC analysis), excess ozone
was removed with a stream of Ar gas. To the reaction mixture was
added Me2S (0.48 mL, 6.6 mmol) at ꢁ78 ꢀC and the mixture was
stirred at room temperature for 5 h. The resulting mixture was di-
luted with EtOAc and washed with brine, and dried. Removal of the
solvent gave a crude aldehyde (400 mg) as a pale yellow syrup. To
a solution of the crude aldehyde (400 mg) in t-BuOH (4.4 mL) and
H2O (4.4 mL) were added NaH2PO4$2H2O (206 mg, 1.32 mmol),
HOSO2NH2 (192 mg, 1.98 mmol), and NaClO2 (239 mg, 2.64 mmol).
After being stirred at room temperature for 15 h, the reaction mix-
ture was diluted with 20 wt % aqueous Na2S2O3 solution, and
products were extracted with CHCl3 five times. The combined or-
ganic layers were dried and concentrated to give a crude carboxylic
acid (540 mg) as a white solid. To a solution of the crude carboxylic
acid in MeOH (1.7 mL) and benzene (6.6 mL) at 0 ꢀC was added
(trimethylsilyl)diazomethane (2.0 M solution in Et2O, 0.43 mL,
0.86 mmol), and the mixture was stirred at room temperature for
1.5 h. Removal of the solvent gave a residue, which was purified by
methyl-1,3-dioxan-5-ylidene}ethanol (13). To
a solution of 12
(4.09 g, 8.73 mmol) in toluene (80 mL) at ꢁ78 ꢀC was added DIBAL
(1.01 M solution in toluene, 21.6 mL, 21.8 mmol) dropwise under Ar.
After being stirred at ꢁ78 ꢀC for 1 h, to the reaction mixture at
ꢁ78 ꢀC was added acetone (10 mL), and the mixture was further
stirred at 0 ꢀC for 10 min. The reaction mixture was diluted with
EtOAc, and washed successively with 1 M aqueous HCl solution,
saturated aqueous NaHCO3 solution and brine, and dried. Removal
of the solvent gave a residue, which was purified by column
chromatography (150 g silica gel, 1:3 EtOAc/hexane as an eluent) to
21
afford 13 (3.62 g 97%) as a colorless syrup: [
a]
ꢁ40.4 (c 1.75,
D
CHCl3); IR nmax (neat) 3400, 2930, 2860, 1475, 1425, 1380, 1370,
1225, 1135, 1115, 1080, 1010 cmꢁ1 1H NMR
;
d
1.07 (9H, s), 1.36 and
1.41 (each 3H, 2s), 3.82 (1H, dd, J¼6.1, 10.7 Hz), 3.92 (1H, dd, J¼4.9,
10.7 Hz), 4.00–4.17 (2H, m), 4.27 and 4.36 (each 1H, 2d, J¼14.4 Hz),
4.41 (1H, ddd, J¼1.7, 4.9, 6.1 Hz), 5.49 (1H, dt, J¼1.7 and 6.1 Hz),
7.34–7.46 (6H, m), 7.66–7.74 (4H, m); 13C NMR
d 19.4, 23.5, 26.6,
27.0, 58.3, 59.4, 65.7, 72.1, 99.9, 121.4,127.8,127.8,129.8, 129.9, 133.7,
133.8, 135.8, 135.9, 138.2; HRMS (FAB) m/z calcd for C25H34O4SiNa,
(MþNa)þ 449.2124, found: 449.2126.
4.2.5. N-{(4R,5S)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,2-di-
methyl-5-vinyl-1,3-dioxan-5-yl}-2,2,2-trichloroacetamide (14) and
its (4R,5R)-isomer (epi-14). To a solution of 13 (741 mg, 1.74 mmol)
column chromatography (15 g silica gel,1:5 EtOAc/hexane) to afford
20
15 (382 mg, 97%) as a colorless syrup: [
a
]
þ16.7 (c, CHCl3); IR nmax
D
(neat) 3410, 2955, 2930, 1740, 1715, 1505, 1430, 1385, 1255, 1200,
in CH2Cl2 (20 mL) at 0 ꢀC were added DBU (26.0
mL, 0.17 mmol) and
1115, 1060 cmꢁ1; 1H NMR
d
1.08 (9H, s), 1.47 and 1.49 (each 3H, 2s),
trichloroacetonitrile (0.440 mL, 4.34 mmol), and the mixture was
stirred at 0 ꢀC for 10 min. The reaction mixture was concentrated to
give a residue, which was passed through a short column of silica
gel (8 g,1:5 EtOAc/hexane containing 1% Et3N as an eluent) to afford
crude imidate 8 (961 mg) as a pale yellow syrup. A mixture of crude
8 (961 mg) and K2CO3 (48 mg) in o-xylene (96 mL) was heated in
a sealed tube at 140 ꢀC for 48 h. The reaction mixture was con-
centrated to give a residue, which was purified by column chro-
matography (50 g silica gel, 1:20 EtOAc/hexane) to afford first, 14
(615 mg, 62% from 12) as a colorless syrup. Further elution gave
3.72 (3H, s), 3.79 (1H, dd, J¼4.4,11.5 Hz), 3.96 (1H, dd, J¼3.9,11.5 Hz),
4.20 (1H, dd, J¼3.9, 4.4 Hz), 4.27 and 4.34 (each 1H, 2d, J¼12.4 Hz),
7.34–7.45 (6H, m), 7.65–7.71 (4H, m), 7.86 (br s, 1H, NH); 13C NMR
d
18.9, 19.6, 27.2, 28.9, 53.1, 60.9, 62.9, 63.7, 73.0, 92.3, 99.9, 127.9,
127.9,130.1,133.2,133.2,135.9,161.8,168.6; HRMS (FAB) m/z calcd for
C27H35Cl3NO6Si, (MþH)þ 602.1300, found: 602.1285.
4.2.7. Methyl (4R,5S)-2,2-dimethyl-4-(hydroxymethyl)-5-(2,2,2-trich-
loroacetamido)-1,3-dioxane-5-carboxylate (16). To a solution of 15
(382 mg, 0.633 mmol) in THF (6.3 mL) was added Bu4NF (1.0 M

H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
9195
solution in THF, 1.10 mL, 1.10 mmol) at ꢁ15 ꢀC. After being stirred at
ꢁ15 ꢀC for 1 h, the reaction mixture was diluted with EtOAc, and
washed with brine, and dried. Removal of the solvent left a residue,
which was purified by column chromatography (6 g silica gel, 1:2–
found: 448.0686. Anal. Calcd for C16H24NO7Cl3: C, 42.83; H, 5.39; N,
3.12. Found: C, 43.00; H, 5.51; N, 3.02.
4.2.10. Methyl (4R,5S)-2,2-dimethyl-4-[(R,E)-4-iodo-1-(methoxymeth-
oxy)but-3-enyl]-5-(2,2,2-trichloroacetamido)-1,3-dioxane-5-carboxyl-
ate (2). Ozone was introduced into a solution of 17 (32 mg,
0.071 mmol) in EtOH (2 mL) at ꢁ78 ꢀC for 1.5 min. After purging of
excess ozone with a stream of Ar gas, to the reaction mixture at
ꢁ78 ꢀC was added Me2S (0.052 mL, 0.71 mmol), and the resulting
mixture was stirred at room temperature for 5 h. The mixture was
diluted with EtOAc and washed with brine, and dried. Removal of the
solvent gave a crude aldehyde (35 mg) as a pale yellow syrup. To
a suspension of CrCl2 (349 mg, 2.84 mmol) in THF (3.5 mL) and 1,4-
dioxane (3.5 mL) at 0 ꢀC under Ar was added a solution of the crude
aldehyde (35 mg) and CHI3 (335 mg, 0.85 mmol) in THF (3.5 mL) via
a cannula. After being stirred at room temperature for 20 h, the re-
action was quenched by the addition of H2O (1 mL). The resulting
mixture was diluted with Et2O and washed successively with
30 wt % aqueous Na2S2O3 solution and brine, and dried. Removal of
the solvent left a residue, which was purified by column chroma-
1:1 EtOAc/hexane as an eluent) to afford 16 (231 mg, 100%) as
28
a crystalline residue: mp 57.3–58.9 ꢀC; [
a]
D
þ38.1 (c 1.20, CHCl3); IR
nmax (neat) 3570, 3480, 3300, 1735, 1715, 1655, 1520, 1390, 1260,
1205, 1125, 1085 cmꢁ1 1H NMR
;
d
1.46 and 1.53 (each 3H, 2s), 2.38
(1H, br s), 3.76–3.84 (1H, m), 3.77 (3H, s), 3.90 (1H, dd, J¼3.4,
12.4 Hz), 4.15 (1H, dd, J¼3.2, 3.4 Hz), 4.34 (2H, s), 8.60 (br s, 1H, NH);
13C NMR
d 19.2, 28.8, 53.3, 61.4, 62.3, 62.8, 71.4, 92.4, 100.0, 162.1,
168.9; HRMS (FAB) m/z calcd for C11H17Cl3NO6, (MþH)þ 364.0122,
found: 364.0123.
4.2.8. Methyl (4R,5S)-2,2-dimethyl-4-[(R)-1-hydroxybut-3-enyl]-5-(2,2,
2-trichloroacetamido)-1,3-dioxane-5-carboxylate (6). To a solution of
16 (249 mg, 0.683 mmol) in benzene (6.8 mL) at room temperature
were added pyridine (0.055 mL, 0.68 mmol), TFA (0.026 mL,
0.34 mmol), DMSO (3.4 mL), and DCC (561 mg, 2.72 mmol). After
being stirred at room temperature for 5 h, the reaction mixture was
diluted with Et2O, and washed successively with water and brine, and
dried. The organic layer was concentrated to give crude aldehyde 7
(589 mg), which was used for the next reaction without further pu-
rification. To a solution of MgBr2 (0.068 mL, 1.37 mmol) in CH2Cl2
(7.0 mL) at room temperature was added a solution of crude aldehyde
7 (589 mg) in CH2Cl2 (6.6 mL) via a cannula under Ar. The mixture
was stirred at ꢁ78 ꢀC for 10 min. To this mixture at ꢁ78 ꢀC was added
allyl tributyltin (0.32 mL, 1.02 mmol). After stirring at ꢁ78 ꢀC for
15 min, the cooling bath was removed, and the resulting mixture was
stirred at ambient temperature for 25 h. The reaction mixture was
diluted with 1 M aqueous HCl solution at 0 ꢀC, and products were
extracted with EtOAc. The organic layer was washed successively with
1 M aqueous HCl solution, saturated aqueous NaHCO3 solution and
brine, and dried. Removal of the solvent left a residue, which was
purified by column chromatography (25 g silica gel, 1:30 EtOAc/tol-
tography (1.5 g, silica gel, 1:5 EtOAc/hexane as an eluent) to afford 2
30
(28 mg, 60% from 17) as a colorless syrup: [
a
]
þ61.0 (c 0.82, CHCl3);
D
IR nmax (neat) 3370, 2915, 2850, 1730, 1715, 1515, 1380, 1260,
1150 cmꢁ1; 1H NMR
d
1.46 and 1.49 (each 3H, 2s), 2.42–2.60 (2H, m),
3.42 (3H, s), 3.75–3.83 (1H, m), 3.81 (3H, s), 4.01 (1H, d, J¼1.0 Hz),
4.26 and 4.54 (each 1H, 2d, J¼12.2 Hz), 4.77 and 4.80 (each 1H, 2d,
J¼7.1 Hz), 6.15 (1H, d, J¼14.4 Hz), 6.40 (1H, ddd, J¼6.8, 8.3, 14.4 Hz),
8.64 (1H, br s); 13C NMR
d 18.5, 29.0, 38.0, 53.1, 56.6, 62.1, 62.2, 71.5,
75.8, 78.4, 96.8,100.1,100.5,140.6,161.1,168.5; HRMS (FAB) m/z calcd
for C16H24Cl3INO7, (MþH)þ 573.9664, found: 573.9650.
4.2.11. (2R,3R,4S)-4-Acetamido-4-(acetoxymethyl)-2-allyl-5-oxote-
trahydrofuran-3-yl acetate (30). A solution of 6 (185 mg, 0.457 mmol)
in AcOH (16 mL) and H2O (4 mL) was stirred at 80 ꢀC for 11 h. The
reaction mixture was concentrated to give a residue, which was dis-
solved in pyridine (6 mL) and Ac2O (5 mL). After stirring at room
temperature for 9 h, the reaction mixture was concentrated to give
a residue, which was purified by column chromatography (4 g silica
uene as an eluent) to give 6 (207 mg, 75%) as a crystalline residue: mp
22
98.2–99.2 ꢀC (from EtOAc); [
a]
D
þ56.1 (c 1.04, CHCl3); IR nmax (neat)
3580, 3305, 1750, 1710, 1540, 1385, 1245, 1200 cmꢁ1; 1H NMR
d 1.44
and 1.47 (each 3H, 2s), 2.26 (1H, ddd, J¼7.1, 7.1, 13.9 Hz), 2.35–2.45
(2H, m), 3.76 (3H, s), 3.89 (1H, ddd, J¼1.0, 7.1, 16.1 Hz), 3.94 (1H, d,
J¼1.0 Hz), 4.36 (1H, d, J¼12.4 Hz), 4.45 (1H, d, J¼12.4 Hz), 5.11 (1H, d,
J¼16.8 Hz), 5.13 (1H, d, J¼8.5 Hz), 5.68 (1H, m), 9.22 (1H, br s); 13C
gel, 1:5–2:3 EtOAc/hexane as an eluent) to give 30 (141 mg, 98%) as
22
a colorlesssyrup: [
a
]
þ71.4 (c 0.63, CHCl3). IR nmax (neat)3350, 3270,
D
3050, 2930, 1780, 1755, 1750, 1670, 1540, 1375, 1230, 1185, 1050,
1030 cmꢁ1; 1H NMR
2.03, 2.05 and 2.10 (each 3H, 3s), 2.37–2.56 (2H,
m), 4.50 (2H, s, 2H), 4.77 (1H, td, J¼4.9, 8.3 Hz), 5.13–5.21 (2H, m),
5.75–5.89(2H,m), 6.07(1H, brs);13CNMR
20.3, 20.5, 22.7, 33.2,62.6,
d
NMR
d 19.4, 28.1, 39.2, 53.1, 62.3, 62.4, 69.9, 70.8, 92.3, 99.9, 119.2,
132.8, 162.0, 169.1; HRMS (FAB) m/z calcd for C14H21Cl3NO6, (MþH)þ
404.0434, found: 404.0428. Anal. Calcd for C14H20NO6Cl3: C, 41.55; H,
4.98; N, 3.46. Found: C, 41.66; H, 4.99; N, 3.48.
d
62.8, 72.0, 80.9,118.8,132.0,168.9,169.4,170.1,172.2; HRMS (FAB) m/z
calcd for C14H19NO7, (MþH)þ 314.1240, found: 314.1242.
4.2.9. Methyl (4R,5S)-2,2-dimethyl-4-[(R)-1-(methoxymethoxy)but-
3-enyl]-5-(2,2,2-trichloroacetamido)-1,3-dioxane-5-carboxylate
(17). To a solution of 6 (25 mg, 0.062 mmol) in (CH2Cl)2 (1 mL) at
room temperature were added i-Pr2NEt (0.12 mL, 0.68 mmol),
MOMCl (0.028 mL, 0.37 mmol), and tetrabutylammonium chloride
(2.5 mg, 0.007 mmol). Afterstirringatroomtemperaturefor 17 h, the
reaction mixture was diluted with EtOAc, and washed successively
with saturated aqueous NH4Cl solution, saturated aqueous NaHCO3
solution and brine, and dried. Removal of the solvent gave a residue,
which was purified by column chromatography (1 g silica gel, 1:7
4.2.12. (2R,3R,4S)-4-Acetamido-4-(acetoxymethyl)-2-[(E)-3-io-
doallyl]-5-oxotetrahydrofuran-3-yl acetate (3). Ozone was in-
troduced into a solution of 30 (113 mg, 0.361 mmol) in EtOH
(10 mL) at ꢁ78 ꢀC for 10 min. After confirming the complete
consumption of the starting material (TLC analysis), excess ozone
was removed with a stream of Ar gas. To the reaction mixture was
added Me2S (0.30 mL, 4.1 mmol) at ꢁ78 ꢀC and the mixture was
stirred at 0 ꢀC for 6 h. The reaction mixture was concentrated to
give a residue, which was diluted with EtOAc. The organic layer was
washed with brine, and dried. Removal of the solvent left a crude
aldehyde (115 mg). To a suspension of CrCl2 (442 mg, 3.60 mmol) in
dioxane (6.0 mL) under Ar at 0 ꢀC was added a THF solution
(3.0 mL) of the crude aldehyde (115 mg) and CHI3 (433 mg,
1.10 mmol) via a cannula. After stirring at room temperature for
1.5 h, the reaction was quenched by addition of 20 wt % aqueous
Na2S2O3 solution (20 mL), and then diluted with EtOAc. The organic
layer was washed successively with 20 wt % aqueous Na2S2O3 so-
lution, H2O and brine, and dried. Removal of the solvent left a res-
idue, which was purified by column chromatography (3 g silica gel,
EtOAc/hexane as an eluent) to afford 17 (22 mg, 79%) as a colorless
30
syrup: [
a
]
þ88.9 (c 0.77, CHCl3); IR nmax (neat) 3365, 2995, 2955,
D
1730,1715,1515,1505,1385,1260,1200 cmꢁ1; 1H NMR
d 1.46 and1.49
(each 3H, 2s), 2.44–2.54 (2H, m), 3.43 (3H, s), 3.72–3.80 (1H, m), 3.78
(3H, s), 4.08 (1H, d, J¼1.0 Hz), 4.25 and 4.54 (each 1H, 2d, J¼12.2 Hz),
4.78 and 4.82 (each 1H, 2d, J¼7.1 Hz), 5.11 (1H, d, J¼16.1 Hz), 5.12 (1H,
d, J¼10.2 Hz), 5.58–5.64 (1H, m), 8.73 (1H, br s); 13C NMR
d 18.8, 29.1,
35.4, 53.1, 56.7, 62.4, 62.5, 71.1, 76.7, 92.7, 96.5,100.2,119.1,133.1,161.3,
168.8; HRMS (FAB) m/z calcd for C16H25Cl3NO7, (MþH)þ 448.0697,

9196
H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
1:2–2:1 EtOAc/hexane as an eluent) to give first, the Z-isomer of 3
(20 mg, 13%) as a colorless syrup. Further elution afforded 3
temperature were added i-Pr2NEt (0.72 mL, 4.16 mmol) and MOMCl
(0.16 mL, 2.1 mmol). After stirring at room temperature for 3 h, the
reaction mixture was quenched by addition of saturated aqueous
NH4Cl solution. Products were extracted with EtOAc, and the organic
layer was washed with brine, and dried. Removal of the solvent left
a residue, which was purified bycolumn chromatography (1.6 g silica
(115 mg, 73%) as a crystalline residue. Data for 3: mp 58.0–58.9 ꢀC;
24
[
a]
þ83.5 (c 0.93, CHCl3); IR nmax (KBr disk) 3350, 3050, 1780,
D
1755, 1750, 1680, 1540, 1375, 1230, 1185, 1050, 1030 cmꢁ1; 1H NMR
2.03, 2.06 and 2.12 (each 3H, 3s), 2.38–2.56 (2H, m), 4.49 (2H, s),
d
4.77 (1H, ddd, J¼4.9, 8.6, 8.6 Hz), 5.75 (1H, d, J¼4.9 Hz), 5.99 (1H, br
gel, 1:5 EtOAc/hexane as an eluent) to give 21a (81 mg, 96%) as
24
s), 6.27 (1H, ddd, J¼1.2, 1.2, 14.4 Hz), 6.55 (ddd, 1H, J¼7.1, 7.1,
a colorless syrup: [
a
]
þ47.0 (c 0.73, CHCl3); IR nmax (neat) 2930,
D
14.4 Hz); 13C NMR
d
20.8, 21.1, 23.1, 35.9, 62.6, 63.8, 72.3, 79.5, 79.8,
2860, 1470, 1155, 1100 cmꢁ1; 1H NMR
d
0.88 (3H, t, J¼6.8 Hz), 1.21–
140.1, 169.7, 170.2, 170.5, 170.7; HRMS (FAB) m/z calcd for
1.67 (10H, m), 2.53 (1H, dd, J¼2.7, 4.9 Hz), 2.78 (1H, dd, J¼4.4, 4.9 Hz),
2.98 (1H, ddd, J¼2.7, 4.4, 7.1 Hz), 3.26 (1H, td, J¼6.1, 7.1 Hz), 3.40 (3H,
s), 4.66 and 4.88 (each 1H, 2d, J¼6.6 Hz); 13C NMR (75 MHz, CDCl3)
C14H18NO7INa, (MþNa)þ 462.0026, found: 462.0031. Data for Z-
19
isomer of 3: [
a]
þ67.1 (c 0.24, CHCl3); IR nmax (neat) 3350, 3050,
D
1780, 1755, 1750, 1680, 1540, 1375, 1230, 1185, 1050 cmꢁ1; 1H NMR
2.03, 2.09 and 2.10 (each 3H, 3s), 2.51–2.68 (2H, m), 4.50 (2H, s),
d 14.3, 22.8, 25.6, 29.5, 31.9, 32.5, 44.1, 54.9, 55.8, 78.2, 95.7; HRMS
d
(FAB) m/z calcd for C11H22O3Na, (MþNa)þ 225.1467, found: 225.1482.
4.84 (1H, ddd, J¼4.6, 5.2, 5.2 Hz), 5.79 (1H, d, J¼4.6 Hz), 6.06 (1H, br
s), 6.31 (1H, ddd, J¼6.8, 6.8, 7.2 Hz), 6.46 (1H, ddd, J¼1.5,1.5, 7.2 Hz);
4.3.4. (R)-2-{(R)-1-[(2-(Trimethylsilyl)ethoxy)methoxy]heptyl}oxi-
rane (21b). To a solution of 20 (2.30 g,14.3 mmol) in CH2Cl2 (65 mL)
at room temperature were added i-Pr2NEt (9.90 mL, 56.8 mmol) and
SEMCl (5.00 mL, 28.4 mmol). After stirring at room temperature for
7 h, the reaction mixture was diluted with EtOAc and washed with
brine, and dried. Removal of the solvent left a residue, which was
purified by column chromatography (150 g silica gel, 1:50–1:30
13C NMR (75 MHz, CDCl3)
d 20.4, 20.6, 22.6, 34.5, 62.4, 62.9, 71.8,
86.3, 134.8, 169.0, 169.5, 170.3, 172.0; HRMS (FAB) m/z calcd for
C14H19NO7I, (MþH)þ 440.0206, found: 440.0214.
4.3. Synthesis of the right-half segment
4.3.1. [(4R,5R)-2,2-Dimethyl-5-hexyl-1,3-dioxolan-4-yl]methanol 4-
methylbenzenesulfonate (19). To a suspension of CuBr (1.30 g,
9.03 mmol) in THF (30 mL) at 0 ꢀC under Ar was added n-pentyl-
magnesium bromide (1.5 M solution in Et2O, 34.4 mL, 51.6 mmol),
and the mixture was cooled to ꢁ30 ꢀC. To this suspension was
added a THF solution (22 mL) of [(4R,5R)-2,2-dimethyl-5-hexyl-1,3-
EtOAc/hexane as an eluent) to give 21b (4.20 g, 100%) as a colorless
26
syrup: [
a]
þ52.0 (c 1.44, CHCl3); IR nmax (neat) 2960, 2930, 2860,
D
1470, 1380, 1250, 1100 cmꢁ1; 1H NMR
d 0.01 (9H, s), 0.84–0.98 (5H,
m), 1.20–1.70 (10H, m), 2.52 (1H, dd, J¼2.7, 4.9 Hz), 2.75 (1H, dd,
J¼4.9, 4.9 Hz), 2.96 (1H, ddd, J¼2.7, 4.9, 6.8 Hz), 3.28 (1H, td, J¼6.8,
7.1 Hz), 3.58 and 3.70 (each 1H, 2dt, J¼7.1, 10.0 Hz), 4.71 and 4.88
dioxolan-4-yl]-4,5-dimethanol
4,5-bis(4-methylbenzenesulfo-
(each 1H, 2d, J¼6.8 Hz); 13C NMR
d
ꢁ1.3, 14.2, 18.2, 22.7, 25.6, 29.5,
nate)22 (18) (6.09 g, 12.9 mmol). After being stirred for 19 h at
ꢁ30 ꢀC, the reaction mixture was diluted with 1 M aqueous HCl
solution (30 mL) at ꢁ30 ꢀC, and products were extracted with
EtOAc. The organic layer was washed successively with 1 M aque-
ous HCl solution, saturated aqueous NaHCO3 solution and brine,
and dried. Removal of the solvent gave a residue, which was puri-
31.9, 32.5, 43.9, 54.9, 65.4, 77.8, 93.9; HRMS (FAB) m/z calcd for
C15H33O3Si, (MþH)þ 289.2199, found: 289.2195.
4.3.5. tert-Butyl{(R)-1-[(R)-oxyran-2-yl]heptyloxy}diphenylsilane
(21c). To a solution of 20 (257 mg, 1.63 mmol) in DMF (6.4 mL) at
0 ꢀC were added imidazole (664 mg, 9.75 mmol) and TBDPSCl
(1.25 mL, 4.88 mmol). After being stirred at room temperature for
6.5 h, the reaction mixture was diluted with EtOAc and washed
with brine, and dried. Removal of the solvent left a residue, which
was purified by column chromatography (40 g silica gel, 1:100–
fied by column chromatography (150 g silica gel, 1:10 EtOAc/hex-
21
ane as an eluent) to afford 19 (2.55 g, 53%) as a colorless syrup: [a]
D
þ19.9 (c 1.44, CHCl3); IR nmax (neat) 2935, 2855, 1370, 1190, 1180,
1100, 980 cmꢁ1; 1H NMR
1.29 and 1.35 (each 3H, 2s), 2.45 (3H, s), 3.74–3.82 (2H, m), 4.05 (1H,
d
0.88 (3H, t, J¼6.9 Hz),1.24–1.58 (10H, m),
1:75 EtOAc/hexane as an eluent) to give 21c (644 mg, 100%) as
20
dd, J¼4.1, 10.5 Hz), 4.11 (1H, dd, J¼3.7, 10.5 Hz), 7.34 and 7.79 (each
a colorless syrup: [
a]
ꢁ17.5 (c 0.49, CHCl3); IR nmax (neat) 2960,
D
2H, 2d, J¼8.0 Hz); 13C NMR
d
14.2, 21.8, 22.7, 26.0, 26.9, 27.5, 29.4,
2930, 2860, 1470, 1430, 1100, 1070, 930 cmꢁ1; 1H NMR
d 0.82 (3H, t,
31.8, 33.2, 69.4, 78.0, 78.4, 109.5, 128.2, 130.0, 132.9, 145.2; HRMS
J¼6.8 Hz), 1.01–1.30 (17H, m), 1.45–1.52 (2H, m), 2.46 (1H, dd, J¼2.8,
4.9 Hz), 2.71 (1H, dd, J¼4.1, 4.9 Hz), 3.05 (1H, ddd, J¼2.8, 4.1, 6.6 Hz),
3.35 (1H, td, J¼6.1, 6.6 Hz), 7.34–7.45 (6H, m), 7.67–7.73 (4H, m); 13C
(EI) m/z calcd for C19H30O5S, (M)þ 370.1814, found: 370.1820.
4.3.2. (R)-1-[(R)-Oxiran-2-yl]heptan-1-ol (20). A solution of 19
(6.50 g, 17.5 mmol) in AcOH (80 mL) and H2O (20 mL) was heated at
70 ꢀC for 13 h. The reaction mixture was concentrated to give
a crude diol (6.12 g) as a crystalline residue, which was dissolved in
CH2Cl2 (88 mL). To this solution at room temperature was added
DBU (7.35 mL, 49.1 mmol), and the resulting mixture was stirred at
room temperature for 2 h. After addition of saturated aqueous
NH4Cl solution (40 mL), the reaction mixture was diluted with
EtOAc, and washed with brine, and dried. Removal of the solvent
left a residue, which was purified by column chromatography (65 g
NMR d 14.0, 19.4, 22.5, 24.8, 27.0, 29.0, 31.6, 34.7, 44.8, 55.7, 75.2,
127.4, 127.4, 129.5, 134.0, 134.3, 136.0; HRMS (FAB) m/z calcd for
C25H37O2Si, (MþH)þ 397.2563, found: 397.2562.
4.3.6. (R,E)-4-(Methoxymethoxy)dec-2-en-1-ol (22a). To a solution
of 21a (581 mg, 2.87 mmol) in 1,4-dioxane (14 mL) at room tem-
perature was added a solution of HIO4$2H2O (1.50 g, 6.60 mmol) in
H2O (2.9 mL). After being stirred at room temperature for 14 h, the
reaction mixture was diluted with EtOAc and washed with brine,
anddried. Removal of the solvent gavea crude aldehyde (571 mg). To
a solution of the crude aldehyde (571 mg) in toluene (28 mL) was
added Ph3P]CHCO2Et (1.70 g, 4.90 mmol), and the resulting mix-
ture was stirred at 60 ꢀC for 15 h. The reaction mixture was con-
centratedto givea residue, which waspurified bycolumn of silica gel
(20 g, 1:100 EtOAc/hexane as an eluent) to afford a geometrical
mixture (E/Z¼ca. 6.5:1) of an ethyl ester (588 mg, 79%) as a yellow
syrup. To a solution of the crude ethyl ester (588 mg, 2.28 mmol) in
toluene (11 mL) was added at ꢁ78 ꢀC under Ar dropwise DIBAL
(0.99 M solution in toluene, 12.4 mL, 12.4 mmol), and the mixture
was stirred at ꢁ78 ꢀC for 20 min. The reaction mixture was
quenched by addition of acetone (1.5 mL) at ꢁ78 ꢀC. After stirring at
silica gel, 1:15–1:4 EtOAc/hexane as an eluent) to give 20 (2.58 g,
23
93%) as a colorless syrup: [
a
]
D
ꢁ3.6 (c 2.51, CHCl3); IR nmax (neat)
3440, 3955, 2930, 2860, 1730, 1460, 1255, 1085, 980 cmꢁ1; 1H NMR
d
0.88 (3H, t, J¼7.1 Hz), 1.20–1.67 (10H, m), 1.82 (1H, br s), 2.72 (1H,
dd, J¼2.7, 4.9 Hz), 2.82 (1H, dd, J¼4.1, 4.9 Hz), 2.98 (1H, ddd, J¼2.7,
4.1, 5.0 Hz), 3.44 (1H, dt, J¼5.0, 5.9 Hz); 13C NMR (75 MHz, CDCl3)
d
14.2, 22.7, 25.4, 29.4, 31.8, 34.4, 45.3, 55.7, 71.9; HRMS (FAB) m/z
calcd for C9H19O2, (MþH)þ 159.1385, found: 159.1394.
4.3.3. (R)-2-[(R)-1-(Methoxymethoxy)heptyl]oxirane (21a). To a so-
lution of 20 (66 mg, 0.42 mmol) in (CH2Cl)2 (2 mL) at room

H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
9197
0 ꢀC for 10 min, to the mixture was added Na2SO4$10H2O (2 g) and
the whole mixture was further stirred at room temperature for 4 h.
The insoluble material was removed by filtration through Celite, and
the filtratewas concentrated to give a residue, which was purified by
column chromatography (10 g silica gel, 1:8 EtOAc/hexane as an
129.5, 134.4, 134.7, 135.9, 136.1; HRMS (FAB) m/z calcd for
C
26H38O2SiNa, (MþNa)þ 433.2539, found: 433.2550.
4.3.9. (R,E)-7-(Methoxymethoxy)trideca-1,5-diene (23a). To a solu-
tion of 22a (339 mg,1.57 mmol) in CH2Cl2 (8 mL) at 0 ꢀC were added
Et3N (0.440 mL, 3.16 mmol) and MsCl (0.220 mL, 2.84 mmol). After
stirring at 0 ꢀC for 30 min, the reaction was quenched by addition of
1 M aqueous HCl solution (2 mL) at 0 ꢀC. The resulting mixture was
diluted with EtOAc and washed successively with 1 M aqueous HCl
solution, saturated aqueous NaHCO3 solution and brine, and dried.
Removal of the solvent gave a crude mesylate (502 mg). To a solu-
tion of the crude mesylate (502 mg) inTHF (16 mL) under Ar at room
temperature was added allylmagnesium chloride (2.0 M solution in
THF, 2.75 mL, 5.50 mmol), and the mixture was stirred at 50 ꢀC for
10 h. The reaction was quenched by addition of 1 M aqueous HCl
solution (5 mL) at 0 ꢀC. The mixture was diluted with EtOAc and
washed successively with 1 M aqueous HCl solution, saturated
aqueous NaHCO3 solution and brine, and dried. Removal of the
solvent left a residue, which was purified by column chromatogra-
eluent) to afford first, Z-isomer of compound 22a (54 mg, 9% from
23
21a) as a colorless syrup: [
a
]
D
þ106.4 (c 0.58, CHCl3); IR nmax (neat)
3420, 2930, 2860, 1470, 1155, 1130 cmꢁ1 1H NMR
; d 0.87 (3H, t,
J¼6.6 Hz),1.19–1.69 (10H, m), 2.43 (1H, dd, J¼4.4, 7.1 Hz), 3.37 (3H, s),
4.01 (1H, ddd, J¼1.2, 6.1, 7.1 Hz), 4.26–4.42 (2H, m), 4.53 and 4.73
(each 1H, 2d, J¼7.1 Hz), 5.36 (1H, ddd, J¼1.2, 9.8, 11.0 Hz), 5.88 (1H,
dddd, J¼1.0, 6.1, 8.0, 11.0 Hz); 13C NMR
d 14.3, 22.8, 25.5, 29.4, 32.0,
35.6, 55.4, 58.3, 70.6, 93.6, 132.4, 132.7; HRMS (FAB) m/z calcd for
C12H24O3Na, (MþNa)þ 239.1624, found: 239.1618. Further elution
23
afforded 22a (345 mg, 56% from 21a) as a colorless syrup: [a]
D
þ89.5 (c 0.51, CHCl3); IR nmax (neat) 3420, 2930, 2860, 1470, 1155,
1095 cmꢁ1; 1H NMR
d
0.87 (3H, t, J¼6.6 Hz),1.22–1.68 (11H, m), 3.63
(3H, s), 4.01 (1H, ddd, J¼6.8, 6.8, 7.8 Hz), 4.14–4.17 (2H, m), 4.52 and
4.69 (each 1H, 2d, J¼6.8 Hz), 5.55 (1H, bdd, J¼7.8, 15.6 Hz), 5.81 (1H,
btd, J¼5.4, 15.6 Hz); 13C NMR
d
14.3, 22.8, 25.6, 29.4, 32.0, 35.8, 55.6,
phy (10 g silica gel, 1:15 EtOAc/hexane as an eluent) to afford 23a
23
63.1, 76.5, 93.9, 131.8, 132.1; HRMS (FAB) m/z calcd for C12H24O3Na,
(MþNa)þ 239.1624, found: 239.1630. Anal. Calcd for C12H24O3: C,
66.63; H, 11.18. Found: C, 66.60; H, 11.21.
(307 mg, 81%) as a colorless syrup: [
a
]
þ99.1 (c 0.92, CHCl3); IR
D
nmax (neat) 2930, 2860, 1470, 1115, 1095, 1040 cmꢁ1; 1H NMR
d 0.88
(3H, t, J¼7.1 Hz), 1.21–1.66 (10H, m), 2.12–2.15 (4H, m), 3.35 (3H, s),
3.92 (1H, td, J¼6.3, 8.3 Hz), 4.48 and 4.71 (each 1H, 2d, J¼6.6 Hz),
4.96 (1H, d, J¼10.2 Hz), 5.01 (1H, d, J¼18.5 Hz), 5.26 (1H, dd, J¼8.3,
15.3 Hz), 5.60 (1H, td, J¼6.3, 15.3 Hz), 5.72–5.86 (1H, m); 13C NMR
4.3.7. (R,E)-4-{[(Trimethylsilyl)methoxy]ethoxy}dec-2-en-1-ol (22b). By
the similar reaction conditions as described for the preparation of
22a from 21a, compound 21b (304 mg, 1.05 mmol) was converted
d
14.3, 22.8, 25.7, 29.4, 31.8, 32.0, 33.6, 35.9, 55.5, 76.9, 93.4, 115.0,
into 22b (168 mg, 53%) and Z-isomer of 22b (22 mg, 7%). Data for Z-
130.8, 133.7, 138.3; HRMS (FAB) m/z calcd for C15H28O2Na, (MþNa)þ
28
isomer of 22b: colorless syrup; [
a]
þ104.0 (c 1.90, CHCl3); IR nmax
263.1987, found: 263.1982.
D
(neat) 3420, 2955, 2930, 2860,1250,1100,1060 cmꢁ1; 1H NMR
d 0.01
(9H, s), 0.84–1.00 (5H, m), 1.20–1.70 (10H, m), 2.47 (1H, br s), 3.53
and 3.71 (each 1H, 2dt, J¼7.1, 10.0 Hz), 3.98 (1H, ddd, J¼1.0, 6.1,
12.9 Hz), 4.32 (1H, ddd, J¼1.0, 8.3, 12.9 Hz), 4.42 (1H, dt, J¼6.3 and
10.0 Hz), 4.61 and 4.74 (each 1H, 2d, J¼7.1 Hz), 5.35 (1H, dddd, J¼1.0,
4.3.10. (R,E)-Trimethyl{[2-(trideca-1,5-dien-7-yloxy)ethoxy]methyl}-
silane (23b). By the similar reaction conditions as described for the
preparation of 23a from 22a, compound 22b (954 mg, 3.16 mmol)
27
was converted into 23b (691 mg, 67%): colorless syrup; [
a]
þ98.4
D
1.0, 10.0, 11.0 Hz), 5.89 (1H, ddd, J¼6.1, 8.3, 11.0 Hz); 13C NMR
d
ꢁ1.4,
(c 0.74, CHCl3); IR nmax (neat) 2960, 2930, 2860, 1640, 1380, 1250,
14.2,18.1, 22.7, 25.5, 29.4, 31.9, 35.6, 58.2, 65.1, 70.7, 91.7,132.4,132.7;
1100, 1060 cmꢁ1 1H NMR
;
d
0.02 (9H, s), 0.85–0.96 (5H, m), 1.20–
HRMS (FAB) m/z calcd for C16H35O3Si, (MþH)þ 303.2356, found:
1.65 (10H, m), 2.12–2.15 (4H, m), 3.49 and 3.73 (each 1H, 2dt, J¼6.6,
9.5 Hz), 3.94 (1H, dt, J¼6.3, 6.8 Hz), 4.57 and 4.70 (each 1H, 2d,
J¼6.8 Hz), 4.96 (1H, dd, J¼2.0, 11.0 Hz), 5.01 (1H, dd, J¼2.0, 18.1 Hz),
5.26 (1H, dd, J¼8.3, 15.4 Hz), 5.55–5.66 (1H, m), 5.72–5.86 (1H, m);
27
303.2353. Data for 22b: colorless syrup; [
a]
þ86.4 (c 2.43, CHCl3);
D
IR nmax (neat) 3400, 2930, 2860, 1460, 1380, 1250, 1100, 1060 cmꢁ1
;
1H NMR
d
0.02(9H, s), 0.85–0.96(5H, m),1.20–1.70(11H, m), 3.51 and
3.73 (each 1H, 2dt, J¼7.1, 10.0 Hz), 4.04 (1H, dt, J¼5.9, 7.8 Hz), 4.15
(2H, dd, J¼1.2, 5.3 Hz), 4.60 and 4.69 (each 1H, 2d, J¼7.1 Hz), 5.55
(1H, dddd, J¼1.2, 1.2, 7.8, 15.6 Hz), 5.81 (1H, td, J¼5.3, 15.6 Hz); 13C
13C NMR
d
ꢁ1.3, 14.2, 18.3, 22.8, 25.7, 29.4, 31.8, 32.0, 33.6, 35.9, 65.1,
76.8, 91.7, 115.0, 130.9, 133.4, 138.2; HRMS (FAB) m/z calcd for
C19H39O2Si, (MþH)þ 327.2719, found: 327.2712.
NMR
d
ꢁ1.3,14.2,18.3, 22.8, 25.6, 29.4, 32.0, 35.8, 63.1, 65.2, 76.2, 92.1,
131.9, 132.0; HRMS (FAB) m/z calcd for C16H35O3Si, (MþH)þ
4.3.11. (R,E)-tert-Butyldiphenyl(trideca-1,5-dien-7-yloxy)silane
(23c). By the similar reaction conditions as described for the
303.2356, found: 303.2356.
preparation of 23a from 22a, compound 22c (217 mg, 0.527 mmol)
26
4.3.8. (R,E)-4-(tert-Butyldiphenylsilyloxy)dec-2-en-1-ol
the similar reaction conditions as described for the preparation of
22a from21a, compound 21c (1.00 g, 2.52 mmol) was converted into
(22c). By
was converted into 23c (192 mg, 84%): colorless syrup; [
a]
þ21.8
D
(c 0.75, CHCl3); IR nmax (neat) 2960, 2930, 2860, 1470, 1430, 1100,
1070, 970 cmꢁ1; 1H NMR
d
0.85 (3H, t, J¼6.8 Hz), 1.05 (9H, s), 1.10–
22c (692 mg, 67%) and its Z-isomer (49 mg, 5%). Data for Z-isomer of
1.55 (10H, m), 1.97–1.99 (4H, m), 4.06 (1H, ddt, J7–6¼1.0, 7.1, 7.1 Hz),
4.91 (1H, ddd, J¼1.0, 2.2, 10.1 Hz), 4.96 (1H, ddd, J¼1.0, 2.2, 17.1 Hz),
5.23 (1H, td, J¼5.6, 15.4 Hz), 5.39 (1H, dd, J¼7.1, 15.4 Hz), 5.67–5.80
19
22c: colorless syrup; [
a]
ꢁ24.4 (c 0.595, CHCl3); IR nmax (neat)
D
3300, 2960, 2930, 2860,1470,1430,1100,1080 cmꢁ1; 1H NMR
d 0.86
(3H, t, J¼6.7 Hz), 1.05 (9H, s), 1.18–1.29 (9H, m), 1.39–1.66 (2H, m)
3.58–3.69 (2H, m), 4.35 (1H, td, J¼7.3, 8.7 Hz), 5.33 (1H, td, J2–1¼6.8,
11.2 Hz), 5.49 (1H, dd, J¼8.7, 11.2 Hz), 7.34–7.47(6H, m), 7.66–7.71
(1H, m), 7.31–7.44 (6H, m), 7.64–7.70 (4H, m); 13C NMR
d 14.1, 19.3,
22.6, 24.8, 27.1, 29.2, 31.5, 31.8, 33.3, 38.1, 74.7, 114.5, 127.2, 127.4,
129.3, 129.4, 130.1, 133.4, 134.71, 134.74, 136.0, 136.1, 138.3; HRMS
(FAB) m/z calcd for C29H43OSi, (MþH)þ 435.3083, found: 435.3098.
(4H, m); 13C NMR (75 MHz, CDCl3)
d 14.1, 19.3, 22.6, 24.8, 26.9, 29.2,
31.8, 38.2, 58.6, 69.4, 127.4, 127.5, 128.1, 129.6, 129.7, 134.2, 134.3,
135.9,136.1; HRMS (FAB) m/z calcd for C26H39O2Si, (MþH)þ 411.2719,
4.3.12. (R,E)-7-(Methoxymethoxy)tridec-5-en-1-ol (24a). To neat
23a (135 mg, 0.56 mmol) under Ar at room temperature was added
a solution of 9-BBN (0.5 M in THF, 9.0 mL, 4.5 mmol), and the
resulting mixture was sonicated (47 kHz, 60 W) in a water bath at
ambient temperature for 2 h. To the reaction mixture at 0 ꢀC were
added H2O (9 mL) and NaBO3$4H2O (2.58 g, 16.8 mmol), and the
mixture was further stirred at 0 ꢀC for 17 h. The reaction mixture
was diluted with EtOAc and washed with brine, and dried. Removal
21
found: 411.2713. Data for 22c: colorless syrup; [
a
]
þ5.9 (c 0.66,
D
MeOH); IR nmax (neat) 3300, 2960, 2930, 2860, 1470, 1430, 1100,
1080, 970 cmꢁ1; 1H NMR
d
0.86 (3H, t, J¼6.9 Hz), 1.07 (9H, s), 1.11–
1.59 (11H, m), 3.90 (2H, dd, J¼1.2, 5.6 Hz), 4.18 (1H, dt, J¼6.1, 6.3 Hz),
5.40 (1H, td, J¼5.6, 15.4 Hz), 5.56 (1H, tdd, J¼1.2, 6.1, 15.4 Hz), 7.33–
7.54 (6H, m), 7.65–7.70 (4H, m); 13C NMR (75 MHz, CDCl3)
d 14.1,19.3,
22.6, 24.7, 27.0, 29.2, 31.8, 37.9, 63.1, 73.9, 127.3, 127.5, 129.1, 129.4,

9198
H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
of the solvent left a residue, which was purified by column chro-
(1H, tdd, J¼1.0, 8.1, 15.3 Hz), 5.58 (1H, ddd, J¼6.8, 6.8, 15.4 Hz); 13
C
matography (15 g silica gel,1:5 EtOAc/hexane as an eluent) to afford
NMR
d
ꢁ1.3, 6.8, 14.3, 18.3, 22.8, 25.7, 25.7, 29.4, 30.1, 31.2, 32.0, 33.1,
27
24a (124 mg, 86%) as a colorless syrup: [
a
]
þ95.2 (c 1.05, CHCl3); IR
35.9, 65.1, 76.7, 91.7, 131.2, 133.3; HRMS (FAB) m/z calcd for
C19H40O2ISi, (MþH)þ 455.1843, found: 455.1853.
D
nmax (neat) 3400, 2930, 2860, 1470, 1115, 1095, 1040 cmꢁ1; 1H NMR
d
0.87 (3H, t, J¼6.3 Hz), 1.22–1.70 (15H, m), 2.07 (2H, dt, J¼6.8,
7.1 Hz), 3.35 (3H, s), 3.64 (2H, t, J¼6.6 Hz), 3.92 (1H, td, J¼6.6, 8.3 Hz),
4.49 and 4.71 (each 1H, 2d, J¼6.8 Hz), 5.26 (1H, dd, J¼8.3, 15.4 Hz),
4.3.17. Determination of optical purities of 5a, 5b, and 24c. Starting
from dimethyl L-tartrate, enantiomers of 5a (ent-5a), 5b (ent-5b),
5.60 (1H, td, J¼6.8, 15.4 Hz); 13C NMR
d
14.3, 22.8, 25.5, 25.7, 29.4,
and 24c (ent-24c) were synthesized by the similar reaction pro-
cedures. Optical purities of 5a, ent-5a, 5b, ent-5b, 24c, and ent-24c
were determined to be all >99% ee by chiral HPLC analyses. Ana-
lytical conditions for 5a and 24c: [DAICEL CHIRALCEL OD-H,
4.6 mm IDꢂ250 mm, i-PrOH/hexane¼1:500, flow rate¼1.0 mL/
min, UV (254 nm) detection]; retention time for 5a, 5.8 min; for
ent-5a, 5.1 min; retention rime for 24c, 34.6 min; for ent-24c,
31.8 min. Analytical conditions for 5b: [DAICEL CHIRALCEL OD-H,
4.6 mm IDꢂ250 mm, i-PrOH/hexane¼1:1000, flow rate¼1.0 mL/
min, UV (254 nm) detection]; retention time for 5b, 7.0 min; for
ent-5b, 5.0 min.
32.0, 32.1, 32.4, 35.9, 55.5, 62.9, 77.0, 93.4, 130.7, 134.1; HRMS (FAB)
m/z calcd for C15H30O3Na, (MþNa)þ 281.2093, found: 281.2094.
4.3.13. (R,E)-7-{[(Trimethylsilyl)methoxy]ethoxy}tridec-5-en-1-ol
(24b). By the similar reaction conditions as described for the
preparation of 24a from 23a, compound 23b (993 mg, 3.04 mmol)
20
was converted into 24b (1.17 g, 100%): colorless syrup; [
a
]
þ96.1
D
(c 1.45, CHCl3); IR nmax (neat) 3420, 2930, 2860, 1455, 1380, 1250,
1100, 1055 cmꢁ1 1H NMR
;
d
0.02 (9H, s), 0.85–0.99 (5H, m), 1.23–
1.62 (15H, m), 2.07 (2H, dtd, J¼1.5, 6.1, 7.1 Hz), 3.50 (1H, dt, J¼7.3,
9.5 Hz), 3.64 (2H, t, J¼6.3 Hz), 3.73 (1H, td, J¼7.3, 9.5 Hz), 3.94 (1H,
td, J¼5.9, 8.3 Hz), 4.58 and 4.70 (each 1H, 2d, J¼6.8 Hz), 5.26 (1H,
4.4. Coupling reactions of the left-half segment with the
right-half segment and total synthesis of mycestericin A
tdd, J¼1.5, 8.3, 15.4 Hz), 5.60 (1H, td, J¼7.1, 15.4 Hz); 13C NMR
ꢁ1.3,
d
14.2, 18.3, 22.8, 25.5, 25.7, 29.4, 32.0, 32.1, 32.4, 35.9, 62.9, 65.1, 76.8,
91.7, 130.8, 133.9; HRMS (FAB) m/z calcd for C19H41O3Si, (MþH)þ
345.2825, found: 345.2808.
4.4.1. Methyl
(4R,5S)-4-[(1R,3E,9E,11R)-1,11-bis(methoxymethoxy)-
3,9-heptadecadiene-1-yl]-2,2-dimethyl-5-[(2,2,2-trichloroacetyl)-
amino]-1,3-dioxane-5-carboxylate (25). To a solution of 5a (30 mg,
0.082 mmol) in THF (0.2 mL) was added tert-BuLi (1.53 M solution in
pentane, 0.28 mL, 0.43 mmol) at ꢁ78 ꢀC under Ar, and the mixture
was stirred for 15 min at ꢁ78 ꢀC. To this mixture at ꢁ78 ꢀC was added
a THF solution of ZnCl2 (1.0 M, 0.13 mL, 0.13 mmol), and the cooling
bath was removed. After stirring at ambient temperature for 30 min,
the resulting colorless solution of Zn reagent was added to a solution
of 2 (11 mg, 0.019 mmol) and Pd(PPh3)4 (2.3 mg, 0.002 mmol) in THF
(0.25 mL) and benzene (0.25 mL) via a cannula at room temperature.
After stirring at room temperature for 2 h, the reaction was
quenched by addition of saturated aqueous NH4Cl solution (2 mL) at
0 ꢀC, and products were extracted with Et2O. The organic layer was
washed successively with saturated aqueous NH4Cl solution, satu-
rated aqueous NaHCO3 solution and brine, and dried. Removal of the
solvent left a residue, which was purified by column chromatogra-
4.3.14. (R,E)-7-{[(Trimethylsilyl)methoxy]ethoxy}tridec-5-en-1-ol
(24c). By the similar reaction conditions as described for the prep-
aration of 24a from 23a, compound 23c (56 mg, 0.014 mmol) was
26
converted into 24c (53 mg, 90%): colorless syrup; [
a
]
D
þ14.3 (c 0.26,
CHCl3); IR nmax (neat) 3350, 2960, 2930, 2860, 1470, 1430,
1100 cmꢁ1 1H NMR
;
d
0.83 (3H, t, J¼7.0 Hz), 1.03 (9H, s), 1.15–1.58
(15H, m),1.88 (2H, tdd, J¼1.0, 6.8, 6.8 Hz), 3.56 (2H, t, J¼6.4 Hz), 4.05
(dt, J¼6.8, 6.8 Hz), 5.18 (1H, tdd, J¼1.0, 6.8, 15.5 Hz), 5.36 (1H, tdd,
J¼1.0, 6.8, 15.5 Hz), 7.30–7.41 (6H, m), 7.63–7.67 (4H, m); 13C NMR
d
14.0,19.3, 22.6, 24.8, 25.2, 27.1, 29.2, 31.8, 32.2, 38.1, 62.8, 74.7,127.2,
127.4, 129.2, 129.4, 130.6, 133.3, 134.7, 134.8, 135.9, 136.0; HRMS
(FAB) m/z calcd for C29H45O2Si, (MþH)þ 452.3189, found: 452.3198.
4.3.15. (R,E)-1-Iodo-7-(methoxymethoxy)tridec-5-ene (5a). To a so-
lution of 24a (172 mg, 0.67 mmol) in CH3CN (5.0 mL) and Et2O
(1.7 mL) at 0 ꢀC were added imidazole (273 mg, 4.01 mmol), Ph3P
(526 mg, 2.01 mmol), and I2 (382 mg, 3.01 mmol). After stirring at
room temperature for 13 h, the reaction mixture was diluted with
hexane (5 mL) and the insoluble material was removed by filtration
through a pad of silica gel. The filtrate was concentrated to give
a residue, which was purified by column chromatography (20 g
phy (1.3 g silica gel, 1:20 EtOAc/toluene as an eluent) to afford 25
25
(11.3 mg, 86%) as a colorless syrup: [
a
]
þ82.6 (c 0.21, CHCl3); IR nmax
D
(neat) 3375, 2930, 2855,1740, 1700,1520, 1380,1260, 1200 cmꢁ1; 1H
NMR
0.88 (3H, t, J¼6.8 Hz), 1.24–1.58 (14H, m), 1.45 and 1.50 (each
d
3H, 2s),1.95–2.09 (4H, m), 2.39–2.46 (2H, m), 3.36 and 3.45 (each 3H,
2s), 3.70 (1H, ddd, J¼1.0, 6.1, 8.3 Hz), 3.77 (3H, s), 3.92 (1H, dt, J¼6.6,
7.8 Hz), 4.08 (1H, d, J¼1 Hz), 4.25 (1H, d, J¼12.2 Hz), 4.49 (1H, d,
J¼6.6 Hz), 4.52 (1H, d, J¼12.2 Hz), 4.71 (1H, d, J¼6.6 Hz), 4.81 and
4.85 (each 1H, 2d, J¼7.1 Hz), 5.18–5.30 (2H, m), 5.50 (1H, ddd, J¼6.8,
6.8, 15.4 Hz), 5.60 (1H, ddd, J¼6.8, 6.8, 15.4 Hz), 8.54 (1H, br s); 13C
silica gel, toluene as an eluent) to afford 5a (215 mg, 87%) as a col-
26
orless syrup: [
a
]
þ69.9 (c 3.71, CHCl3); IR nmax (neat) 2915, 2855,
D
1455, 1150, 1095 cmꢁ1
;
1H NMR
d
0.87 (3H, t, J¼6.8 Hz), 1.24–1.54
(12H, m), 1.82 (2H, m), 2.07 (2H, dt, J¼6.6, 6.8 Hz), 3.18 (2H, t,
J¼7.1 Hz), 3.36 (3H, s), 3.92 (2H, td, J¼6.6, 8.0 Hz), 4.50 and 4.70
(each 1H, 2d, J¼6.6 Hz), 5.27 (1H, dd, J¼8.0, 15.3 Hz), 5.58 (1H, ddd,
NMR d 14.3,18.9, 22.8, 25.7, 28.9, 29.1, 29.1, 29.4, 32.1, 32.3, 32.7, 34.1,
35.9, 53.0, 55.5, 56.8, 62.0, 62.7, 66.7, 71.0, 76.9, 77.0, 93.4, 96.5,100.1,
124.5, 130.5, 134.3, 135.2, 163.7, 169.2; HRMS (FAB) m/z calcd for
C31H52Cl3NO9Na, (MþNa)þ 710.2605, found: 710.2600.
J¼6.6, 6.6, 15.3 Hz); 13C NMR
d 6.8, 14.3, 22.8, 25.7, 29.4, 30.1, 31.3,
32.0, 33.1, 35.9, 55.5, 76.9, 93.5, 131.1, 133.5; HRMS (FAB) m/z calcd
for C15H29IO2Na, (MþNa)þ 391.1111, found: 391.1108. Anal. Calcd for
C15H29IO2: C, 48.92; H, 7.94. Found: C, 48.80; H, 7.94.
4.4.2. N-{(3S,4R,5R)-4-(Acetyloxy)-3-[(acetoxy)methyl]tetrahydro-2-
oxo-5-[(2E,8E,10R)-10-[[2-(trimethylsilyl)ethoxy]methoxy]-2,8-hexa-
decadien-1-yl]-3-furanyl}-acetamide (31). To
a solution of 5b
4.3.16. (R,E)-1-Iodo-7-{[(trimethylsilyl)methoxy]ethoxy}tridec-5-ene
(5b). By the similar reaction conditions as described for the prep-
(226 mg, 0.050 mmol) in THF (4.0 mL) was added tert-BuLi (1.53 M
solution in pentane, 0.65 mL,1.00 mmol) at ꢁ78 ꢀC under Ar, and the
mixture was stirred for 15 min at ꢁ78 ꢀC. To this mixture at ꢁ78 ꢀC
was added ZnCl2 (1.0 M solutioninTHF, 0.50 mL, 0.50 mmol), and the
cooling bath was removed. After stirring at ambient temperature for
30 min, the resulting colorless solution of Zn reagent was added to
aration of 5a from 24a, compound 24b (28 mg, 0.080 mmol) was
28
converted into 5b (31 mg, 84%): colorless syrup; [
a]
þ70.8 (c 1.43,
D
CHCl3); IR nmax (neat) 2955, 2930, 2855, 1460, 1380, 1250,
1100 cmꢁ1 1H NMR
;
d
0.02 (9H, s), 0.85–0.96 (5H, m), 1.24–1.61
(12H, m), 1.82 (2H, tt, J¼7.1, 7.1 Hz), 2.06 (2H, dt, J¼6.8, 7.1 Hz), 3.17
(2H, t, J¼7.1 Hz), 3.49 and 3.75 (each 1H, 2td, J¼7.1, 9.8 Hz), 3.95
(1H, td, J¼6.6, 8.1 Hz), 4.58 and 4.69 (each 1H, 2d, J¼6.8 Hz), 5.26
a solution of 3 (56 mg, 0.13 mmol) and Pd(PPh3)4 (43.7 mg,
0.038 mmol) in THF (5.0 mL) via a cannula at room temperature.
After stirring at room temperature for 1.5 h, the reaction was

H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
9199
quenched by addition of saturated aqueous NH4Cl solution (15 mL)
at 0 ꢀC, and products were extracted with Et2O. The organic layer was
washed successively with saturated aqueous NH4Cl solution, satu-
rated aqueous NaHCO3 solution and brine, and dried. Removal of the
solvent left a residue, which was roughly purified by column chro-
matography (3 g silica gel, 1:1 EtOAc/hexane as an eluent) to afford
crude coupling product. The crude product was dissolved in pyridine
(2.0 mL) and Ac2O (1.0 mL) and the resulting solution was stirred at
room temperature for 5 h. The reaction mixture was concentrated to
give a residue, which was purified by column chromatography (3 g
products were extracted with EtOAc. The organic layer was washed
successively with saturated aqueous NH4Cl solution, water and
brine, and dried. Removal of the solvent left a residue, which was
purified by column chromatography (0.3 g silica gel, 1:3 EtOAc/
hexane as an eluent) to afford 32 (9.0 mg, 87%) as a colorless syrup:
25
[a
]
þ47.2 (c 0.94, CHCl3); IR nmax (neat) 3350, 2950, 2930, 2860,
D
1790, 1755, 1750, 1680, 1540, 1460, 1430, 1370, 1230, 1190, 1110,
1055, 1030 cmꢁ1; 1H NMR
d
0.84 (3H, t, J¼6.6 Hz), 1.04 (9H, s), 1.15–
1.62 (14H, m), 1.83–2.11 (4H, m), 2.03, 2.04, and 2.09 (each 3H, 3s),
2.34–2.43 (2H, m), 4.05 (1H, ddt, J¼1.0, 6.8, 6.8 Hz), 4.49 and 4.53
(each 1H, 2d, J¼13.4 Hz), 4.71 (1H, ddd, J¼4.6, 8.3, 8.3 Hz), 5.20 (1H,
dddd, J¼1.0, 6.6, 6.6, 15.4 Hz), 5.32–5.43 (2H, m), 5.54 (1H, dddd,
J¼1.0, 6.6, 6.6, 15.4 Hz), 5.79 (1H, d, J¼4.6 Hz), 6.03 (1H, br s), 7.30–
silica gel, 1:2–1:1 EtOAc/hexane as an eluent) to afford 31 (35.1 mg,
24
44%) as a colorless syrup: [
a
]
þ95.9 (c 1.14, CHCl3); IR nmax (neat)
D
3300, 2950, 2930, 2860, 1790, 1755, 1750, 1680, 1370, 1230,
1055 cmꢁ1; 1H NMR
d
0.02 (9H, s), 0.83–0.96 (5H, m),1.20–1.60 (14H,
7.42 (6H, m), 7.63–7.68 (4H, m); 13C NMR
d 14.0, 19.3, 20.3, 20.5,
m), 1.92–2.15 (4H, m), 2.02, 2.04 and 2.10 (each 3 H, 3s), 2.31–2.46
(2H, m), 3.50 and 3.72 (each 1H, 2dt, J¼6.6, 9.8 Hz), 3.94 (1H, dt, J¼7.1,
7.1 Hz), 4.51 (2H, s), 4.58 and 4.70 (each 1H, 2d, J¼6.8 Hz), 4.68–4.74
(1H, m), 5.23 (1H, dd, J¼6.1, 15.3 Hz), 5.40 (1H, ddd, J¼6.6, 6.6,
15.6 Hz), 5.51–5.63 (2H, m), 5.79 (1H, d, J¼4.2 Hz), 6.00 (1H, br s); 13C
22.6, 22.8, 24.8, 27.1, 28.6, 28.7, 29.3, 31.8, 31.9, 32.2, 32.4, 38.1, 62.6,
62.7, 71.9, 74.7, 81.6, 123.1, 127.2, 127.3, 129.2, 129.4, 130.8, 133.0,
134.7, 135.1, 135.9, 136.0, 168.0, 169.3, 170.1, 172.4; HRMS (FAB) m/z
calcd for C43H62NO8Si, (MþH)þ 748.4244, found: 748.4251.
NMR
d
ꢁ1.3, 14.2, 18.2, 20.5, 20.7, 22.8, 22.9, 25.7, 28.8, 29.3, 32.0,
4.4.5. Tetraacetyl mycestericin A
lution of 32 (3.7 mg, 4.9 mol) in THF (0.7 mL) at room temperature
was added Bu4NF (1.0 M solution in THF, 90 L, 90 mol), and the
g-lactone (28b) from 32. To a so-
32.2, 32.3, 32.5, 35.9, 62.8, 72.0, 76.7, 81.7, 91.5, 123.3, 130.4, 134.2,
135.1, 169.0, 169.6, 170.3, 172.6; HRMS (FAB) m/z calcd for
C33H58NO9Si, (MþH)þ 640.3881, found: 640.3878.
m
m
m
mixture was stirred at 65 ꢀC for 7 h. After cooling, to the resulting
mixture were added Ac2O (0.5 mL) and pyridine (1.0 mL). After
stirring at room temperature for 15 h, the reaction mixture was
diluted with H2O at 0 ꢀC, and products were extracted with EtOAc.
The organic layer was washed successively with H2O and brine, and
dried. Removal of the solvent left a residue, which was purified by
column chromatography (0.3 g silica gel,1:2–1:1.5 EtOAc/hexane as
4.4.3. N-{(3S,4R,5R)-4-(Acetyloxy)-5-[(2E,8E,10R)-10-(acetyloxy)-
2,8-hexadecadien-1-yl]-3-[(acetyloxy)methyl]tetrahydro-2-oxo-3-
furanyl}-acetamide (tetraacetyl mycestericin A
g-lactone) (28b). To
a mixture of 31 (2.8 mg, 4.4 mol) and MS4A (50 mg) at room
m
temperature under Ar was added Bu4NF (57.3 mg, 0.22 mmol) in
N,N-dimethyl propylene urea (DMPU, 1.0 mL), and the resulting
mixture was stirred at 80 ꢀC for 12 h. After cooling, to the reaction
mixture at room temperature were added pyridine (1.0 mL) and
Ac2O (0.5 mL). After stirring at room temperature for 15 h, the re-
action mixture was poured into H2O (2 mL), and products were
extracted with EtOAc. The organic layer was washed with brine,
and dried. Removal of the solvent left a residue, which was purified
an eluent) to give 26b (1.7 mg, 63%) as a colorless syrup. The [a]
D
value and spectral (IR, 1H and 13C NMR, and MS) data were fully
identical with those of 28b obtained from 31.
4.4.6. Mycestericin A (1). To a solution of 28b (6.8 mg, 1.2 mmol) in
MeOH (0.5 mL) at room temperature was added 15% aqueous NaOH
solution (0.5 mL). The mixture was stirred at 70 ꢀC for 3 h, and then
neutralized with IRC-76 resin (Hþ form) at room temperature. In-
soluble materials were removed by filtration and the filtrate was
concentrated to give a residue, which was purified by column
chromatography [0.3 g silica gel, 1:5–2:5 MeOH/CHCl3 (saturated
by preparative TLC (4:1 EtOAc/hexane as an eluent) to afford 28b
21
(0.9 mg, 38%) as a colorless syrup: [
a
]
D
þ58.2 (c 0.41, CHCl3); IR
nmax (neat) 3350, 2920, 2855, 1790, 1750, 1725, 1680, 1540, 1460,
1375, 1240, 1030 cmꢁ1 1H NMR
;
d
0.87 (3H, t, J¼7.0 Hz), 1.22–1.40
(12H, m), 1.50–1.66 (2H, m), 1.99–2.05 (4H, m), 2.02, 2.03, 2.05, and
2.10 (each 3 H, 4s), 2.29–2.49 (2H, m), 4.50 and 4.52 (each 1H, 2d,
J¼11.5 Hz), 4.71 (1H, ddd, J¼4.4, 8.0, 8.0 Hz), 5.17 (1H, dt, J¼6.8,
6.8 Hz), 5.32–5.44 (2H, m), 5.51–5.71 (2H, m), 5.79 (1H, d, J¼4.4 Hz),
with H2O) as an eluent] to afford mycestericin A (1) (4.6 mg, 93%) as
21
an amorphous solid: [
a
]
D
ꢁ8.6 (c 0.45, MeOH); IR nmax (KBr disk)
3400, 3270, 2920, 2855, 1630, 1460, 1400, 1050, 965 cmꢁ1; 1H NMR
(CD3OD)
d
0.89 (3H, t, J¼7.1 Hz), 1.25–1.60 (14H, m), 1.93–2.10 (4H,
6.01 (1H, br s); 13C NMR
d
14.0, 20.3, 20.5, 21.4, 22.5, 22.7, 25.2, 28.5,
m), 2.26 (2H, t, J¼6.8 Hz), 3.77–3.95 (4H, m), 4.00 (1H, d, J¼11.0 Hz),
28.7, 29.0, 31.7, 32.0, 32.2, 32.3, 34.5, 62.6, 62.7, 71.8, 75.0, 81.6,
123.2, 128.6, 134.0, 135.0, 168.8, 169.3, 170.2, 170.4, 172.4; HRMS
(FAB) m/z calcd for C29H46NO9, (MþH)þ 552.3172, found: 552.3181.
The spectral data were fully identical with those reported for the
authentic sample derived from natural mycestericin A.1a
5.34–5.47 (2H, m), 5.53 (1H, ddd, J¼6.8, 6.8, 15.3 Hz), 5.59 (1H, ddd,
J¼6.8, 6.8 15.3 Hz); 13C NMR (CD3OD)
d 14.4, 23.6, 26.6, 29.97, 30.0,
30.4, 33.0, 33.1, 33.6, 38.5, 38.6, 65.2, 70.5, 71.2, 73.66, 73.74, 126.9,
132.3, 134.57, 134.64, 173.5; HRMS (FAB) m/z calcd for C21H40NO6,
(MþH)þ 402.2856, found: 402.2857. The spectral data were fully
identical with those reported for natural mycestericin A.1a
4.4.4. N-{(3S,4R,5R)-4-(Acetyloxy)-3-[(acetoxy)methyl]tetrahydro-2-
oxo-5-[(2E,8E,10R)-10-(tert-butyldimethylsilyloxy)-2,8-hex-
adecadien-1-yl]-3-furanyl}-acetamide (32). To neat 23c (25 mg,
0.057 mmol) under Ar at room temperature was added a solution of
9-BBN (0.5 M in THF, 0.91 mL, 0.46 mmol), and the resulting mix-
ture was sonicated (47 kHz, 60 W) in a water bath at ambient
temperature for 1 h. To the reaction mixture at 0 ꢀC was added H2O
(0.12 mL), and the mixture was stirred at room temperature for
10 min. The resulting organoborane solution was added to a solu-
4.5. Synthesis of 14-epi-mycestericin A
4.5.1. (S,E)-tert-Butyldiphenyl(trideca-1,5-dien-7-yloxy)silane (ent-
23c). The same reaction sequence for the preparation of 23c from
diisopropyl D-tartrate was applied to dimethyl L-tartrate to provide
26
ent-23c: [
a]
ꢁ21.2 (c 0.55, CHCl3). The spectral data were fully
D
identical with those of 23c.
tion of 3 (6.1 mg, 0.014 mmol) and AsPh3 (0.9 mg, 2.8
(1.0 mL) via a cannula at room temperature. To this mixture at room
temperature were added K2CO3 (7.9 mg, 0.057 mmol) and
m
mol) in DMF
4.5.2. N-{(3S,4R,5R)-4-(Acetyloxy)-3-[(acetoxy)methyl]tetrahydro-2-
oxo-5-[(2E,8E,10S)-10-(tert-butyldimethylsilyloxy)-2,8-hexadecadien-
1-yl]-3-furanyl}-acetamide (33). Coupling reaction of ent-23c
(56 mg, 0.13 mmol) with 3 (15 mg, 0.034 mmol) by the similar re-
PdCl2(dppf)$CH2Cl2 (2.3 mg, 2.8 mmol), and the whole mixture was
stirred at room temperature for 1.5 h. The reaction mixture was
diluted with saturated aqueous NH4Cl solution at 0 ꢀC, and
action conditions as described for the reaction of 23c with 3
25
afforded 33 (19 mg, 77%) as a colorless syrup: [
a]
þ26.6 (c 0.95,
D

9200
H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
CHCl3); IR nmax (neat) 3350, 2950, 2930, 2860, 1790, 1755, 1750,
4.6.2. (R)-Octane-1,2-diyl dibenzoate (36) and its (S)-isomer (ent-
36). Ozone was introduced into solution of 35 (13.2 mg,
1680, 1540, 1460, 1430, 1370, 1230, 1190, 1110, 1055, 1030 cmꢁ1; 1H
a
NMR
d
0.84 (3H, t, J¼6.6 Hz), 1.04 (9H, s), 1.15–1.62 (14H, m), 1.83–
0.052 mmol) in MeOH (0.8 mL) at ꢁ78 ꢀC for 5 min. After con-
firming the complete consumption of the starting material (TLC
analysis), excess ozone was removed with a stream of Ar gas. To the
reaction mixture was added NaBH4 (9.8 mg, 0.26 mmol) at ꢁ78 ꢀC
and the mixture was stirred for 5 min at ꢁ78 ꢀC. To this mixture
was added K2CO3 (36 mg, 0.26 mmol) at ꢁ78 ꢀC, and the reaction
mixture was stirred at 0 ꢀC for 40 min. The reaction mixture was
diluted with saturated aqueous NH4Cl solution, and products were
extracted with EtOAc. The organic layer was washed with saturated
aqueous NH4Cl solution, and dried. Removal of the solvent gave
a crude diol. To a solution of the crude diol in pyridine (1.0 mL) at
2.11 (4H, m), 2.03, 2.04 and 2.09 (each 3H, 3s), 2.29–2.48 (2H, m),
4.05 (ddt, 1H, H-14, J¼1, 6.8, 6.8 Hz), 4.49 and 4.53 (each 1H, 2d,
J¼13.4 Hz), 4.70 (1H, ddd, J¼4.6, 8.3, 8.3 Hz), 5.20 (1H, dddd, J¼1.0,
6.6, 6.6, 15.4 Hz), 5.32–5.43 (2H, m), 5.54 (1H, dddd, J¼1.0, .6.6, 6.6,
15.4 Hz), 5.79 (1H, d, J¼4.6 Hz), 6.02 (1H, br s), 7.30–7.43(6H, m),
7.63–7.68 (4H, m); 13C NMR
d 14.1, 19.3, 20.3, 20.5, 22.6, 22.8, 24.8,
27.1, 28.6, 28.7, 29.2, 31.8, 31.9, 32.2, 32.4, 38.1, 62.6, 62.7, 72.0, 74.7,
81.6, 123.1, 127.2, 127.4, 129.3, 129.4, 130.8, 133.1, 134.7, 135.1, 135.9,
136.0, 168.8, 169.4, 170.1, 172.4; HRMS (FAB) m/z calcd for
C43H62NO8Si, (MþH)þ 748.4244, found: 748.4248.
0 ꢀC was added BzCl (46 L, 0.40 mmol) at 0 ꢀC and the mixture was
m
4.5.3. N-{(3S,4R,5R)-4-(Acetyloxy)-5-[(2E,8E,10S)-10-(acetyloxy)-
2,8-hexadecadien-1-yl]-3-[(acetyloxy)methyl]tetrahydro-2-oxo-3-
furanyl}-acetamide (28a). By the similar reaction conditions
employed for the preparation of 28b from 31, compound 33 (14 mg,
stirred at room temperature for 19 h. The reaction mixture was
diluted with saturated aqueous NH4Cl solution, and products were
extracted with EtOAc. The organic layer was washed successively
with saturated aqueous NH4Cl solution, and saturated aqueous
NaHCO3 solution, H2O and brine, and dried. Removal of the solvent
left a residue, which was purified by column chromatography (0.3 g
0.018 mmol) was converted into 28a (2.6 mg, 26%): colorless syrup;
21
[
a]
þ30.0 (c 0.22, CHCl3); IR nmax (neat) 3350, 2920, 2855, 1790,
D
1750, 1725, 1680, 1540, 1460, 1375, 1240, 1030 cmꢁ1; 1H NMR
d
0.87
silica gel, 1:40 EtOAc/hexane as an eluent) to afford 36 (9.1 mg, 49%
24
(3H, t, J¼7.0 Hz), 1.22–1.40 (12H, m), 1.50–1.66 (2H, m), 1.99–2.05
(4H, m), 2.02, 2.03, 2.05, and 2.10 (each 3H, 4s), 2.29–2.49 (2H, m),
4.50 and 4.52 (each 1H, 2d, J¼11.5 Hz), 4.72 (1H, ddd, J¼4.4, 8.0,
8.0 Hz), 5.17 (1H, dt, J¼6.8, 6.8 Hz), 5.32–5.44 (2H, m), 5.51–5.71
for three steps) as a colorless syrup: [
a]
þ5.4 (c 0.63, CHCl3); IR
D
nmax (neat) 2960, 2930, 2860, 1740, 1710, 1600, 1460, 1315, 1280,
1240, 1110, 1070, 1025 cmꢁ1; 1H NMR
d
0.87 (3H, t, J¼6.6 Hz), 1.26–
1.51 (8H, m), 1.71–1.92 (2H, m), 4.47 (1H, dd, J¼6.6, 11.7 Hz), 4.56
(1H, dd, J¼3.4, 11.7 Hz), 5.50 (1H, ddt, J¼3.4, 6.6, 7.3 Hz), 7.38–7.47
(2H, m), 5.79 (1H, d, J¼4.4 Hz), 5.99 (1H, br s); 13C NMR
d 14.0, 20.3,
20.5, 21.4, 22.6, 22.8, 25.2, 28.5, 28.7, 29.0, 31.7, 32.0, 32.2, 32.3, 34.5,
62.6, 62.7, 71.9, 75.0, 81.6, 123.2, 128.6, 134.0, 135.0, 168.8, 169.3,
170.2, 170.4, 172.4; HRMS (FAB) m/z calcd for C29H45NO9Na,
(MþNa)þ 574.2992, found: 574.2988.
(4H, m), 7.51–7.58 (2H, m), 7.99–8.07 (4H, m); 13C NMR
d 14.0, 22.5,
25.2, 29.1, 31.0, 31.6, 65.7, 72.3, 128.4, 129.7, 132.95, 133.01, 166.1;
Retention time of HPLC [DAICEL CHIRLCEL OJ-H, 4.6 mm
IDꢂ250 mm, i-PrOH/hexane¼1:300, flow rate¼0.8 mL/min, UV
(254 nm) detection], 21.9 min (>99% ee); HRMS (FAB) m/z calcd for
C22H27O4, (MþH)þ 355.1909, found: 355.1904.
4.5.4. 14-epi-Mycestericin A (34). By the similar reaction conditions
employed for the preparation of 1 from 28b, compound 28a
By the similar reaction conditions as employed for the synthesis
(4.3 mg, 7.8
m
mol) was converted into 34 (2.5 mg, 81%): amorphous
of 36 from 35, ent-35 (8.5 mg, 0.033 mmol) was converted into ent-
21
21
solid; [
a
]
ꢁ5.0 (c 0.15, MeOH); IR nmax (KBr disk) 3400, 3270, 2920,
36 (5.3 mg, 45%): [
a
]
ꢁ6.0 (c 0.15, CHCl3); Retention time of HPLC
D
D
2855, 1630, 1460, 1400, 1050, 965 cmꢁ1
;
1H NMR (CD3OD)
d
0.89
[DAICEL CHIRLCEL OJ-H, 4.6 mm IDꢂ250 mm, i-PrOH/
hexane¼1:300, flow rate¼0.8 mL/min, UV (254 nm) detection],
19.0 min (>99% ee).
(3H, br t, J¼6.8 Hz), 1.25–1.60 (14H, m), 1.93–2.10 (4H, m), 2.26 (2H,
br t, J¼6.8 Hz), 3.77–3.95 (4H, m), 4.00 (1H, d, J¼11.0 Hz), 5.34–5.64
(4H, m); 13C NMR (CD3OD)
d 14.4, 23.6, 26.6, 29.95, 30.0, 30.4, 33.0,
33.1, 33.6, 38.5, 38.7, 65.1, 70.5, 71.3, 73.7, 73.8, 126.9, 132.3, 134.59,
134.64 (a signal of the carboxyl carbon could not be detected due to
its low intensity); HRMS (FAB) m/z calcd for C21H40NO6, (MþH)þ
402.2856, found: 402.2847.
4.6.3. Degradation of synthetic mycestericin A (1). To a solution of
mycestericin A (1) (2.5 mg, 6.2 mmol) in pyridine (1.5 mL) was
added Ac2O (1.0 mL), and the mixture was stirred at room tem-
perature for 15 h. The reaction mixture was concentrated to give
a residue, which was purified by column chromatography (0.3 g
silica gel, 1:2–1:1 EtOAc/hexane as an eluent) to afford tetraacetyl
4.6. Degradation study of mycestericin A and its 14-epimer
mycestericin A
g-lactone (28b) (2.5 mg, 73%) as a colorless syrup.
4.6.1. (R,E)-Dec-2-ene-1,4-diyl diacetate (35) and its (S,E)-isomer
(ent-35). To a mixture of 22b (7.2 mg, 0.024 mmol) and MS4A
(50 mg) was added TBAF (62 mg, 0.24 mmol) in DMPU (0.4 mL), and
the mixture was stirred at 90 ꢀC for 3 h. To the mixture at room
temperature were added pyridine (1.5 mL) and Ac2O (1.0 mL), and
the mixture was stirred at room temperature for 19 h. The reaction
mixture was diluted with EtOAc, and washed with brine, and dried.
Removal of the solvent left a residue, which was purified by column
Ozone was introduced into a solution of 28b (2.5 mg, 4.5 mmol) in
MeOH (1.5 mL) at ꢁ78 ꢀC for 5 min. After confirming the complete
consumption of the starting material (TLC analysis), excess ozone
was removed with a stream of Ar gas. To the reaction mixture was
added NaBH4 (0.5 mg 13.2
m
mol) at ꢁ78 ꢀC. After being stirred for
5 min, the reaction was quenched by addition of 1 M aqueous HCl
solution (0.1 mL) and diluted with water. Products were extracted
with EtOAc. The organic layer was washed with 1 M aqueous HCl
solution, and dried. Removal of the solvent left a residue, which
was roughly purified by column chromatography (0.1 g silica gel,
1:7 EtOAc/hexane as an eluent). The active fractions were col-
lected and concentrated to give an oil, which was dissolved in
MeOH (1.0 mL). To this solution at 0 ꢀC was added K2CO3 (1.8 mg,
chromatography (0.3 g silica gel, 1:15–1:10 EtOAc/hexane as an el-
21
uent) to afford 35 (4.7 mg, 77%) as a colorless syrup: [
a
]
þ26.5 (c
D
1.20, CHCl3); IR nmax (neat) 2960, 2930, 2860, 1740, 1460, 1430, 1370,
1240, 1025 cmꢁ1; 1H NMR
d
0.87 (3H, t, J¼6.6 Hz), 1.24–1.31 (8H, m),
1.49–1.67 (2H, m), 2.05 and 2.06 (each 3H, 2s), 4.54 (2H, d, J¼4.9 Hz),
5.24 (1H, dt, J¼6.0, 6.8 Hz), 5.67 (1H, dd, J¼6.0, 15.6 Hz), 5.77 (1H, td,
13.2 mmol). After being stirred for 30 min, the reaction mixture
J¼4.9,15.6 Hz); 13C NMR (75 MHz, CDCl3)
d
14.0, 20.9, 21.2, 22.5, 25.0,
was diluted with saturated aqueous NH4Cl solution, and products
were extracted with EtOAc. The organic layer was washed with
saturated NH4Cl aqueous, and dried. Removal of the solvent gave
crude octane-1,2-diol. To a solution of crude octane-1,2-diol in
29.0, 31.6, 34.2, 64.0, 73.6, 126.3, 132.6, 170.3, 170.6; HRMS (FAB) m/z
calcd for C14H25O4, (MþH)þ 257.1753, found: 257.1751.
By the similar reaction conditions as employed for the synthesis
of 35 from 22b, ent-22b (5.0 mg, 0.016 mmol) was converted into
pyridine (1.0 mL) was added BzCl (50
mixture was stirred at room temperature for 13 h. The reaction
mL, 380 m
mol) at 0 ꢀC. The
21
ent-35 (3.2 mg, 75%): [
a
]
ꢁ26.6 (c 0.23, CHCl3).
D

H. Yamanaka et al. / Tetrahedron 65 (2009) 9188–9201
9201
Toto, T.; Furuta, T.; Wakimoto, T.; Kan, T. Tetrahedron: Asymmetry 2008, 19,
2771–2773.
mixture was diluted with saturated NH4Cl aqueous, and products
were extracted with EtOAc. The organic layer was washed suc-
cessively with saturated aqueous NH4Cl solution, and saturated
aqueous NaHCO3 solution, H2O and brine, and dried. Removal of
the solvent left a residue, which was purified by preparative TLC
(1:50 EtOAc/hexane, developed three times) to afford 36 (1.1 mg,
50% for four steps) as a colorless syrup: HRMS (FAB) m/z calcd for
C22H27O4, (MþH)þ 355.1909, found: 355.1908. The 1H NMR spec-
tral data were fully identical with those of 36 prepared from 35,
and chiral HPLC analysis assigned the absolute configuration of 36
prepared from 1 as R with >99% ee.
10. For total synthesis of sphingofungins
E and/or F, see: (a) Kobayashi, S.;
Matsumura, M.; Furuta, T.; Hayashi, T.; Iwamoto, S. Synlett 1997, 301–303;
(b) Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima, M.; Hanada, K. J. Am. Chem.
Soc. 1998, 120, 908–919; (c) Kobayashi, S.; Furuta, T. Tetrahedron 1998, 54,
10275–10294; (d) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 1998, 120, 6818–6819;
Trost, B. M.; Lee, C. J. Am. Chem. Soc. 2001, 123, 12191–12201; (e) Liu, D.-G.;
Wang, B.; Lin, G.-Q. J. Org. Chem. 2000, 65, 9114–9119; (f) Wang, B.; Yu, X.-M.;
Lin, G.-Q. Synlett 2001, 904–906; (g) Nakamura, T.; Shiozaki, M. Tetrahedron Lett.
2001, 42, 2701–2704; Tetrahedron 2002, 58, 8779–8791; (h) Oishi, T.; Ando, K.;
Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Org. Lett. 2002, 4, 151–154; Bull. Chem.
Soc. Jpn. 2002, 75, 1927–1947; (i) Lee, K.-Y.; Oh, C.-Y.; Ham, W.-H. Org. Lett. 2002,
4, 4403–4405; (j) Li, M.; Wu, A. Synlett 2006, 2985–2988.
11. For total synthesis of mycestericins, see: (a) Fujita, T.; Hamamichi, N.; Matsu-
zaki, T.; Kitao, Y.; Kiuchi, M.; Node, M.; Hirose, R. Tetrahedron Lett. 1995, 36,
8599–8602; (b) Shibata, K.; Shingu, K.; Vassilev, V. P.; Nishide, K.; Fujita, T.;
Node, M.; Kajimoto, T.; Wong, C.-H. Tetrahedron Lett. 1996, 37, 2791–2794;
(c) Nishide, K.; Shibata, K.; Fujita, T.; Kajimoto, T.; Wong, C.-H.; Node, M.
Heterocycles 2000, 52, 1191–1201; (d) Iwabuchi, Y.; Furukawa, M.; Esumi, T.;
Hatakeyama, S. Chem. Commun. 2001, 2030–2031. Synthesis and biological
activity of sulfamisterin and its derivatives, see: (e) Sato, H.; Maeba, T.; Yanase,
R.; Yamaji-Hasegawa, A.; Kobayashi, T.; Chida, N. J. Antibiot. 2005, 58, 37–49.
12. A part of this work has been published as a preliminary communication, see:
Sato, H.; Sato, K.; Iida, M.; Yamanaka, H.; Oishi, T.; Chida, N. Tetrahedron Lett.
2008, 49, 1943–1947.
4.6.4. Degradation of 14-epi-mycestericin A (34). The similar re-
action conditions as described for conversion of 1 to 36 were applied
to 14-epi-mycestericin A (34, 1.5 mg, 3.7 mmol) to afford ent-36
(0.5 mg, 38% for four steps) as a colorless syrup: HRMS (FAB) m/z
calcd for C22H27O4, (MþH)þ 355.1909, found: 355.1907. The 1H NMR
spectral data were fully identical with those of 36 prepared from 35,
and chiral HPLC analysis assigned the absolute configuration of ent-
36 prepared from 34 as S with >99% ee.
13. Chida, N.; Takeoka, J.; Tsutsumi, N.; Ogawa, S. J. Chem. Soc., Chem. Commun.
1995, 793–794; Chida, N.; Takeoka, J.; Ando, K.; Tsutsumi, N.; Ogawa, S. Tetra-
hedron 1997, 53, 16287–16298.
Acknowledgements
14. For a comprehensive review on Overman rearrangement and related reactions,
see: Overman, L. E.; Carpenter, N. E. In Organic Reactions; Overman, L. E., Ed.;
Wiley: New York, NY, 2005; Vol. 66, pp 1–107.
This work was supported in part by a Grant-in-Aid for the 21st
Century COE Program ‘Keio Life Conjugate Chemistry’ from the Min-
istry of Education, Culture, Sports, Science, and Technology, Japan.
15. Recent reports on syntheses of natural products and related compounds uti-
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Sato, T.; Chida, N. Synthesis 2009, 2983–2991; (b) Imaoka, T.; Iwamoto, O.;
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32. The optical purities of 23c and ent-23c were determined to be >99% ee, by
chiral column analyses (Chiralcel OD-H) of the derived alcohols 24c and ent-
24c. See Experimental section.