Enantioselective Modular Total Synthesis of Macrolides Sch725674 and C-4-epi-Sch725674

Article abstract of DOI:10.1002/ejoc.201501531

The convergent total synthesis of Sch725674 has been accomplished by starting from (R)-1,2-epoxyheptane and assembling five modules in a highly stereoselective manner to give the final product in 6.6 % overall yield. The same strategy was extended to the

Full text of DOI:10.1002/ejoc.201501531

DOI: 10.1002/ejoc.201501531
Full Paper
Total Synthesis
Enantioselective Modular Total Synthesis of Macrolides
Sch725674 and C-4-epi-Sch725674
Brijesh M. Sharma,[a] Arjun Gontala,[a] and Pradeep Kumar*[a]
Abstract: The convergent total synthesis of Sch725674 has resolution of an epoxide followed by its regioselective opening
been accomplished by starting from (R)-1,2-epoxyheptane and through a Yamaguchi–Hirao alkynylation, and ring-closing
assembling five modules in a highly stereoselective manner to metathesis reaction to furnish the unique 14-membered ring
give the final product in 6.6 % overall yield. The same strategy macrolactone. In addition, the influence of protecting groups
was extended to the synthesis of its C-4 epimer. Key reactions on the efficiency of the ring-closing metathesis (RCM) macrocy-
of the synthetic pathway include a Jacobsen hydrolytic kinetic clization has been studied to maximize its yields.
Introduction
Fourteen-membered ring macrolides have been research tar-
gets because of their exceptional biological activity and have
been subjected to chemical modifications to establish struc-
ture–activity relationships for more than five decades.[1] The
most distinguished feature of macrolides is their antimicrobial
activity. However, their use has resulted in macrolide resistance
in many organisms, which fuels the quest for newer potentially
active macrolides. A new Sch725674 macrolide was recently iso-
lated by Yang et al. from an Aspergillus sp., which has good
antifungal activity against S. cereviceae and C. albicans with
minimum inhibitory concentrations (MICs) of 8 and 32 μg mL–1
respectively.[2]
Additionally, this molecule can be converted into products
that contain the structural scaffolds of pyran and furan rings[3]
by using a simple intramolecular transannular oxy-Michael reac-
tion to afford compounds that resemble those with established
antineoplastic activity (Figure 1). Such transformations would
Figure 1. Structures of some representative macrolides.
help to tune the biological activity of a lead structure by incor-
porating activity-determining structural features. Hence, the to-
tal synthesis of Sch725674 can lead to a plethora of opportuni-
ties in terms of achieving a function-oriented synthesis of new
egy.[5] A few more total syntheses of the same macrolactone
were reported by Prasad et al.[6] and Kaliappan et al.[7] During
the preparation of our manuscript, Reddy et al.[8] reported the
formal total synthesis of Sch725674 (1).
macrolides.[4]
This structurally and stereochemically complex 14-mem-
bered ring macrolactone is comprised of an oxygenated hydro-
carbon skeleton that contains four stereogenic centers, an α,ꢀ-
unsaturated ester, and an unusual n-pentyl carbon chain. Be-
cause of its distinctive framework, Sch725674 has gained rapid
intrigue among synthetic organic chemists. The first total syn-
thesis of Sch725674 along with its 16 stereoisomeric analogues
was reported by Curran et al. using a fluorous-tagging strat-
For the synthesis of a library of compounds in terms of func-
tional groups and stereochemical diversity,[9] an modular syn-
thesis was envisioned as optimal to allow for maximum variabil-
ity. This approach allows for parallel combinatorial and syn-
thetic strategies. Thus, a convergent approach amenable for the
easy synthesis of Sch725674 and C-4-epi-Sch725674 was de-
signed, which was comprised of the assembly of five modules
through sequential Jacobsen hydrolytic kinetic resolution,[10]
Yamaguchi–Hirao alkynylation,[11] and ring-closing metathesis
(RCM) steps to construct the core skeleton of the macrolide as
shown in Scheme 1.
[a] Division of Organic Chemistry, CSIR – National Chemical Laboratory,
Pune 411008, India
E-mail: pk.tripathi@ncl.res.in
http://www.ncl-india.org/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501531.
Eur. J. Org. Chem. 2016, 1215–1226
1215
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 2. Synthesis of alkyne fragment 8.
was oxidized by treatment with meta-chloroperoxybenzoic acid
(m-CPBA) to give epoxide 11 in 94 % yield as a diastereomeric
mixture (anti/syn, 2:1). Epoxide 11 was subjected to the Jacob-
sen hydrolytic kinetic resolution by using the (S,S)-(salen)CoIII-
OAc [salen = N,N′-ethylenebis(salicylideneaminato)] catalyst to
give diastereomerically pure epoxide 12a in 60 % yield along
with diol 12b in 28 % yield. Enantiopure diol 12b was con-
verted into the desired epoxide 12a through a sequence of
reactions (i.e., 12b→12a), as depicted in Scheme 3. Accordingly,
the chemoselective benzoylation of 12b followed by tosylation
of the secondary hydroxy group and treatment of the crude
tosylate product with K2CO3 in methanol led to the deprotec-
tion of the benzoyl ester. The concomitant ring closure by an
intramolecular SN2 displacement of the tosylate furnished epox-
ide 12a in 70 % overall yield Scheme 3.[13]
Scheme 1. Retrosynthetic analysis (TBDPS = tert-butyldiphenylsilyl, TBS = tert-
butyldimethylsilyl, PMB = p-methoxybenzyl).
Results and Discussion
For this new approach, we have designed a unified, efficient,
and convergent strategy to access both the target natural prod-
uct Sch725674 (1) and its C-4 epimer 2. Our strategy involves
the disconnection of Sch725674 into five modules as outlined
in Scheme 1.
To allow for maximum flexibility, the assembly of a 14-mem-
bered ring lactone was envisioned by carrying out a ring-
closing metathesis of diene 22, which could be obtained by a
Yamaguchi–Hirao alkynylation between epoxide 12a and alk-
yne fragment 8. Alkyne 8 could be obtained by employing a
Grignard reaction with (R)-1,2-epoxyheptane (6), which would
be our commercially available chiral starting material. Access to
fragment 12a could be achieved by a Jacobsen hydrolytic ki-
netic resolution (HKR), the material for which could be prepared
from commercially available (PMB)-protected (S)-glycidol (9). To
synthesize target molecule 1, we first embarked on the prepara-
tion of both required fragments 8 and 12a. To access alkyne
fragment 8, readily available (R)-1,2-epoxyheptane (6) was sub-
jected to a Grignard reaction. The regioselective epoxide ring-
opening reaction with propargylmagnesium bromide (i.e.,
6→7) followed by protection of the resulting hydroxy group as
a TBDPS ether gave the required alkyne fragment 8 in 90 %
yield as shown in Scheme 2.
Scheme 3. Synthesis of epoxide fragment 12a (THF = tetrahydrofuran,
DMAP = 4-(dimethylamino)pyridine, Ts = p-tolylsulfonyl).
After the successful synthesis of both fragments in substan-
tial amounts, our next task was to couple them under the Yama-
guchi–Hirao protocol (Scheme 4).[11] Accordingly, the sequential
As illustrated in Scheme 3, the synthesis of epoxy compo- treatment of alkyne 8 with nBuLi and BF3·Et2O followed by the
nent 12a started from PMB-protected (S)-glycidol (9), which addition of epoxide 12a in THF at –78 °C resulted in the forma-
upon treatment with vinylmagnesium chloride in a Grignard tion of ꢀ-hydroxy alkyne 13 in 86 % yield. The triple bond of
reaction followed by protection of the resulting hydroxy group 13 was then completely reduced in the presence of Raney Ni
as a TBS ether gave homoallylic alcohol 10.[12] Compound 10 and H2 under 1 atm to give 14, the free hydroxy group of which
Eur. J. Org. Chem. 2016, 1215–1226
www.eurjoc.org
1216
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 4. Coupling of fragments 8 and 12a (PNBA = p-nitrobenzoic acid, DIAD = diisopropyl azodicarboxylate).
Figure 2. Determination of relative configuration by 13C NMR analysis of anti-acetonide 14b (TBAF = tetra-n-butylammonium fluoride, PPTS = pyridinium p-
toluenesulfonate).
was protected as a methoxymethyl (MOM) ether by using dimethoxypropane (2,2-DMP) gave acetonide 14b. The struc-
MOMCl and N,N-diisopropylethylamine (DIPEA) and heating the ture of anti-acetonide 14b was confirmed by the appearance
reaction mixture at reflux to give 15 in 76 % yield over the two of the methyl carbon signals at δ = 24.7 and 24.8 ppm and the
steps. The removal of the PMB group by using 2,3-dichloro-5,6- acetal carbon signal at δ = 100.3 ppm, as shown in Figure 2.
dicyano-1,4-benzoquinone (DDQ) in a mixture of CHCl3/pH = 7
phosphate buffer (20:1) afforded primary alcohol 16 in 89 %
yield. The oxidation of 16 with 2-iodoxybenzoic acid (IBX) fur-
nished the corresponding aldehyde, which was subsequently
treated with vinylmagnesium bromide at –78 °C to give com-
pounds 18a and 18b as a diastereomeric mixture (anti/syn, 4:1)
in 82 % yield over the two steps.[14]
Furthermore, the relative configurations of the more desh-
ielded chiral protons of acetonides derived from trans-1,2-diol
20a and syn-1,2-diol 20b were established by comparing the
coupling constants and NOE correlations of the protons, as
shown in Figure 3.[16]
The diastereomers were separated by flash chromatography,
and the minor syn isomer 18b was carried forward to synthesize
the C-4 epimer. The stereochemistry of anti isomer 18a, pre-
pared by the Grignard reaction, led to the desired natural
stereoisomer. However, isomer 18b can also be smoothly con-
verted into the major anti isomer 18a by employing a Mitsu-
nobu reaction.
The relative stereochemistry at C-5 and C-7 of 14 was deter-
mined by using Rychnovsky's acetonide method,[15] as shown
in Figure 2. Towards this end, the TBS group of compound 14
was removed to furnish a diol, which upon treatment with 2,2-
Figure 3. Coupling constants and NOE correlations to determine the relative
configurations of chiral protons of the acetonide derived from trans-1,2-diol
(20a) and the acetonide derived from syn-1,2-diol (20b).
Eur. J. Org. Chem. 2016, 1215–1226
www.eurjoc.org
1217
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
After synthesizing compound 18a in a substantial amount eventually furnished the target molecule, C-4-epi-Sch725674, al-
and also converting the minor isomer syn-18b into 18a by us- beit in only 40 % yield, as shown in Scheme 7.
ing Mitsunobu protocol (Scheme 4), we subjected 18a to a des-
ilylation procedure with TBAF (18a→19a) followed by the in-
stallation of an acetonide protecting group using 2,2-DMP to
give compound 20a in 84 % yield over the two steps. A desilyla-
tion reaction (20a→21a) followed by the esterification of 21a
using acryloyl chloride gave compound 22a in 74 % yield, as
shown in Scheme 5.
Scheme 7. Synthesis of unnatural C-4-epi-Sch725674.
In an effort to increase the overall yield of the total synthesis,
we set out to optimize the yield of the last step in the prepara-
tion of natural isomer 1. The influence of protecting groups on
highly functionalized dienes has been known to play an impor-
tant role in the failure of a reaction, as this final step only led
to a mixture of unidentifiable products, even after the employ-
ment of a variety of Grubbs catalysts under different reaction
conditions, as depicted in Scheme 8. The failure could be attrib-
uted to the steric hindrance from the protecting groups, as
there is precedence in the literature that the presence of an
acetonide group in the vicinity of a RCM site may hinder the
progress and, thus, disfavor the RCM reaction.[17] Upon removal
Scheme 5. Synthesis of key precursor for target molecule 1.
of all of the protecting groups, the yield of the RCM step was
comparable to that of C-4 epimer 2.
Poor yields of the RCM reaction could also be tentatively
A similar sequence of reactions were then executed for the
ascribed to the unproductive coordination/chelation of Ru with
a free hydroxy group present in the substrate.[18] Therefore, a
substrate that has free allylic and homoallylic hydroxy groups
along with one extra protected hydroxy group was sought, as
documented in the literature.[19] In yet another attempt, we ex-
amined the RCM step of the olefin that has the adjacent free
hydroxy groups.
synthesis of key precursor 22b to be used for the preparation
of the unnatural C-4 epimer, as shown in Scheme 6.
Towards this end, we initially carried out the selective depro-
tection of the acetonide group of 22a by using PPTS to obtain
diol 24. The subsequent ring-closing metathesis of 24 was quite
efficient, and to our delight, we observed a significant increase
in the yield (70 %) of anticipated compound 25, as shown in
Scheme 8. The removal of the MOM protecting group from 25
by using aqueous HCl (3
N) gave the target macrolide
Scheme 6. Synthesis of key precursor for unnatural C-4 epimer.
Sch725674 (1) in 68 % yield, as shown in Scheme 9. All of the
spectroscopic data (1H NMR, 13C NMR, and HRMS) of synthe-
sized Sch725674 (1) were identical with those of the isolated
The global deprotection of 22b by treatment with aqueous natural product. The optical rotation of synthetic Sch725674 (1)
HCl afforded compound 23b in 62 % yield. The ring-closing was determined to be [α]D26 = + 4.8 (c = 0.3, CH3OH), and the
metathesis step by employing Grubbs 2nd generation catalyst reported value was [α]D25 = + 5.15 (c = 0.27, CH3OH).
3
N
Eur. J. Org. Chem. 2016, 1215–1226
www.eurjoc.org
1218
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 8. Attempts for ring-closing metathesis: the effects of protecting groups.
Experimental Section
General Methods: All reactions were carried out under anhydrous
conditions by using flame-dried glassware under a positive pressure
of argon, unless otherwise mentioned. CH2Cl2, Et3N, and iPr2NEt
were distilled from CaH2. Et2O and THF were distilled from Na/ben-
zophenone. Other reagents were obtained from commercial suppli-
ers and used as received. Air-sensitive reagents and solutions were
transferred by using a syringe or cannula and introduced to the
reaction system through a rubber septum. The progress of the reac-
tions was monitored by thin layer chromatography using precoated
silica gel plates (60 F254, 0.25 mm). Visualization of the developed
plates was accomplished by either UV light, iodine adsorbed onto
the silica gel, or immersion in an ethanolic solution of phosphomo-
lybdic acid (PMA), p-anisaldehyde, or KMnO4 followed by heating
with a heat gun for approximately 15 s. Flash chromatography was
Scheme 9. End game for the total synthesis of natural Sch725674 (1).
Conclusions
1
performed on silica gel (230–400 mesh). All of the H and 13C NMR
The total synthesis of Sch725674 and C-4-epi-Sch725674 was
accomplished in 15 steps from commercially available (S)-PMB-
protected glycidol and (R)-1,2-epoxyheptane. Although the
number of steps are greater than that of the previously re-
ported synthesis, each of the employed steps were accom-
plished in very high yields, and as a result, the overall yield of
the synthesis was 6.6 % compared with that of previous reports
at 2.6 % (by Prasad et al.)[3] and 2.04 % (by Kaliappan et al.).[4]
spectroscopic data were recorded in CDCl3 or CD3OD with a 200,
400, or 500 MHz spectrometer, and the coupling constants are re-
ported in Hertz. All chemical shifts are reported in ppm relative to
TMS by using the residual solvent peak as the reference standard.
The following abbreviations were used to report the multiplicities
of the signals: s (singlet), d (doublet), t (triplet), quin (quintet), m
(multiplet), and br. (broad). HRMS (ESI+) were recorded on an ORBI-
TRAP mass analyzer. Infrared spectra were recorded as thin films on
This strongly demonstrates the merit of our modular synthetic NaCl plates with an FTIR spectrometer, and the wavenumbers are
reported in cm–1. Optical rotations were measured on a polarimeter
with a path length of 1 dm. The chemical nomenclature was gener-
ated by using Chem. Bio Draw Ultra 14.0.
approach to this natural product. The synthetic pathway also
led to the formation of the C-4 epimer. Hence, this strategy
might enable a practical parallel synthesis of a library of
Sch725674 stereoisomers. Efforts to extend this synthetic strat-
egy to the synthesis of gloeosporone and other related ana-
logues are also underway and will be disclosed in due course.
(R)-Dec-1-yn-5-ol (7): Magnesium turnings (13.84 g, 569.27 mmol,
13 equiv.) were flame-dried under a vacuum, flushed with argon
(3×), and suspended in Et2O (50 mL). A crystal of I2 was added, and
Eur. J. Org. Chem. 2016, 1215–1226
www.eurjoc.org
1219
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
the solution was stirred until the color disappeared. HgCl2
(713.4 mg, 2.63 mmol, 0.06 equiv.) was added, and after 10 min,
the solution was cooled to 0 °C. Propargyl bromide (23.4 mL,
262.72 mmol, 6 equiv.) was slowly added at 0 °C, and the mixture
was stirred at the same temperature for an additional 1 h. The dark
grey solution was then decanted to give the propargylmagnesium
bromide solution, which was added to a solution of epoxide 6 (5 g,
43.79 mmol, 1 equiv.) in Et2O (170 mL) at – 30 °C. After 2 h, the
reaction was poured into a saturated aqueous solution of NH4Cl
(200 mL), and the aqueous layer was extracted with Et2O (3 ×
150 mL). The combined organic layers were dried with Na2SO4 and
concentrated in vacuo to give a residue, which was purified by flash
column chromatography (petroleum ether/EtOAc, 39:1) to afford 7
(4 g, 60 %) as a colorless liquid; Rf = 0.3 (petroleum ether/EtOAc,
Flash column chromatography of the crude product (petroleum
ether/EtOAc, 19:1) provided 10 (12.3 g, 85 %, over two steps) as a
colorless liquid; Rf = 0.5 (petroleum ether/EtOAc, 49:1). [α]D25 = –0.6,
(c = 2.36, CHCl3). IR (CHCl3): νmax = 3019, 2943, 2860, 1612, 1515,
˜
1464, 1372, 1299, 1217, 1091, 1040, 836, 768, 671 cm–1
.
1H NMR
(200 MHz, CDCl3): δ = 7.25 (d, J = 8.2 Hz, 6 H), 6.87 (d, J = 8.2 Hz,
6 H), 5.92–5.72 (m, 1 H), 5.09–5.00 (m, 2 H), 4.44 (s, 2 H), 3.92–3.83
(m, 1 H), 3.80 (s, 3 H), 3.36 (d, J = 5.4 Hz, 2 H), 2.41–2.13 (m, 2 H),
0.88 (s, 9 H), 0.05 (s, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 159.1,
135.0, 130.5, 129.2, 116.9, 113.7, 73.9, 72.9, 71.2, 55.2, 39.4, 25.8,
18.2, –4.5, –4.7 ppm. HRMS (ESI+): calcd. for C19H32O3SiNa [M + Na]+
359.2014; found 359.2013.
tert-Butyl({(2S)-1-[(4-methoxybenzyl)oxy]-3-(oxiran-2-yl)pro-
pan-2-yl}oxy)dimethylsilane (11): To a stirred solution of olefin 10
(12 g, 35.71 mmol, 1 equiv.) in CH2Cl2 (100 mL) at 0 °C was added
m-CPBA (50 %, 2.9 g, 60.71 mmol, 1.7 equiv.). The reaction mixture
was stirred at 0 °C for 1 h and then quenched by the addition of a
saturated NaHCO3 solution. The mixture was extracted with CH2Cl2,
and the organic layer was washed with saturated NaHCO3 and
brine, dried with Na2SO4, and concentrated in vacuo. The crude
residue was purified by flash column chromatography (petroleum
ether/EtOAc, 24:1) to yield epoxide 11 (11.8 g, 94 %, anti/syn, 2:1)
19:1). [α]D25 = –9.5 (c = 1.01, CHCl ). IR (CHCl ): ν
= 3526, 3020,
max
˜
3
3
2986, 1737, 1451, 1375, 1247, 1100, 1047, 931, 846, 762 cm–1 1H
.
NMR (400 MHz, CDCl3): δ = 3.77–3.71 (m, 1 H), 2.34 (td, J = 2.7,
7.1 Hz, 2 H), 1.97 (t, J = 2.7 Hz, 1 H), 1.74–1.60 (m, 2 H), 1.40–1.48
(m, 3 H), 1.35–1.26 (m, 5 H), 0.89 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 84.3, 77.3, 77.0, 76.7, 70.8, 68.6, 37.3, 35.6,
31.8, 25.2, 22.6, 15.0, 14.0 ppm.
(R)-tert-Butyl(dec-1-yn-5-yloxy)diphenylsilane (8): To a stirred
solution of alcohol 7 (3.8 g, 24.67 mmol, 1 equiv.) in CH2Cl2 (60 mL)
as a colorless liquid; Rf = 0.4 (petroleum ether/EtOAc, 19:1). [α]D25
=
was added imidazole (3.3 g, 49.34 mmol, 1 equiv.). To this solution –12.3 (c = 1.1, CHCl3). IR (CHCl3): νmax = 3020, 2936, 2403, 1603,
˜
was added tert-butyl(chloro)diphenylsilane (7 mL, 27.14 mmol) at
0 °C, and the resulting mixture was stirred at room temperature for
1 h. The reaction was quenched with a saturated aqueous solution
of NH4Cl, and the aqueous layer was extracted with CH2Cl2 (3 ×
30 mL). The combined organic layers were washed with brine, dried
1517, 1217, 1104, 1040, 767, 671 cm–1 1H NMR (500 MHz, CDCl3):
.
δ = 7.30–7.26 (m, 2 H), 6.90 (d, J = 8.5 Hz, 2 H), 4.51–4.45 (m, 2 H),
4.09–4.02 (m, 1 H), 3.83 (s, 3 H), 3.51–3.39 (m, 2 H), 3.10–3.05 (m, 1
H), 2.82–2.76 (m, 1 H), 2.52–2.48 (m, 1 H), 1.79–1.70 (m, 2 H), 0.92
(s, 9 H), 0.11–0.09 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
with Na2SO4, and concentrated in vacuo. Flash column chromatog- 159.1, 130.4, 130.3, 129.2, 113.7, 74.3, 74.0, 73.0, 72.9, 69.7, 69.2,
raphy of the crude product provided 8 as a colorless liquid (9.1 g, 55.2, 49.6, 49.4, 47.8, 46.8, 38.0, 37.9, 25.8, 18.1, –4.4, –4.5, –4.9,
90 %); Rf = 0.6 (petroleum ether/EtOAc, 19:1). [α]D25 = –4.7, (c = 3.19, –5.0 ppm. HRMS (ESI+): calcd. for C19H32O4SiNa [M + Na]+ 375.1957;
CHCl3). IR (CHCl3): νmax = 3305, 3132, 3062, 3014, 2951, 2863, 1463,
found 375.1962.
˜
1433, 1376, 1218, 1104, 1064, 998, 934, 822, 760, 703 cm–1. 1H NMR
(200 MHz, CDCl3): δ = 7.72–7.67 (m, 4 H), 7.44–7.33 (m, 6 H), 3.83
(quin, J = 5.6 Hz, 1 H), 2.24 (td, J = 2.6, 7.3 Hz, 2 H), 1.87 (t, J =
2.6 Hz, 1 H), 1.70 (td, J = 5.6, 7.3 Hz, 2 H), 1.46–1.07 (m, 17 H), 0.81
(t, J = 6.5 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 135.9, 134.6,
134.3, 129.5, 129.4, 127.5, 127.4, 84.6, 72.1, 68.0, 36.1, 35.1, 31.7,
27.1, 24.5, 22.5, 19.4, 14.3, 14.0 ppm. HRMS (ESI+): calcd. for
tert-Butyl({(S)-1-[(4-methoxybenzyl)oxy]-3-[(S)-oxiran-2-yl]pro-
pan-2-yl}oxy)dimethylsilane (12a) and (2R,4S)-4-[(tert-Butyldi-
methylsilyl)oxy]-5-[(4-methoxybenzyl)oxy]pentane-1,2-diol
(12b): A solution of epoxide 11 (10 g, 28.41 mmol, 1 equiv.) and
(S,S)-(salen)CoIII-OAc (343 mg, 0.568 mmol, 0.02 equiv.) in THF (2 mL)
was stirred at 0 °C for 5 min, and then distilled water (0.17 mL,
9.64 mmol, 0.34 equiv.) was added. After stirring for 8 h, the mixture
was concentrated, and the residue was purified by flash column
chromatography (petroleum ether/EtOAc, 24:1) to afford 12a (6.0 g,
60 %) as a yellow liquid; Rf = 0.4 (petroleum ether/EtOAc, 19:1).
Continued chromatography (petroleum ether/EtOAc, 2:3) provided
diol 12b (2.8 g, 28 %) as a brown liquid, almost as a single diastereo-
C
26H37OSi [M + H]+ 393.2601; found 393.2608.
(S)-tert-Butyl({1-[(4-methoxybenzyl)oxy]pent-4-en-2-yl}oxy)-
dimethylsilane (10): A round-bottomed flask was charged with
copper(I) iodide (490 mg, 2.57 mmol, 0.05 equiv.), and the system
was gently heated under vacuum and then slowly cooled under the
flow of argon. Dry THF (120 mL) was added. The resulting suspen-
mer; Rf = 0.4 (petroleum ether/EtOAc, 2.3:1). The diastereoselectivity
sion was cooled to –40 °C and vigorously stirred, and the vinylmag- was determined by H and 13C NMR spectroscopic and chiral HPLC
1
nesium chloride solution (1.6
M
in THF, 64 mL, 102.97 mmol,
analyses. Data for 12a: [α]D25 = –15.6 (c = 1.2, CHCl3). IR (CHCl3):
2 equiv.) was then added. A solution of (S)-PMB-protected glycidol νmax = 3017, 2955, 2930, 2857, 1613, 1513, 1464, 1363, 1250, 1217,
˜
(9, 10 g, 51.48 mmol, 1 equiv.) in THF (50 mL) was slowly added to
the above mixture. The reaction was stirred at –40 °C for 1 h and (m, 2 H), 6.91 (d, J = 8.5 Hz, 2 H), 4.51–4.46 (m, 2 H), 4.10–4.05 (m,
1100, 1037, 836, 771 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.30–7.27
then quenched by the addition of a saturated solution of NH4Cl.
The organic and aqueous layers were separated, and the aqueous
layer was extracted with EtOAc. The combined organic layers were
washed with brine, dried with Na2SO4, and concentrated to dryness
to afford crude product 9a as a yellow liquid. To a mixture of crude
alcohol 9a in CH2Cl2 (40 mL) was added imidazole (5.2 g,
76.48 mmol, 2 equiv.) followed by tert-butyl(chloro)dimethylsilane
(6.3 g, 42.06 mmol, 1.1 equiv.) at 0 °C, and the resulting mixture
was stirred at room temperature for 1 h. The reaction was quenched
with a saturated aqueous solution of NH4Cl, and the mixture was
extracted with CH2Cl2 (3 × 30 mL). The combine organic layers were
washed with brine, dried with Na2SO4, and concentrated in vacuo.
1 H), 3.84 (s, 3 H), 3.42 (ddd, J = 5.5, 9.8, 15.2 Hz, 2 H), 3.09–3.06
(m, 1 H), 2.83–2.81 (m, 1 H), 2.53–2.51 (m, 1 H), 1.76–1.69 (m, 2 H),
0.92 (s, 9 H), 0.09 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.1, 130.3, 129.2, 113.7, 74.3, 72.9, 69.2, 55.2, 49.6,
47.8, 38.0, 25.8, 18.1, –4.4, –5.0 ppm. HRMS (ESI+): calcd. for
C19H32O4SiNa [M + Na]+ 375.19574; found 375.19621. Data for 12b:
[α]D25 = +35.6 (c = 2.58, CHCl3). IR (CHCl3): νmax = 3436, 3017, 2943,
˜
2864, 1613, 1514, 1463, 1300, 1250, 1218, 1095, 1039, 835, 768,
670 cm–1 1H NMR (400 MHz, CDCl3): δ = 7.28–7.25 (m, 2 H), 6.90
.
(d, J = 8.6 Hz, 2 H), 4.48–4.46 (m, 2 H), 4.17–4.05 (m, 1 H), 3.94 (br.
s, 1 H), 3.82 (s, 3 H), 3.65–3.60 (m, 1 H), 3.51–3.45 (m, 3 H), 3.42–
3.38 (m, 1 H), 2.29 (br. s, 1 H), 1.74–1.65 (m, 2 H), 0.90 (s, 9 H), 0.09
Eur. J. Org. Chem. 2016, 1215–1226
www.eurjoc.org
1220
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.2,
(m, 2 H), 1.81 (ddd, J = 2.2, 5.6, 7.6 Hz, 1 H), 1.71–1.63 (m, 3 H),
129.8, 129.4, 113.8, 74.2, 73.1, 73.0, 70.8, 70.0, 69.8, 68.9, 67.1, 66.9, 1.40–1.33 (m, 3 H), 1.17–1.12 (m, 5 H), 1.05 (s, 9 H), 0.88 (s, 9 H),
55.2, 38.0, 36.7, 25.8, 18.0, –4.3, –4.6, –4.9, –5.1 ppm.
0.79 (t, J = 7.2 Hz, 3 H), 0.08 (s, 3 H), 0.06 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.2, 135.9, 134.6, 134.3, 130.1, 129.5, 129.4,
129.3, 127.4, 127.4, 113.7, 82.5, 76.2, 73.5, 73.0, 72.3, 70.1, 67.4, 55.2,
40.1, 36.2, 35.6, 31.7, 28.0, 27.1, 25.8, 24.4, 22.5, 19.4, 18.0, 14.7, 14.0,
–4.6, –5.0 ppm. HRMS (ESI+): calcd. for C45H68O5Si2Na [M + Na]+
767.4490; found 767.4497.
Experimental Procedure for the Conversion of Compound 12b
into 12a: Diol 12b (2.8 g, 7.55 mmol, 1 equiv.) was dissolved in dry
CH2Cl2 (15 mL) under argon, and the solution was treated with
benzoyl chloride (1.23 mL, 10.58 mmol, 1.4 equiv.), Et3N (2.63 mL,
18.88 mmol, 2.5 equiv.), and a catalytic amount of DMAP. The mix-
ture was stirred at room temperature for 2 h followed by the
workup procedure (i.e., extraction with CH2Cl2). The removal of vola-
tiles under reduced pressure and purification by flash column chro-
matography (petroleum ether/EtOAc, 85:15) gave monobenzoate
12c (3.1 g, 88 %) as a colorless liquid; Rf = 0.38 (petroleum ether/
(5S,7R,13R)-5-{[(4-Methoxybenzyl)oxy]methyl}-2,2,3,3,16,16-
hexamethyl-13-pentyl-15,15-diphenyl-4,14-dioxa-3,15-disila-
heptadecan-7-ol (14): Compound 13 (3 g, 4.02 mmol) in EtOH
(10 mL) was hydrogenated under 1 atm with Raney-Ni catalyst. After
the reaction stirred overnight, the mixture was filtered through a
EtOAc, 9:1). [α]D25 = –4.8 (c = 1.66, CHCl3). IR (CHCl3): νmax = 3455, short bed of Celite. The filtrate was concentrated, and the residue
˜
3020, 2946, 1716, 1606, 1516, 1457, 1260, 1217, 1107, 1037, 768,
was purified by flash column chromatography (petroleum ether/
EtOAc, 34:1) to afford the completely hydrogenated product 14
(2.86 g, 95 %) as a pale yellow liquid; Rf = 0.26 (petroleum ether/
1
671 cm–1. H NMR (400 MHz, CDCl3): δ = 8.10–8.07 (m, 2 H), 7.62–
7.57 (m, 1 H), 7.48–7.44 (m, 2 H), 7.29–7.25 (m, 2 H), 6.90–6.87 (m,
2 H), 4.50–4.48 (m, 2 H), 4.36–4.29 (m, 2 H), 4.27–4.19 (m, 1 H), 4.17–
4.10 (m, 1 H), 3.82–3.81 (m, 3 H), 3.53–3.41 (ddd, J = 5.9, 9.5, 15.6 Hz, 3015, 2934, 2860, 1718, 1614, 1514, 1463, 1373, 1250, 1217, 1102,
EtOAc, 19:1). [α]D25 = –1.49 (c = 0.8, CHCl3). IR (CHCl3): νmax = 3455,
˜
2 H), 1.97–1.76 (m, 2 H), 0.91 (s, 9 H), 0.12 (s, 3 H), 0.10 (s, 3 H) ppm.
1042, 830, 764, 671 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.68 (dt,
13C NMR (100 MHz, CDCl3): δ = 166.6, 159.2, 133.4, 133.0, 130.1,
J = 1.2, 7.9 Hz, 4 H), 7.41–7.34 (m, 6 H), 7.25 (d, J = 8.6 Hz, 2 H),
130.0, 129.9, 129.8, 129.7, 129.4, 129.2, 128.4, 128.3, 113.8, 113.7, 6.88 (d, J = 8.6 Hz, 2 H), 4.50–4.42 (m, 2 H), 4.14–4.10 (m, 1 H), 3.81
74.1, 73.1, 73.0, 72.9, 70.5, 69.7, 69.0, 68.7, 67.7, 66.8, 55.2, 38.4, 37.2,
25.9, 25.8, 18.0, –4.3, –4.6, –4.9, –5.1 ppm. Compound 12c (3.1 g,
6.53 mmol, 1 equiv.) was then dissolved in dry CH2Cl2 (15 mL) under
argon, and the solution was treated with TsCl (1.5 g, 7.84 mmol,
1.2 equiv.), Et3N (2.3 mL, 16.32 mmol, 2.5 equiv.), and catalytic
(s, 3 H), 3.80–3.78 (m, 1 H), 3.70 (quin, J = 5.8 Hz, 1 H), 3.46 (ddd,
J = 5.8, 9.5, 15.2 Hz, 2 H), 1.72–1.70 (ddd, J = 2.0, 4.6, 14.6 Hz, 1 H),
1.62 (dd, J = 4.6, 10.1 Hz, 1 H), 1.43–1.37 (m, 5 H), 1.31–1.30 (m, 1
H), 1.24–1.08 (m, 12 H), 1.05 (s, 9 H), 0.89 (s, 9 H), 0.83 (t, J = 7.1 Hz,
3 H), 0.09 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ =
amount of DMAP. The reaction mixture was stirred at room temper- 159.2, 135.9, 134.8, 130.1, 129.4, 129.3, 127.3, 113.8, 73.2, 73.1, 73.0,
ature for 6 h and then quenched with water. The aqueous layer was
extracted with CH2Cl2 (3 × 30 mL). The combined organic layers
were washed with brine, dried with Na2SO4, and concentrated to
give a residue. The crude product was dissolved in CH3OH (20 mL),
and the solution was treated with K2CO3 (1.0 g, 6.53 mmol). The
reaction mixture was stirred at room temperature for 1 h and then
filtered through Celite. Concentration of the filtrate under reduced
pressure and flash column chromatography on silica gel (petroleum
ether/EtOAc, 19:1) gave epoxide 12a (1.5 g, overall yield 70 %, over
three steps) as a yellow liquid.
70.5, 68.5, 55.2, 40.5, 38.0, 36.3, 36.2, 31.9, 29.8, 27.1, 25.8, 25.6, 24.9,
24.5, 22.6, 19.4, 18.0, 14.0, –4.6, –5.1 ppm. HRMS (ESI+): calcd. for
C
45H72O5Si2Na [M + Na]+ 771.48059; found 771.48105.
tert-Butyl{[(R)-1-[(4R,6S)-6-{[(4-methoxybenzyl)oxy]methyl}-2,2-
dimethyl-1,3-dioxan-4-yl]undecan-6-yl]oxy}diphenylsilane
(14b): To a stirred solution of 14 (50 mg, 0.067 mmol, 1 equiv.) in
THF (0.2 mL) was added TBAF (1.0
M in THF, 0.1 mL, 0.1 mmol,
1.5 equiv.) at 0 °C. After the mixture was stirred at room tempera-
ture for 2 h, the reaction was quenched by the addition of H2O
(1 mL). The aqueous layer was extracted with EtOAc (5 × 3 mL), and
the combined organic layers were washed with brine (5 mL), dried
with Na2SO4, and concentrated under reduced pressure to obtain
the crude 1,3-diol. To a solution of the crude 1,3-diol in CH2Cl2
(5S,7R,13R)-5-{[(4-Methoxybenzyl)oxy]methyl}-2,2,3,3,16,16-
hexamethyl-13-pentyl-15,15-diphenyl-4,14-dioxa-3,15-disila-
heptadec-9-yn-7-ol (13): n-Butyllithium (1.6
M in hexanes, 11 mL,
17.5 mmol, 3 equiv.) was added dropwise to a stirred solution of (0.2 mL) were added 2,2-DMP (0.082 mL, 0.67 mmol, 10 equiv.) and
alkyne 8 (4.9 g, 12.5 mmol, 2.0 equiv.) in dry THF (30 mL) under
nitrogen at –78 °C. The resulting solution was stirred for 30 min and
then treated dropwise with BF3·Et2O complex (2.3 mL, 18.75 mmol,
3 equiv.). After stirring at –78 °C for 15 min, epoxide 12a (2.2 g,
6.25 mmol, 1 equiv.) in dry THF (12 mL) was added, and the mixture
was stirred at – 78 °C for approximately 1 h. The reaction was
quenched by the addition of a saturated aqueous solution of
a catalytic amount of PPTS (8 mg, 0.0335 mmol, 0.5 equiv.). The
reaction mixture was stirred at room temperature for 1 h. When
TLC analysis showed the completion of reaction, the mixture was
quenched by the addition of dry Et3N, and the solvent was evapo-
rated in vacuo at room temperature. The crude product was purified
by flash column chromatography (petroleum ether/EtOAc, 39:1) to
give the six-membered ring acetonide 14b (36 mg, 80 %) as a color-
ammonium chloride (40 mL), and the organic layer was separated. less liquid; Rf = 0.3 (petroleum ether/EtOAc, 9:1). [α]D25 = –2.25 (c =
The aqueous layer was then extracted with diethyl ether (5 ×
30 mL), and the combined organic solutions were washed with
brine and dried with Na2SO4. The solvents were evaporated to give
2.4, CHCl3). IR (CHCl3): νmax = 3407, 3013, 2933, 2861, 1775, 1716,
˜
1599, 1517, 1426, 1218, 1104, 1040, 759 cm–1
.
1H NMR (400 MHz,
CDCl3): δ = 7.66 (d, J = 6.6 Hz, 4 H), 7.42–7.32 (m, 6 H), 7.25 (d, J =
the crude material, which was purified by flash column chromatog- 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 4.56–4.46 (m, 2 H), 4.04–3.98
raphy (petroleum ether/EtOAc, 7:1) to afford the coupled product
(m, 1 H), 3.80 (s, 3 H), 3.74–3.65 (m, 2 H), 3.48–3.37 (m, 3 H), 1.65–
1.57 (m, 2 H), 1.49–1.42 (m, 4 H), 1.37 (s, 3 H), 1.35 (s, 3 H), 1.21–
13 (4 g, 86 %) as a yellow liquid; Rf = 0.3 (petroleum ether/EtOAc, 19:1).
[α]D25 = –1.02 (c = 0.7, CHCl3). IR (CHCl3): νmax = 3417, 3021, 2970, 1.08 (m, 14 H), 1.03 (s, 9 H), 0.81 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
˜
2403, 1600, 1427, 1216, 1043, 768, 671 cm–1 1H NMR (400 MHz, (100 MHz, CDCl3): δ = 159.1, 135.9, 134.8, 134.7, 130.3, 129.34, 129.3,
.
CDCl3): δ = 7.70–7.67 (m, 4 H), 7.43–7.35 (m, 6 H), 7.25 (d, J = 8.6 Hz, 127.3, 113.7, 100.3, 73.2, 72.9, 72.4, 66.5, 66.2, 55.2, 36.2, 35.8, 34.9,
2 H), 6.88 (d, J = 8.6 Hz, 2 H), 4.50–4.43 (m, 2 H), 4.12 (quin, J = 31.9, 29.6, 27.1, 25.3, 24.8, 24.77, 24.74, 24.5, 24.1, 22.5, 19.4,
5.6 Hz, 1 H), 3.93–3.87 (m, 1 H), 3.81–3.77 (m, 4 H), 3.45 (ddd, J =
5.6, 9.5, 15.2 Hz, 2 H), 3.33 (br. s, 1 H), 2.29–2.26 (m, 2 H), 2.22–2.17
14.0 ppm. HRMS (ESI+): calcd. for C42H62O5SiNa [M + Na]+
697.42511; found 697.42587.
Eur. J. Org. Chem. 2016, 1215–1226
www.eurjoc.org
1221
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(5S,7R,13R)-5-{[(4-Methoxybenzyl)oxy]methyl}-7-(methoxy-
methoxy)-2,2,3,3,16,16-hexamethyl-13-pentyl-15,15-diphenyl-
4,14-dioxa-3,15-disilaheptadecane (15): A mixture of compound
14 (2.6 g, 3.47 mmol, 1 equiv.), N,N-diisopropylethylamine (3 mL,
17.35 mmol, 5 equiv.), and methoxymethyl chloride (0.8 mL,
the reaction was then cautiously quenched by the addition of a
saturated solution of NH4Cl (10 mL). The mixture was poured into
H2O (10 mL), and the resulting mixture was extracted with Et2O
(3 × 30 mL). The combined extracts were washed with brine (2 ×
10 mL) and dried with Na2SO4. Removal of solvent under reduced
10.41 mL, 3 equiv.) in CH2Cl2 (6 mL) was heated at 40 °C for 4 h. pressure gave the crude residue as a diastereomeric mixture
The reaction mixture was cooled to room temperature, and the (anti/syn, 4:1). The diastereomers were separated by flash column
reaction was quenched by the addition of water. The aqueous
phase was extracted with CH2Cl2, and the organic layer was washed
with water and brine, dried with Na2SO4, and concentrated. Flash
column chromatography of the crude product (petroleum ether/
EtOAc, 33:1) gave alcohol 15 (2.2 g, 80 %) as a colorless liquid; Rf =
chromatography (petroleum ether/EtOAc, 39:1) to afford alcohol
18a [952 mg, 65.6 %; Rf = 0.34 (petroleum ether/EtOAc, 9:1)] and
18b [238 mg, 16.4 %; Rf = 0.17 (petroleum ether/EtOAc, 9:1)] as a
pale yellow liquid. Data for 18a: [α]D25 = –1.5 (c = 1.0, CHCl3). IR
(CHCl3): νmax = 3393, 3021, 2934, 2861, 1596, 1528, 1426, 1217,
˜
1
0.5 (petroleum ether/EtOAc, 19:1). [α]D25 = –2.9 (c = 3.3, CHCl3). IR 1040, 766, 671 cm–1. H NMR (400 MHz, CDCl3): δ = 7.68 (doublet-
(CHCl3): νmax = 3416, 3019, 2937, 2861, 1608, 1515, 1463, 1217, like, 4 H), 7.44–7.34 (m, 6 H), 5.85 (ddd, J = 5.9, 10.8, 17.1 Hz, 1 H),
˜
1103, 1040, 831, 767, 671 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.70 5.34 (dt, J = 1.5, 17.1 Hz, 1 H), 5.23 (dt, J = 1.5, 10.5 Hz, 1 H), 4.65–
(doublet-like, 4 H), 7.44–7.36 (m, 6 H), 7.80 (d, J = 8.6 Hz, 2 H), 6.90
(d, J = 8.6 Hz, 2 H), 4.66 (s, 2 H), 4.51–4.44 (m, 2 H), 4.02–3.97 (m, 1
H), 3.83 (s, 3 H), 3.74–3.65 (m, 2 H), 3.39–3.36 (m, 5 H), 1.73–1.67
(m, 1 H), 1.59–1.51 (m, 2 H), 1.46–1.40 (m, 5 H), 1.25–1.11 (m, 12 H),
1.07 (s, 9 H), 0.90 (s, 9 H), 0.84 (t, J = 7.1 Hz, 3 H), 0.07 (s, 3 H), 0.05
4.61 (m, 2 H), 4.17–4.14 (m, 1 H), 3.89 (m, 1 H), 3.73–3.67 (m, 1 H),
3.62–3.56 (m, 1 H), 3.36 (s, 3 H), 1.62–1.56 (m, 3 H), 1.44–1.37 (m, 5
H), 1.27–1.08 (m, 12 H), 1.05 (s, 9 H), 0.92 (s, 9 H), 0.83 (t, J = 7.3 Hz,
3 H), 0.13 (s, 3 H), 0.11 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
136.2, 135.9, 134.8, 129.3, 127.3, 116.6, 95.7, 76.2, 75.8, 73.2, 72.9,
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.0, 135.9, 134.8, 55.6, 37.1, 36.3, 35.2, 31.9, 29.9, 27.1, 25.9, 25.0, 24.9, 24.5, 22.5, 19.4,
130.5, 129.3, 129.2, 127.3, 113.7, 95.8, 75.5, 75.0, 73.2, 72.8, 69.1,
55.5, 55.2, 40.4, 36.3, 36.2, 35.4, 31.9, 29.9, 27.1, 25.9, 25.0, 24.9,
24.5, 22.6, 19.4, 18.2, 14.0, –4.0, –4.8 ppm. HRMS (ESI+): calcd. for
18.1, 14.0, –4.3, –4.5 ppm. HRMS (ESI+): calcd. for C41H70O5Si2Na [M
+ Na]+ 721.4651; found 721.4654. Data for 18b: [α]D25 = –6.6 (c = 0.5,
CHCl3). IR (CHCl3): νmax = 3375, 3021, 2972, 1599, 1524, 1428, 1217,
˜
C
47H76O6Si2Na [M + Na]+ 815.50702; found 815.50726.
1042, 927, 768, 671 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.68 (d,
J = 6.8 Hz, 4 H), 7.42–7.35 (m, 6 H), 5.97–5.87 (ddd, J = 5.1, 10.5,
17.0 Hz, 1 H), 5.33 (d, J = 17.1 Hz, 1 H), 5.21 (d, J = 10.5 Hz, 1 H),
4.67–4.63 (m, 2 H), 4.05 (triplet-like, 1 H), 3.82–3.78 (m, 1 H), 3.71
(quin, J = 5.4 Hz, 1 H), 3.66–3.60 (m, 1 H), 3.38 (s, 3 H), 1.56–1.46
(m, 2 H), 1.43–1.38 (m, 4 H), 1.25–1.18 (m, 10 H), 1.13–1.10 (m, 4 H),
1.06 (s, 9 H), 0.90 (s, 9 H), 0.83 (t, J = 7.3 Hz, 3 H), 0.10 (s, 3 H), 0.09
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.4, 135.9, 134.8,
129.3, 127.3, 115.7, 95.3, 75.4, 74.9, 73.2, 72.8, 55.7, 39.0, 36.3, 34.9,
31.9, 29.9, 27.1, 25.9, 25.8, 24.9, 24.8, 24.5, 22.5, 19.4, 18.1, 14.0, –4.3,
–4.3 ppm. HRMS (ESI+): calcd. for C41H70O5Si2Na [M + Na]+
721.4652; found 721.4654.
(2S,4R,10R)-2-[(tert-Butyldimethylsilyl)oxy]-10-[(tert-butyldi-
phenylsilyl)oxy]-4-(methoxymethoxy)pentadecan-1-ol (16): To a
solution of compound 15 (2.1 g, 2.65 mmol, 1 equiv.) in a mixture
of CHCl3/pH = 7 phosphate buffer (20:1) (20 mL), was added DDQ
(1.8 g, 7.94 mmol, 3 equiv.), and the resulting mixture was stirred
at room temperature for 1 h. The reaction was quenched by the
addition of a saturated aqueous solution of NaHCO3. The organic
layer was separated, washed with brine, dried with Na2SO4, and
concentrated under reduced pressure. The crude residue was puri-
fied by flash column chromatography (petroleum ether/EtOAc, 19:1)
to afford 16 (1.58 g, 89 %) as a pale yellow liquid; Rf = 0.5 (petro-
leum ether/EtOAc, 9:1). [α]D25 = –2.4 (c = 0.6, CHCl3). IR (CHCl3):
Experimental Procedure for the Conversion of Compound 18b
into 18a: To a stirred solution of alcohol 18b (200 mg, 0.286 mmol,
1 equiv.) in dry toluene (1 mL) were added PPh3 (225 mg,
0.858 mmol, 3 equiv.), p-nitrobenzoic acid (144 mg, 0.858 mmol,
3 equiv.), and diisopropyl azodicarboxylate (0.17 mL, 0.858 mmol,
3 equiv.) at 0 °C, and the mixture was stirred at room temperature
for 2 h. The toluene was evaporated, and the resulting mixture was
directly transferred onto a silica gel column and purified by flash
column chromatography (petroleum ether/EtOAc, 24:1) to furnish
18c (219 mg, 90 %) as a pale yellow liquid; Rf = 0.5 (petroleum
νmax = 3377, 3022, 2932, 2403, 1595, 1525, 1426, 1216, 1040, 927,
˜
1
768, 671 cm–1. H NMR (500 MHz, CDCl3): δ = 7.68 (d, J = 7.3 Hz, 4
H), 7.43–7.35 (m, 6 H), 4.66–4.63 (m, 2 H), 3.90–3.85 (m, 1 H), 3.72–
3.67 (m, 1 H), 3.63–3.56 (m, 2 H), 3.50–3.45 (m, 1 H), 3.37 (s, 3 H),
1.52–1.37 (m, 7 H), 1.24–1.08 (m, 13 H), 1.05 (s, 9 H), 0.91 (s, 9 H),
0.82 (t, J = 7.3 Hz, 3 H), 0.11 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 135.9, 134.8, 129.3, 127.3, 95.6, 75.6, 73.2, 70.7, 67.1, 55.6, 39.6,
36.3, 35.0, 31.9, 29.9, 29.7, 27.1, 25.8, 24.9, 24.8, 24.5, 22.6, 19.4, 18.1,
14.0, –4.4, –4.6 ppm. HRMS (ESI+): calcd. for C39H68O5Si2Na [M +
Na]+ 695.44891; found 695.44975.
ether/EtOAc, 9:1). [α]D25 = 4.03 (c = 0.8, CHCl3). IR (CHCl3): νmax
=
˜
(3R,4S,6R,12R)-4-[(tert-Butyldimethylsilyl)oxy]-12-[(tert-butyldi-
phenylsilyl)oxy]-6-(methoxymethoxy)heptadec-1-en-3-ol (18a)
and (3S,4S,6R,12R)-4-[(tert-Butyldimethylsilyl)oxy]-12-[(tert-
butyldiphenylsilyl)oxy]-6-(methoxymethoxy)heptadec-1-en-3-
ol (18b): A stirred solution of 16 (1.4 g, 2.08 mmol, 1 equiv.) in
3425, 3020, 2935, 2860, 1725, 1604, 1530, 1463, 1428, 1359, 1270,
1218, 1107, 1041, 931, 835, 765, 671 cm–1 1H NMR (500 MHz,
.
CDCl3): δ = 8.30 (d, J = 8.9 Hz, 2 H), 8.23 (d, J = 8.9 Hz, 2 H), 7.68
(d, J = 7.3 Hz, 4 H), 7.43–7.39 (m, 6 H), 6.01 (ddd, J = 7.0, 10.4,
17.4 Hz, 1 H), 5.53 (dt, J = 0.9, 7.0 Hz, 1 H), 5.42–5.37 (m, 2 H), 4.67–
EtOAc (30 mL) was treated with IBX (00.0 g, 00.0 mmol) in a portion- 4.64 (m, 2 H), 4.15–4.13 (m, 1 H), 3.74–3.70 (m, 1 H), 3.68–3.63 (m,
wise manner, and the resulting mixture was heated at 80 °C for 3 h.
The reaction was quenched by the addition of a saturated NaHCO3
solution. The mixture was then filtered through Celite, and the filter
cake was washed with EtOAc. The organic layer was isolated,
washed with water and brine, and then dried with Na2SO4. Evapora-
tion of the solvent gave 17 as a yellow liquid, which was used
in subsequent experiments without any further purification. To a
1 H), 3.37 (s, 3 H), 1.81–1.74 (ddd, J = 4.3, 8.5, 12.8 Hz, 1 H), 1.62
(ddd, J = 3.4, 7.6, 11.0 Hz, 1 H), 1.54–1.39 (m, 7 H), 1.24–1.15 (m, 9
H), 1.13–1.08 (m, 2 H), 1.05 (s, 9 H), 0.88 (s, 9 H), 0.82 (t, J = 7.3 Hz,
3 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
164.0, 150.6, 135.9, 134.9, 134.8, 131.9, 130.7, 129.3, 127.3, 123.6,
119.8, 95.8, 80.3, 75.5, 73.3, 71.1, 55.6, 39.0, 36.3, 35.2, 31.9, 29.9,
29.7, 27.1, 25.8, 25.0, 24.9, 24.6, 22.5, 19.4, 18.1, 14.0, –4.3, –4.5 ppm.
precooled (–78 °C) solution of 17 in anhydrous THF (5.0 mL) was HRMS (ESI+): calcd. for C48H73O8NSi2Na [M + Na]+ 870.47662; found
added vinylmagnesium bromide in (1 THF, 2.3 mL, 2.29 mmol, 1.1 870.47669. To a stirred solution of the p-nitrobenzoate ester 18c
equiv.) under argon. The mixture was stirred at –78 °C for 1 h, and (200 mg, 0.235 mmol, 1 equiv.) in CH3OH (1 mL) was added K2CO3
M
Eur. J. Org. Chem. 2016, 1215–1226
www.eurjoc.org
1222
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(65.2 mg, 0.472 mmol, 2 equiv.), and the resulting mixture was compound 20a (696 mg, 93 %) as a yellow liquid; Rf = 0.46 (petro-
stirred at room temp. for 1 h. Upon the complete consumption of
the starting material (monitored by TLC analysis), the reaction was
quenched by the addition of water, and the resulting mixture was
leum ether/EtOAc, 19:1). [α]D25 = –3.7, (c = 3.0, CHCl3). IR (CHCl3):
1
νmax = 3620, 3400, 2938, 1592, 1350, 1218, 1021, 760, 670 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 7.68 (d, J = 6.7 Hz, 4 H), 7.43–7.35 (m,
extracted with EtOAc (5 × 3 mL). The combined organic layers were 6 H), 5.81 (ddd, J = 7.6, 10.4, 17.2 Hz, 1 H), 5.31 (d, J = 17.2 Hz, 1
washed with brine, dried with Na2SO4, and concentrated in vacuo.
The crude product was purified by flash column chromatography
(petroleum ether/EtOAc, 39:1) to give 18a (140.2 mg, 85 %) as color-
less oil.
H), 5.24 (d, J = 10.4 Hz, 1 H), 4.69–4.66 (m, 2 H), 4.52 (t, J = 6.7 Hz,
1 H), 4.38 (ddd, J = 2.9, 6.7, 9.8 Hz, 1 H), 3.75–3.69 (m, 2 H), 3.39 (s,
3 H), 1.59–1.54 (m, 1 H), 1.49 (s, 3 H), 1.45–1.40 (m, 6 H), 1.38 (s, 3
H), 1.25–1.08 (m, 13 H), 1.06 (s, 9 H), 0.83 (t, J = 7.3 Hz, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 135.9, 134.8, 134.7, 134.6, 129.3,
127.3, 118.1, 108.1, 95.9, 79.7, 74.9, 74.7, 73.2, 55.6, 36.3, 35.8, 35.2,
31.9, 29.9, 28.3, 27.1, 25.7, 24.9, 24.5, 22.5, 19.4, 14.0 ppm. HRMS
(ESI+): calcd. for C38H60O5SiNa [M + Na]+ 647.40926; found
647.41022.
(3R,4S,6R,12R)-12-[(tert-Butyldiphenylsilyl)oxy]-6-(methoxy-
methoxy)heptadec-1-ene-3,4-diol (19a): A solution of TBAF (1
M
in THF, 2.2 mL, 2.15 mmol, 1.5 equiv.) was added to a stirred solution
of compound 18a (1 g, 1.431 mmol, 1 equiv.) in THF (4 mL) at 0 °C.
The resulting mixture was stirred at room temperature for 2 h and
then diluted with water. The mixture was extracted with EtOAc, and
the organic layer was washed with water, dried with Na2SO4, and
concentrated. The crude product was purified by flash column chro-
(5R,11R)-5-{[(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl]methyl}-14,14-dimethyl-11-pentyl-13,13-diphenyl-2,4,12-tri-
oxa-13-silapentadecane (20b): Compound 19b (140 mg,
matography (petroleum ether/EtOAc, 85:15) to provide compound 0.239 mmol, 1 equiv.) was treated with 2,2-DMP (0.31 mL,
19a (754 mg, 90 %) as a pale yellow liquid; Rf = 0.45 (petroleum 2.39 mmol, 10 equiv.) and PPTS (30 mg, 0.119 mmol, 0.5 equiv.) in
ether/EtOAc, 1.5:1). [α]D25 = –3.5 (c = 1.4, CHCl3). IR (CHCl3): νmax
=
CH2Cl2 (1 mL) under the same conditions as described for the syn-
˜
3423, 3018, 2936, 2861, 1639, 1462, 1428, 1376, 1217, 1104, 1037,
thesis of 20a to give compound 20b (139 mg, 92 %) as a yellow
768, 671 cm–1 1H NMR (500 MHz, CDCl3): δ = 7.68 (dd, J = 1.4,
.
liquid; [α]D25 = –1.8 (c = 1.6, CHCl3). IR (CHCl3): νmax = 3412, 3020,
˜
8.1 Hz, 4 H), 7.43–7.35 (m, 6 H), 5.91 (ddd, J = 6.1, 10.7, 17.1 Hz, 1
2935, 2862, 1594, 1428, 1378, 1217, 1104, 1041, 928, 767, 671 cm–
1
H), 5.35 (dt, J = 1.5, 17.1 Hz, 1 H), 5.26 (dt, J = 1.5, 10.7 Hz, 1 H), 1. H NMR (500 MHz, CDCl3): δ = 7.69–7.67 (m, 4 H), 7.43–7.35 (m,
4.66 (s, 2 H), 4.18–4.17 (m, 1 H), 3.96 (dt, J = 2.8, 10.7 Hz, 1 H), 3.80– 6 H), 5.81 (ddd, J = 7.3, 10.4, 17.2 Hz, 1 H), 5.37 (d, J = 17.2 Hz, 1
3.76 (m, 1 H), 3.71 (quin, J = 5.5 Hz, 1 H), 3.41 (s, 3 H), 1.68 (ddd,
J = 3.4, 10.7, 14.3 Hz, 1 H), 1.53 (ddd, J = 2.4, 10.4, 14.6 Hz, 2 H),
1.42–1.38 (m, 4 H), 1.25–1.09 (m, 13 H), 1.05 (s, 9 H), 0.83 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 136.4, 135.9, 134.8,
134.7, 129.3, 127.3, 116.9, 96.3, 76.1, 75.7, 73.2, 70.4, 55.8, 36.3, 36.2,
H), 5.26 (d, J = 10.4 Hz, 1 H), 4.68–4.65 (m, 2 H), 3.96 (t, J = 8.2 Hz,
1 H), 3.87 (td, J = 2.4, 8.2 Hz, 1 H), 3.77–3.69 (m, 2 H), 3.38 (s, 3 H),
1.69–1.59 (m, 2 H), 1.54–1.46 (m, 1 H), 1.43 (s, 3 H), 1.41–1.39 (m, 7
H), 1.28–1.09 (m, 13 H), 1.06 (s, 9 H), 0.83 (t, J = 7.3 Hz, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 135.9, 135.1, 134.9, 134.8, 129.3,
35.2, 34.7, 31.9, 29.8, 27.1, 25.4, 24.8, 24.6, 22.5, 19.4, 14.0 ppm. 127.4, 118.9, 108.6, 95.8, 83.0, 77.2, 74.7, 73.3, 55.5, 37.1, 36.3, 35.2,
HRMS (ESI+): calcd. for C35H56O5SiNa [M + Na]+ 607.37842; found
607.37892.
31.9, 29.9, 27.4, 27.1, 26.9, 24.9, 24.6, 22.6, 19.4, 14.0 ppm. HRMS
(ESI+): calcd. for C38H60O5SiNa [M + Na]+ 647.40910; found
647.41020.
(3S,4S,6R,12R)-12-[(tert-Butyldiphenylsilyl)oxy]-6-(methoxy-
methoxy)heptadec-1-ene-3,4-diol (19b): Compound 18b
(6R,12R)-13-[(4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-12-
(200 mg, 0.286 mmol, 1 equiv.) was treated with TBAF (1
M
in THF,
(methoxymethoxy)tridecan-6-ol (21a): A solution of TBAF (1
M in
0.43 mL, 0.43 mmol, 1.5 equiv.) in THF (0.5 mL) under the same
THF, 3 mL, 2.88 mmol, 3 equiv.) was added to a stirred solution of
conditions as described for the synthesis of 19a to give compound
TBDPS ether 20a (600 mg, 0.96 mmol, 1 equiv.) in THF. The mixture
19b (150 mg, 90 %) as a pale yellow liquid; [α]D25 = –8.4, (c = 3.6, was heated at 70 °C for 4 h and then diluted with water. The result-
CHCl3). IR (CHCl3): νmax = 3386, 3020, 2933, 1596, 1431, 1217, 1040,
ing mixture was extracted with EtOAc. The organic layer was
˜
767, 670 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.69–7.67 (m, 4 H), washed with water, dried with Na2SO4, and concentrated. The crude
7.42–7.35 (m, 6 H), 5.87 (ddd, J = 6.6, 10.5, 17.1 Hz, 1 H), 5.38 (d,
J = 17.1 Hz, 1 H), 5.25 (d, J = 10.5 Hz, 1 H), 4.68–4.64 (m, 2 H), 3.93
(t, J = 6.2 Hz, 1 H), 3.81–3.75 (m, 1 H), 3.71 (quin, J = 5.6 Hz, 1 H),
3.51 (br. s, 1 H), 3.41 (s, 3 H), 2.72 (br. s, 1 H), 1.65–1.58 (m, 1 H),
1.56–1.49 (m, 1 H), 1.43–1.38 (m, 5 H), 1.24–1.08 (m, 13 H), 1.05 (s,
9 H), 0.83 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
137.3, 135.9, 134.8, 134.7, 129.3, 127.3, 117.5, 96.5, 76.4, 76.1, 73.2,
70.7, 55.9, 37.2, 36.3, 36.2, 34.9, 31.9, 29.8, 27.1, 25.3, 24.8, 24.5, 22.5,
19.4, 14.0 ppm. HRMS (ESI+): calcd. for C35H56O5SiNa [M + Na]+
607.37810; found 607.37892.
product was purified by flash column chromatography (petroleum
ether/EtOAc, 88:12) to provide compound 21a (334 mg, 90 %) as a
pale yellow liquid; Rf = 0.3 (petroleum ether/EtOAc, 85:15). [α]D25
=
–8.7 (c = 1.5, CHCl3). IR (CHCl3): νmax = 3423, 3018, 2936, 2861, 1693,
˜
1462, 1428, 1376, 1217, 1104, 1037, 768, 671 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 5.80 (ddd, J = 7.6, 10.5, 17.2 Hz, 1 H), 5.30 (d,
J = 17.2 Hz, 1 H), 5.24 (d, J = 10.5 Hz, 1 H), 4.71–4.67 (m, 2 H), 4.51
(t, J = 6.6 Hz, 1 H), 4.37 (ddd, J = 3.2, 6.6, 9.8 Hz, 1 H), 3.78–3.72 (m,
1 H), 3.62–3.57 (m, 1 H), 3.40 (s, 3 H), 1.61–1.52 (m, 7 H), 1.48 (s, 3
H), 1.46–1.42 (m, 4 H), 1.37 (s, 3 H), 1.35–1.29 (m, 9 H), 0.90 (t, J =
6.7 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 134.5, 118.1, 108.1,
96.0, 79.7, 74.9, 74.7, 71.9, 55.6, 37.5, 37.4, 35.8, 35.2, 31.9, 30.9, 29.8,
29.7, 28.3, 25.7, 25.6, 25.3, 24.9, 22.6, 14.0 ppm. HRMS (ESI+): calcd.
for C22H42O5Na [M + Na]+ 409.29181; found 409.29245.
(5R,11R)-5-{[(4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl]methyl}-14,14-dimethyl-11-pentyl-13,13-diphenyl-2,4,12-tri-
oxa-13-silapentadecane (20a): Diol 19a (700 mg, 1.197 mmol,
1 equiv.) was dissolved in CH2Cl2 (2 mL), and 2,2-DMP (1.5 mL,
11.97 mmol, 10 equiv.) and a catalytic amount of PPTS (150 mg,
0.598 mmol, 0.5 equiv.) were added to it. The reaction mixture was
stirred at room temperature overnight. When TLC analysis showed
that the reaction had reached completion, it was quenched by the
addition of dry Et3N, and the solvent was evaporated in vacuo at
room temperature to give the crude product, which was purified
(6R,12R)-13-[(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-12-
(methoxymethoxy)tridecan-6-ol (21b): Compound 20b (130 mg,
0.208 mmol, 1 equiv.) was treated with TBAF (1
M in THF, 0.6 mL,
0.624 mmol, 3 equiv.) in THF (2 mL) under the same conditions as
described for the synthesis of 21a to give compound 21b (80 mg,
90 %) as a pale yellow liquid; [α]D25 = –2.3 (c = 1.6, CHCl3). IR (CHCl3):
by column chromatography (petroleum ether/EtOAc, 24:1) to afford νmax = 3424, 3019, 2930, 2857, 1640, 1427, 1218, 1041, 771,
˜
Eur. J. Org. Chem. 2016, 1215–1226
www.eurjoc.org
1223
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
670 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 5.81 (ddd, J = 7.3, 10.1, by using EtOAc (5 × 5 mL). The combine EtOAc layers were dried
17.1 Hz, 1 H), 5.36 (d, J = 17.1 Hz, 1 H), 5.25 (d, J = 10.1 Hz, 1 H),
4.69–4.66 (m, 2 H), 3.97–3.94 (t, J = 8.2 Hz, 1 H), 3.86 (dt, J = 2.8,
with anhydrous Na2SO4 and concentrated. The residue was purified
by flash column chromatography (petroleum ether/EtOAc, 1.5:1) to
8.2 Hz, 1 H), 3.80–3.75 (m, 1 H), 3.57–3.57 (m, 1 H), 3.39 (s, 3 H), give 24 (157.5 mg, 84 %) as a colorless liquid; Rf = 0.26 (petroleum
1.71–1.66 (m, 1 H), 1.64–1.60 (m, 2 H), 1.58–1.54 (m, 1 H), 1.47–1.43 ether/EtOAc, 1.5:1). [α]D25 = –10.2 (c = 2.5, CHCl3). IR (CHCl3): νmax
=
˜
(m, 4 H), 1.42–1.4 (m, 8 H), 1.36–1.28 (m, 10 H), 0.90 (t, J = 6.9 Hz,
3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 135.1, 118.9, 108.6, 95.8,
83.0, 77.2, 74.7, 71.9, 55.6, 37.5, 37.4, 37.1, 35.1, 31.9, 29.8, 27.4, 26.9,
25.6, 25.3, 24.8, 22.6, 14.0 ppm. HRMS (ESI+): calcd. for C22H42O5Na
[M + Na]+ 409.29144; found 409.29245.
3455, 3013, 2937, 2863, 1721, 1629, 1456, 1408, 1375, 1208, 1143,
1098, 1040, 924, 758, 668 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.38
(dd, J = 1.2, 17.1 Hz, 1 H), 6.11 (dd, J = 10.3, 17.1 Hz, 1 H), 5.89 (ddd,
J = 6.1, 10.5, 17.1 Hz, 1 H), 5.80 (dd, J = 1.2, 10.3 Hz, 1 H), 5.33 (d,
J = 17.1 Hz, 1 H), 5.24 (d, J = 10.5 Hz, 1 H), 4.94 (quin, J = 6.2 Hz, 1
H), 4.66 (s, 2 H), 4.17–4.13 (m, 1 H), 3.94 (doublet-like, 1 H), 3.82–
3.77 (m, 1 H), 3.40 (s, 3 H), 3.32 (br. s, 1 H), 2.44 (br. s, 1 H), 1.70–
1.49 (m, 8 H), 1.31–1.27 (m, 12 H), 0.87 (t, J = 6.9 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 166.1, 136.4, 130.2, 128.9, 116.9, 96.3,
76.0, 75.7, 74.5, 70.4, 55.8, 35.3, 34.7, 34.1, 34.0, 31.7, 29.5, 25.3, 25.2,
24.9, 22.5, 14.0 ppm. HRMS (ESI+): calcd. for C22H40O6Na [M + Na]+
423.27185; found 423.27171.
(6R,12R)-13-[(4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-12-
(methoxymethoxy)tridecan-6-yl Acrylate (22a): Acryloyl chloride
(0.095 mL, 1.16 mmol, 1.5 equiv.) was added dropwise under N2 to
a solution of compound 21a (300 mg, 0.776 mmol, 1 equiv.), Et3N
(0.33 mL, 2.33 mmol, 3 equiv.), and a catalytic amount of DMAP in
anhydrous CH2Cl2 (2 mL) at 0 °C, and the mixture was stirred at 0 °C
for 2 h. Upon completion of the reaction, the mixture was poured
into brine (2 mL), and the resulting mixture was extracted with
CH2Cl2 (3 × 4 mL). The combined organic phases were washed with
(6R,12R,14S,15S)-12,14,15-Trihydroxyheptadec-16-en-6-yl
Acrylate (23b): To acetonide 22b (50 mg, 0.113 mmol, 1 equiv.) in
brine (2 × 2 mL), dried with Na2SO4, and evaporated under reduced CH3CN/CH3OH (4:1, 0.2 mL) was added HCl (3
N solution, 19 μL) at
pressure. The crude product was purified by flash column chroma- 0 °C, and the resulting mixture was stirred at room temperature for
tography (petroleum ether/EtOAc, 19:1) to give 22a (253 g, 74 %)
as a pale yellow liquid; Rf = 0.42 (petroleum ether/EtOAc, 85:15).
6 h. Upon completion of the reaction (as indicated by TLC analysis),
the reaction mixture was quenched with a saturated NaHCO3 solu-
[α]D25 = –3.1 (c = 3.8, CHCl3). IR (CHCl3): νmax = 3452, 3063, 2935, tion. The aqueous layer was extracted with EtOAc, and the organic
˜
2861, 1963, 1894, 1829, 1722, 1593, 1461, 1437, 1375, 1220, 1104,
layer was dried with Na2SO4 and concentrated. The crude residue
1
1042, 926, 870, 824, 758, 704 cm–1. H NMR (400 MHz, CDCl3): δ = was purified by flash column chromatography (petroleum ether/
6.39 (dd, J = 1.5, 17.4 Hz, 1 H), 6.12 (dd, J = 10.5, 17.4 Hz, 1 H),
5.84–5.76 (m, 2 H), 5.30 (d, J = 17.1 Hz, 1 H), 5.24 (d, J = 10.5 Hz, 1
H), 4.95 (quin, J = 6.4 Hz, 1 H), 4.68 (s, 2 H), 4.51 (t, J = 6.9 Hz, 1 H),
4.37 (ddd, J = 3.2, 6.9, 9.8 Hz, 1 H), 3.77–3.72 (m, 1 H), 3.39 (s, 3 H),
1.57–1.54 (m, 7 H), 1.48 (s, 3 H), 1.37 (s, 3 H), 1.35–1.25 (m, 13 H),
0.88 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.0,
134.5, 130.1, 129.0, 118.0, 108.1, 96.0, 79.7, 74.9, 74.7, 74.5, 55.6,
35.8, 35.2, 34.1, 31.7, 29.7, 28.2, 25.6, 25.2, 24.9, 24.8, 22.5, 13.9 ppm.
HRMS (ESI+): calcd. for C25H44O6Na [M + Na]+ 463.30240; found
463.30301.
EtOAc, 7:3) to afford 23b (25 mg, 62 %) as a colorless liquid; Rf =
0.26 (petroleum ether/EtOAc, 1.5:1). [α]D25 = –4.4 (c = 0.6, CHCl3). IR
(CHCl3): νmax = 3375, 3020, 2929, 1710, 1600, 1420, 1216, 1044, 928,
˜
763, 670 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.39 (dd, J = 1.0,
17.4 Hz, 1 H), 6.12 (dd, J = 10.5, 17.4 Hz, 1 H), 5.90–5.80 (m, 2 H),
5.37 (d, J = 17.4 Hz, 1 H), 5.26 (d, J = 10.5 Hz, 1 H), 4.95 (quin, J =
6.8 Hz, 1 H), 4.02 (t, J = 6.4 Hz, 1 H), 3.95–3.93 (m, 1 H), 3.81 (br. s,
1 H), 3.10 (br. s, 1 H), 2.52 (br. s, 1 H), 2.41 (br. s, 1 H), 1.74–1.69 (m,
1 H), 1.64–1.60 (m, 1 H), 1.60–1.55 (m, 4 H), 1.47–1.42 (m, 2 H), 1.30–
1.28 (m, 11 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.2, 137.2, 130.3, 128.9, 117.8, 76.2, 74.5, 71.8, 69.2,
38.4, 37.3, 34.1, 34.0, 31.7, 29.2, 25.5, 25.2, 24.9, 22.5, 14.0 ppm.
HRMS (ESI+): calcd. for C20H36O5Na [M + Na]+ 379.24521; found
379.24550.
(6R,12R)-13-[(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-12-
(methoxymethoxy)tridecan-6-yl Acrylate (22b): Compound 21b
(70 mg, 0.181 mmol, 1 equiv.) was treated with acryloyl chloride
(22 μL, 0.272 mmol, 1.5 equiv.), Et3N (76 μL, 0.543 mmol, 3 equiv.),
and a catalytic amount of DMAP in CH2Cl2 (1 mL) under the same
conditions as described for the synthesis of 22a to give compound
(6R,12R,14S,15R)-12,14,15-Trihydroxyheptadec-16-en-6-yl
Acrylate (23a): Compound 22a (40 mg, 0.090 mmol) was treated
22b (59 mg, 74 %) as a pale yellow liquid; [α]D25 = –4.4 (c = 1.2, with with HCl (3
CHCl3). IR (CHCl3): νmax = 3395, 3021, 2935, 1711, 1601, 1526, 1416,
N
solution, 15 μL) in CH3CN/CH3OH (4:1, 0.15 mL)
under the same conditions as described for the synthesis of 23b to
1216, 1041, 927, 766, 671 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.39 give compound 23a (20.1 mg, 62 %) as a colorless liquid; [α]D25
˜
=
(dd, J = 1.2, 17.4 Hz, 1 H), 6.12 (dd, J = 10.4, 17.4 Hz, 1 H), 5.84–5.77
(m, 2 H), 5.36 (d, J = 17.1 Hz, 1 H), 5.25 (d, J = 10.4 Hz, 1 H), 4.95
(quin, J = 5.8 Hz, 1 H), 4.67 (s, 2 H), 3.95 (t, J = 8.2 Hz, 1 H), 3.86 (dt,
J = 2.4, 8.5 Hz, 1 H), 3.78–3.74 (m, 1 H), 3.38 (s, 3 H), 1.71–1.66 (m,
1 H), 1.63–1.50 (m, 8 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.34–1.27 (m, 11
–1.8 (c = 0.9, CHCl3). IR (CHCl3): νmax = 3416, 3018, 2934, 2865, 1711,
˜
1626, 1521, 1412, 1289, 1215, 1110, 1048, 989, 767, 670 cm–1
.
1H
NMR (500 MHz, CDCl3): δ = 6.39 (dd, J = 1.2, 17.4 Hz, 1 H), 6.12 (dd,
J = 10.4, 17.4 Hz, 1 H), 5.91 (ddd, J = 6.4, 10.4, 17.1 Hz, 1 H), 5.81
(dd, J = 1.5, 10.4 Hz, 1 H), 5.35 (dt, J = 1.3, 17.1 Hz, 1 H), 5.27 (dt,
H), 0.88 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = J = 1.3, 10.4 Hz, 1 H), 4.98–4.93 (m, 1 H), 4.15–4.13 (m, 1 H), 4.00–
166.1, 135.1, 130.1, 129.0, 118.9, 108.6, 95.8, 83.0, 77.2, 74.8, 74.5,
55.6, 37.1, 35.1, 34.1, 31.7, 29.7, 27.4, 26.9, 25.3, 24.9, 24.8, 22.5,
14.0 ppm. HRMS (ESI+): calcd. for C25H44O6Na [M + Na]+ 463.30145;
found 463.30301.
3.91 (m, 2 H), 2.94 (br. s, 1 H), 2.47–2.40 (br. s, 2 H), 1.71–1.67 (m, 1
H), 1.58–1.50 (m, 6 H), 1.49–1.46 (m, 2 H), 1.33–1.28 (m, 11 H), 0.88
(t, J = 6.7 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.2, 136.4,
130.3, 128.9, 117.5, 76.1, 74.5, 71.2, 69.2, 37.5, 37.2, 34.1, 34.0, 31.7,
29.2, 25.6, 25.1, 24.9, 22.5, 14.0 ppm. HRMS (ESI+): calcd. for
C20H36O5Na [M + Na]+ 379.24530; found 379.24550.
(6R,12R,14S,15R)-14,15-Dihydroxy-12-(methoxymethoxy)-
heptadec-16-en-6-yl Acrylate (24): A mixture of isopropylidene
ketal 22a (200 mg, 0.4545 mmol, 1 equiv.) and a catalytic amount
(5S,6S,8R,14R,E)-5,6,8-Trihydroxy-14-pentyloxacyclotetradec-3-
of PPTS (12 mg, 0.0455, 0.1 equiv.) in CH3OH (2 mL) was stirred at en-2-one (2): To a solution of 23b (20 mg, 0.0561 mmol, 1 equiv.) in
room temperature for 24 h. Upon completion of the reaction (as
indicated by TLC analysis), the CH3OH was evaporated, and the oily
residue was diluted with water. The crude product was extracted
freshly distilled and degassed anhydrous CH2Cl2 (60 mL) was added
Grubbs second generation catalyst (5 mg, 0.00561 mmol, 0.1 equiv.),
and the resulting mixture was heated at reflux for 8 h under argon
Eur. J. Org. Chem. 2016, 1215–1226
www.eurjoc.org
1224
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
until the starting material was completely consumed (monitored by
TLC analysis). The solvent was evaporated to give a brown residue,
which was purified by flash column chromatography (petroleum
ether/EtOAc, 1:1) to afford 2 (7.36 mg, 40 %) as a white amorphous
solid; Rf = 0.42 (petroleum ether/EtOAc, 1.5:1). [α]D25 = –8.8 (c = 0.7,
Acknowledgments
B. M. S. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for the generous financial support in the form
of a senior research fellowship (SRF). The authors also thank
CH3OH). IR (CH3OH): νmax = 3413, 2955, 2845, 2120, 1649, 1459, Azeocryst Organic Pvt. Ltd. for providing various Grignard rea-
˜
1
1403, 1272, 1109, 1018, 769 cm–1. H NMR (CD3OD, 500 MHz): δ =
gents. Dr. P. R. Rajamohanan [CSIR-National Chemical Labora-
7.04 (dd, J = 5.3, 15.9 Hz, 1 H), 6.11 (dd, J = 1.5, 15.9 Hz, 1 H), 4.95
(dddd, J = 12.5, 7.6, 5.2, 2.4 Hz, 1 H), 4.26 (ddd, J = 7.0, 5.3, 1.5 Hz,
1 H), 3.94–3.89 (m, 1 H), 3.77 (dt, J = 7.3, 4.3 Hz, 1 H), 1.70 (triplet-
like, 2 H), 1.62–1.57 (m, 4 H), 1.43 (br. s, 4 H), 1.34–1.31 (m, 7 H),
1.18 (br. s, 3 H), 0.90 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR (125 MHz,
CD3OD): δ = 168.0, 148.7, 123.5, 77.6, 75.8, 74.4, 69.2, 37.9, 36.8,
36.3, 34.1, 33.0, 29.7, 26.6, 26.4, 25.3, 23.8, 14.5 ppm. HRMS (ESI+):
calcd. for C18H32O5Na [M + Na]+ 351.21347; found 351.21420.
tory (NCL)] is thanked for NMR support, Ms. B. Santhakumari
(CSIR-NCL) for the HRMS data, and Ms. Sunita S. Kunte (CSIR-
NCL) for the HPLC data. The authors are grateful to Dr. Ruchi
Jain (University of Delhi) and Dr. Ankushkumar D. Bhise (CSIR-
NCL) for helpful discussions and their help with some experi-
ments. Financial support by the Council of Scientific and Indus-
trial Research (CSIR), New Delhi in form of a 12th five year
project (Origin CSC0108) is gratefully acknowledged.
(5R,6S,8R,14R,E)-5,6,8-Trihydroxy-14-pentyloxacyclotetradec-3-
en-2-one (1): Compound 23a (15 mg, 0.0421 mmol) was treated
with Grubbs second generation catalyst (3.6 mg, 0.00421 mmol,
0.1 equiv.) in CH2Cl2 (45 mL) under the same conditions as de-
scribed for the synthesis of 2 to give compound 1 (4.1 mg, 30 %)
as a white amorphous solid.
Keywords: Natural products · Asymmetric synthesis ·
Macrocycles · Metathesis · Hydrolytic kinetic resolution
(5R,6S,8R,14R,E)-5,6-Dihydroxy-8-(methoxymethoxy)-14-
pentyloxacyclotetradec-3-en-2-one (25): To a solution of 24
(50 mg, 0.125 mmol, 1 equiv.) in freshly distilled and degassed anhy-
drous CH2Cl2 (150 mL) was added Grubbs second generation cata-
lyst (11 mg, 0.0125 mmol, 0.1 equiv.), and the resulting mixture was
heated at reflux for 24 h under argon until the starting materials
were completely consumed (monitored by TLC analysis). The sol-
vent was evaporated to give a brown residue, which was purified
by column chromatography (petroleum ether/EtOAc, 1:1) to afford
25 (32.6 mg, 70 %) as a white solid; Rf = 0.24 (petroleum ether/
[1] S. Omura, Macrolide Antibiotics: Chemistry, Biology, and Practice, Aca-
demic Press, 2002.
[2] S.-W. Yang, T.-M. Chan, J. Terracciano, D. Loebenberg, M. Patel, M. Chu, J.
Antibiot. 2005, 58, 535.
[3] a) K. Kito, R. Ookura, S. Yoshida, M. Namikoshi, T. Ooi, T. Kusumi, Org.
Lett. 2008, 10, 225–228; b) M. Kanematsu, M. Yoshida, K. Shishido, Angew.
Chem. Int. Ed. 2011, 50, 2618–2620; Angew. Chem. 2011, 123, 2666–2668;
c) M. Mortimore, G. S. Cockerill, P. Kocieński, R. Treadgold, Tetrahedron
Lett. 1987, 28, 3747–3750; d) D. Seebach, G. Adam, R. Zibuck, W. Simona,
M. Rouilly, W. L. Meyer, J. F. Hinton, T. A. Privett, G. E. Templeton, D. K.
Heiny, Liebigs Ann. Chem. 1989, 1233–1240.
[4] a) P. A. Wender, J. L. Baryza, S. E. Brenner, B. A. DeChristopher, B. A. Loy,
A. J. Schrier, V. A. Verma, Proc. Natl. Acad. Sci. USA 2011, 108, 6721–6726;
b) P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res.
2007, 41, 40–49.
EtOAc, 1:1). [α]D25 = –5.8 (c = 0.7, CHCl ). IR (CHCl ): ν
= 3427,
max
˜
3
3
1
3021, 2933, 2863, 1712, 1524, 1431, 1216, 1036, 767, 671 cm–1. H
NMR (500 MHz, CDCl3): δ = 6.83 (dd, J = 5.3, 15.7 Hz, 1 H), 6.18 (dd,
J = 1.4, 15.7 Hz, 1 H), 5.03–4.98 (m, 2 H), 4.72–4.68 (m, 2 H), 4.65–
4.63 (m, 1 H), 4.02–3.98 (m, 1 H), 3.93 (q, J = 3.7 Hz, 1 H), 3.40 (s, 4
H), 1.81 (t, J = 4.0 Hz, 2 H), 1.71–1.66 (m, 2 H), 1.61–1.56 (m, 2 H),
1.54–1.46 (m, 4 H), 1.39–1.30 (m, 8 H), 1.11–1.03 (m, 2 H), 0.88 (t,
J = 6.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.3, 145.5,
122.6, 96.1, 77.4, 76.2, 73.5, 71.4, 55.8, 35.2, 33.9, 33.7, 32.5, 31.7,
28.7, 26.6, 25.2, 25.0, 22.5, 14.0 ppm. HRMS (ESI+): calcd. for
[5] J. D. Moretti, X. Wang, D. P. Curran, J. Am. Chem. Soc. 2012, 134, 7963–
7970.
[6] a) A. K. Bali, S. K. Sunnam, K. R. Prasad, Org. Lett. 2014, 16, 4001–4003;
b) S. K. Sunnam, K. R. Prasad, Tetrahedron 2014, 70, 2096–2101.
[7] K. Ramakrishna, K. P. Kaliappan, Org. Biomol. Chem. 2015, 13, 234–240.
[8] B. Seetharamsingh, P. V. Khairnar, D. S. Reddy, J. Org. Chem. 2016, 81,
290–296.
[9] a) K. Lu, M. Huang, Z. Xiang, Y. Liu, J. Chen, Z. Yang, Org. Lett. 2006, 8,
1193–1196; b) D. R. Schmidt, O. Kwon, S. L. Schreiber, J. Comb. Chem.
2004, 6, 286–292; c) L. M. Xu, Y. F. Liang, Q. D. Ye, Z. Yang, Org. Chem.
2012, 10.
+
C20H36O6Na [M + Na] 395.24033; found 395.24041.
(5R,6S,8R,14R,E)-5,6,8-Trihydroxy-14-pentyloxacyclotetradec-3-
en-2-one (1): To acetonide 25 (20 mg, 0.0537 mmol, 1 equiv.) in
CH3CN/CH3OH (4:1, 90 μL) was added HCl (3
N solution, 9 μL) at
[10] S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga, K. B. Hansen, A. E.
Gould, M. E. Furrow, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 1307–
1315.
[11] M. Yamaguchi, I. Hirao, Tetrahedron Lett. 1983, 24, 391–394.
[12] C. Bonini, L. Chiummiento, V. Videtta, F. Colobert, G. Solladié, Synlett
2006, 2427–2430.
[13] a) P. Kumar, P. Gupta, Synlett 2009, 1367–1382; b) P. Kumar, V. Naidu, P.
Gupta, Tetrahedron 2007, 63, 2745–2785.
[14] a) A. Mengel, O. Reiser, Chem. Rev. 1999, 99, 1191–1224; b) D. A. Evans,
S. J. Siska, V. J. Cee, Angew. Chem. Int. Ed. 2003, 42, 1761–1765; Angew.
Chem. 2003, 115, 1803.
0 °C, and the resulting mixture was stirred at room temperature for
6 h. Upon the completion of the reaction (as indicated by TLC analy-
sis), it was quenched by the additon of a saturated NaHCO3 solu-
tion. The aqueous layer was extracted with EtOAc, and the organic
layer was dried with Na2SO4 and concentrated. The crude residue
was purified by flash column chromatography (petroleum ether/
EtOAc, 1:1) to afford 1 (12 mg, 68 %) as a colorless liquid; Rf = 0.35
(petroleum ether/EtOAc, 1.5:1). [α]D25 = +4.8 (c = 0.3, CH3OH). IR
(CH3OH): νmax = 3557, 2934, 2837, 1716, 1659, 1456, 1418, 1113,
˜
1029, 88 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 6.87 (dd, J = 6.1,
[15] a) D. A. Evans, D. L. Rieger, J. R. Gage, Tetrahedron Lett. 1990, 31, 7099–
7100; b) S. D. Rychnovsky, B. N. Rogers, T. I. Richardson, Acc. Chem. Res.
1998, 31, 9–17; c) S. D. Rychnovsky, D. J. Skalitzky, Tetrahedron Lett. 1990,
31, 945–948.
[16] G. Ryu, B. W. Choi, B. H. Lee, Bull. Korean Chem. Soc. 2002, 23, 1429–
1434.
[17] a) A. G. Giri, M. A. Mondal, V. G. Puranik, C. V. Ramana, Org. Biomol. Chem.
2010, 8, 398–406; b) D. Si, N. M. Sekar, K. P. Kaliappan, Org. Biomol. Chem.
2011, 9, 6988–6997.
15.6 Hz, 1 H), 6.08 (dd, J = 1.2, 15.6 Hz, 1 H), 4.98–4.94 (m, 1 H),
4.50–4.47 (m, 1 H), 3.99 (quin, J = 6.1 Hz, 1 H), 3.87–3.83 (m, 1 H),
1.83 (dt, J = 6.1, 14.7 Hz, 1 H), 1.70–1.52 (m, 5 H), 1.39–1.25 (m, 11
H), 1.20–1.16 (m, 3 H), 0.90 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CD3OD): δ = 168.4, 149.3, 123.1, 77.6, 76.0, 72.9, 69.5,
38.3, 36.8, 36.5, 34.1, 33.0, 29.5, 27.0, 26.4, 25.8, 23.8, 14.5 ppm.
HRMS (ESI+): calcd. for C18H32O5Na [M + Na]+ 351.21417; found
351.21420.
Eur. J. Org. Chem. 2016, 1215–1226
www.eurjoc.org
1225
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[18] a) R. H. Grubbs, D. J. O'Leary (Eds.), Handbook of Metathesis: Applications
in Organic Synthesis, Wiley-VCH, Weinheim, Germany, 2015; b) S. Mon-
fette, D. E. Fogg, Chem. Rev. 2009, 109, 3783–3816; c) Y. A. Lin, J. M.
Chalker, B. G. Davis, ChemBioChem 2009, 10, 959–969.
[19] Y. A. Lin, B. G. Davis, Beilstein J. Org. Chem. 2010, 6, 1219–1228.
Received: December 5, 2015
Published Online: February 1, 2016
Eur. J. Org. Chem. 2016, 1215–1226
www.eurjoc.org
1226
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim