Phosphate tether-mediated approach to the formal total synthesis of (-)-salicylihalamides A and B

Article abstract of DOI:10.1021/jo200337v

A concise formal synthesis of the cytotoxic macrolides (-)- salicylihalamides A and B is reported. Key features of the synthetic strategy include a chemoselective hydroboration, highly regio- and diastereoselective methyl cuprate addition, Pd-catalyzed formate reduction, and an E-selective ring-closing metathesis to construct the 12-membered macrocycle subunit. Overall, two routes have been developed from a readily prepared bicyclic phosphate (4 steps), a 13-step route and a more efficient 9-step sequence relying on regioselective esterification of a key diol.

Full text of DOI:10.1021/jo200337v

ARTICLE
pubs.acs.org/joc
Phosphate Tether-Mediated Approach to the Formal Total Synthesis
of (ꢀ)-Salicylihalamides A and B
Rambabu Chegondi, Mary M. L. Tan, and Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States
S Supporting Information
b
ABSTRACT: A concise formal synthesis of the cytotoxic
macrolides (ꢀ)-salicylihalamides A and B is reported. Key fea-
tures of the synthetic strategy include a chemoselective hydro-
boration, highly regio- and diastereoselective methyl cuprate
addition, Pd-catalyzed formate reduction, and an E-selective
ring-closing metathesis to construct the 12-membered macro-
cycle subunit. Overall, two routes have been developed from a readily prepared bicyclic phosphate (4 steps), a 13-step route and a
more efficient 9-step sequence relying on regioselective esterification of a key diol.
1. INTRODUCTION
The cytotoxic macrolides salicylihalamides A (1a) and B (1b)
were isolated from the Australian marine sponge Halicona sp. in
1997 by Boyd, Erickson, and co-workers (Figure 1).1 The
structure and relative stereochemistry of the salicylihalamides
(1a and 1b) were determined by NMR spectroscopic methods
and Mosher ester analysis. These natural products possess a
12-membered unsaturated benzolactone core and an unusual
enamide side chain with differing geometry about the C17ꢀC18
double bond. In 2000, De Brabander and co-workers reassigned
the absolute stereochemistry in the first total synthesis of 1a.2
When screened against the NCI’s 60 human tumor cell lines
salicylihalamide A (1a) exhibited potent cytotoxicity with an
average GI50 of 15 nM. In comparison to related benzolactone
enamide natural products, e.g., apicularen A (2), salicylihalamide
A (1a) exhibited the highest average sensitivity (GI50 = 7 nM)
against melanoma cell lines.1 Furthermore, salicylihalamide A
(1a) possesses selective inhibition of mammalian vacuolar type
Hþ-ATPase (V-ATPase), with an IC50 value < 1.0 nM against
bovine brain V-ATPase.3 Salicilyhalamide A has attracted sig-
nificant attention from the synthetic community due to its potent
antitumor properties, structural features, and the limited avail-
ability of the material from natural sources.4
Figure 1. Structures of two important benzolactone enamide class
compounds.
56 and the chiral, nonracemic subunit 6 via an E-selective
ring-closing metathesis (RCM) using Grubbs catalyst
(PCy3)2(Cl)2RudCHPh (cat-A)7 in both routes (Scheme 1).
The key intermediate 6 can be derived from enantiomerically
pure bicyclic phosphate (R,R,RP)-75a (derived via desymmetriza-
tion with Grubbs catalyst (IMesH2)(PCy3)(Cl)2RudCHPh
(cat-B))8 involving a chemoselective hydroboration, highly
regio- and diastereoselective cuprate addition, cross metathesis
(CM) with the HoveydaꢀGrubbs second generation catalyst
(cat-C),9 and a Pd-catalyzed reductive allylic transposition using
ammonium formate.5f
Previously, we have reported the synthesis of polyol synthons
utilizing the concept of multivalent activation with temporary
phosphate tethers whereby a number of chemo-, regio-, and
stereoselective transformations were realized.5 Herein, we dis-
close the formal total synthesis of salicylihalamides A and B in 13
steps from bicyclic phosphate 7 featuring the orthogonal pro-
tecting property of chiral aliphatic subunit 6 (overall, 17-step
longest linear sequence (LLS)). A more efficient 9-step synthesis
from 7 using regioselective esterification of diol 6 is also reported
(overall, 13-step LLS) and is on par with the most efficient
syntheses reported to date.4
2. RESULTS AND DISCUSSION
Construction of P-chiral, Nonracemic Bicyclo[4.3.1]phos-
phate 7. 1,3-anti-Diol 810 was desymmetrized using a phosphate
tether-mediated RCM reaction to construct the P-chiral bicyclo[4.3.1]-
phosphate 7 (Scheme 2).5 In this strategy, pseudo-C2-symmetric
phosphate triester 9 was synthesized from a 2-step sequential tripodal
coupling5c of diol 8 and allyl alcohol with POCl3 or via a one-pot diol
coupling with allyl tetraisopropylphosphorodiamidite followed by
Retrosynthetic analysis reveals the construction of the macro-
lactone (3 or 4) from the functionalized benzoic acid derivative
Received: February 15, 2011
Published: April 19, 2011
r
2011 American Chemical Society
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Scheme 1. Retrosynthetic Analysis of (ꢀ)-Salicylihalamides
Scheme 2. Construction of P-Chiral, Nonracemic Bicyclo[4.3.1]phosphate (R,R,Rp)-7
oxidation.5g The method is predicated on facile RCM occurring via
the chair conformer bearing a cis-diaxial relationship in the reacting
olefin pairs (allylphosphate ester cis to the terminal olefin) to yield the
P-chiral, nonracemic bicyclo[4.3.1]phosphate (R,R,Rp)-7.
Pd-catalyzed, reductive allylic transposition [Pd(OAc)2, PPh3,
HCOONH4] on CM adduct 14 occurred with excellent regios-
electivity to afford the terminal olefin 15 in 94% yield.13 Removal
of the phosphate ester in the presence of LiAlH4 provided diol 6
as a single diastereomer in excellent yield (98%).
Synthesis of Chiral Subunit 6. Scheme 3 details the con-
struction of advanced intermediate 6, which is the required
intermediate in both routes from the bicycle (R,R,RP)-7. The
primary alcohol 10 was obtained via a chemoselective hydro-
boration of the exocyclic olefin of (R,R,RP)-7, followed by
oxidation under mild conditions (NaBO3•4H2O) developed by
Burke and co-workers.11 Subsequent PMB-ether formation
using the p-methoxybenzyl trichloroacetimidate derived from
p-MeOPhCH2OH produced 11 in 92% yield. A regio- and
diastereoselective SN20 cuprate addition (CuCN•2LiCl, Me2Zn,
dr = >95:5) to 11, followed by methylation (TMSCHN2 and
MeOH), afforded monocyclic phosphate ester 12 in excellent
overall yield (85%). The orthogonal alignment of the π* orbital
(CdC) to the σ* orbital (CꢀOꢀPO) and concave nature of the
bicycle 11 explains the regio- and diastereoselectivity of the SN20
reaction.5e,f Monocyclic phosphate 12 was subjected to cross
metathesis with (Z)-diacetate 13 using 10 mol % of Hoveydaꢀ
Grubbs catalyst cat-C to generate CM adduct 14 in 83% yield.12
Formal Total Synthesis of (ꢀ)-Salicylihalamide A and B in
13 Steps from (R,R,Rp)-7. Initial efforts focused on the synthesis
of benzolactone 3 from the key diol intermediate 6 utilizing
protection with TIPSCl to differentiate the hydroxyl groups
(Scheme 4). Diol 6 was selectively protected as a TIPS-ether 16
(86% yield),14 followed by MOM protection to furnish the fully
protected triol 17 in 92% yield. Compound 17 was desilylated in
95% yield to afford the key subunit 18, which was ready for
coupling with benzodioxinone 5. Alcohol 18 was treated with
NaH, followed by addition of benzodioxinone 5, to provide ester
19 in 66% yield. Subsequent methylation resulted in the produc-
tion of the known RCM precursor 20 in 90% yield.2a,4e To
complete the formal synthesis, RCM reaction of 20 was
carried out using conditions developed by De Brabander and
co-workers4e (10 mol % of cat-A)7 to furnish the known salicy-
lihalamidemacrolide3 in 82% yield and with excellent E-selectivity
(E/Z = 10:1). The physical and spectroscopic data of the synthetic
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Scheme 3. Synthesis of Key Fragment 6
Scheme 4. Formal Total Synthesis of (ꢀ)-Salicylihalamides in 13 Steps from (R,R,Rp)-7 (17-LLS)
sample (1H, 13C, IR, HRMS), as well as specific rotation, were all
in full agreement with those reported in the literature.2a,4d,4e
Regioselective Esterification Studies on Key Fragment 6.
To further streamline the process, we next explored the feasibility
of a regioselective esterification of diol 6 in order to avoid the
aforementioned orthogonal protection pathway. Scheme 5 high-
lights the key regioselective esterification studies on diol 6.
As shown in entry 1, use of NaH as the base yielded a readily
separable mixture (1:1) of both isomers 21a (known) and 21b in
85% yield, while implementation of LiHMDS gave modest
improvement in selectivity (2:1). However, implementation of
NaHMDS as base resulted in a 3.6:1 mixture of the desired
benzolactone 21a and its regioisomer 21b, which could be readily
converted back to starting diol 6 (K2CO3, MeOH) for recycling.
Formal Total Synthesis of (ꢀ)-Salicylihalamides A and B in
9 Steps from (R,R,Rp)-7. Compound 21a was protected as the
di-MOM ether 22 (86% yield) and subjected to RCM conditions
developed by De Brabander and co-workers4e (cat-A) to afford
salicylihalamide macrolide 4 in 84% yield and with excellent E
selectivity (E/Z = 9:1) (Scheme 6). The spectral data (1H, 13C,
IR, HRMS) of 4 were in complete agreement with those reported
in the literature along with specific rotation {[R]D = ꢀ29.6
(c 0.65, CHCl3)}.4e
3. CONCLUSION
In conclusion, the synthesis of key macrolactones 3 and 4
are reported representing formal syntheses of salicylihalamides
A and B. Overall, a 13-step route (17-LLS) and a 9-step route
(13-LLS) have been developed, from a common, readily pre-
pared, chiral, nonracemic bicyclic phosphate (R,R,RP)-7, with an
overall yield of 17.5% and 22.5%, respectively. Each route
proceeds through the common diol subunit 6. The 13-step route
requires differential protection of diol 6, while the more efficient
9-step sequence relies on a regioselective esterification of diol 6.
The latter route has 13 steps in its longest linear sequence (LLS),
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Scheme 5. Regioselective Esterification Studies on Key Fragment 6
followed by addition of NaBO3 4H2O (10.26 g, 66.69 mmol) in one
Scheme 6. Formal Total Synthesis of (ꢀ)-Salicylihalamides
A and B in 9 Steps from (R,R,Rp)-7
3
portion. After removing the ice bath, additional H2O (7 mL) was added,
and the reaction mixture stirred at rt for 1 h. After complete oxidation as
monitored by TLC, the crude solution was dried (Na2SO4), filtered
through a pad of Celite, and washed with EtOAc. The filtrate was
concentrated under reduced pressure and purified via flash column
chromatography (10:1 EtOAc/MeOH) to provide alcohol 10 (1.30 g,
80%) as a white solid; [R]D = ꢀ96.0 (c = 1.82, CHCl3); FTIR (neat)
1
3454, 3072, 2962, 2935, 2887, 1288, 1066, 975 cmꢀ1; H NMR (500
MHz, CDCl3) δ 6.01 (dddd, J = 11.9, 6.7, 3.0, 2.2 Hz, 1H), 5.59 (ddd,
J = 11.9, 3.9, 2.6 Hz, 1H), 5.18 (ddd, J = 24.6, 3.7, 1.9 Hz, 1H), 4.95 (dtd,
J = 14.1, 5.6, 2.7 Hz, 1H), 4.86ꢀ4.74 (m, 1H), 4.35 (ddd, J = 27.9, 14.7,
6.7 Hz, 1H), 3.84ꢀ3.64 (m, 2H), 3.00 (s, 1H), 2.20 (ddd, J = 14.7, 12.0,
6.2 Hz, 1H), 1.97ꢀ1.89 (m, 1H), 1.86ꢀ1.77 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 129.7, 127.6, 77.4 (d, J = 6.6 Hz), 74.5 (d, J = 6.5 Hz),
63.0 (d, J = 6.4 Hz), 57.4, 38.1 (d, J = 9.2 Hz), 34.8; HRMS calcd for
C8H13O5PK (M þ K)þ 259.0138; found 259.0138 (TOF MS ESþ).
(1R,6R,8S)-8-(2-((4-Methoxybenzyl)oxy)ethyl)-2,9,10-trioxa-
1-phosphabicyclo[4.3.1]dec-4-ene 1-Oxide (11). To a stirring
solution of NaH (142 mg, 5.91 mmol) in anhydrous Et2O (10 mL),
under an argon atmosphere, was slowly cannulated a solution of
PMBOH (8.17 g, 59.09 mmol) in dry Et2O (30 mL) at rt. After stirring
for 40 min, the solution was cooled to 0 °C, and Cl3CCN (8.54 g,
59.1 mmol) was slowly added via dropwise addition. After 5ꢀ10 min,
the solution was removed from the ice bath and stirred for an additional
hour. The reaction was quenched with saturated NaHCO3 (20 mL), and
the layers separated. The aqueous layer was further extracted with Et2O
(3 ꢁ 50 mL), and the combined organic layers were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude mixture
was dissolved in dry CH2Cl2 (118 mL) and cannulated into a flask
containing the phosphate 10 (2.6 g, 11.82 mmol), followed by the
addition of PPTS (300 mg, 1.18 mmol) at rt under an argon atmosphere.
After stirring for 16 h, the reaction was quenched with saturated
NaHCO3 (40 mL), and the layers separated. The aqueous layer was
extracted with CH2Cl2 (3 ꢁ 50 mL), and the combined organic layers
were washed with brine (100 mL), dried (Na2SO4), and concentrated
under reduced pressure. Flash column chromatography (EtOAc)
afforded PMB ether 11 (3.71 g, 92%) as a viscous, light yellow oil;
[R]D = ꢀ64.66 (c = 2.40, CHCl3); FTIR (neat): 3055, 2933, 2866, 1612,
1512, 1298, 1093, 975, 738, 703 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ
7.24 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.02 (dddd, J = 11.9,
6.7, 3.1, 2.2 Hz, 1H), 5.57 (ddd, J = 11.9, 3.9, 2.6 Hz, 1H), 5.22ꢀ5.13 (m,
1H), 5.00 (ddt, J = 14.8, 8.9, 3.0 Hz, 1H), 4.81 (dddd, J = 10.5, 8.5, 4.1,
which is on par with the most efficient syntheses of this key late
stage subunit reported to date.
4. EXPERIMENTAL SECTION
General Methods. All reactions were carried out in oven- or flame-
dried glassware, under an argon atmosphere, using standard gastight
syringes, cannulae, and septa. Stirring was achieved with oven-dried
magnetic stir bars. Et2O, THF, and CH2Cl2 were passed through a
purification system employing activated Al2O3. Et3N was eluted through
basic alumina and stored over KOH. Butyl lithium was titrated prior to
use. All olefin metathesis catalysts were obtained commercially and used
without further purification. All 1H and 13C NMR spectra were recorded
in CDCl3 at 500 MHz and 126 MHz, respectively, and calibrated to the
solvent peak. All mass spectra were obtained using electrospray ioniza-
tion (ESI) (MeOH) coupled to high-resolution mass spectrometry
(HRMS). Observed rotations at 589 nm were measured using an
automatic polarimeter. Infrared spectra were obtained using a Fourier
transform infrared (FTIR) spectrometer.
(1R,6R,8S)-8-(2-Hydroxyethyl)-2,9,10-trioxa-1-phosphabicyclo-
[4.3.1]dec-4-ene 1-Oxide (10). Bicyclic phosphate (R,R,Rp)-7
(1.50 g, 7.41 mmol) was dissolved in anhydrous THF (20 mL), followed
by slow addition of 9-BBN (2.71 g, 22.2 mmol) in anhydrous THF
(45 mL) under an argon atmosphere. The solution was stirred at rt for
3 h. After completion of the reaction as monitored by TLC, the reaction
mixture was cooled to 0 °C, and H2O (3.5 mL) was added dropwise,
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2.1 Hz, 1H), 4.43 (d, J = 2.9 Hz, 2H), 4.46ꢀ4.32 (m, 1H), 3.81 (s, 3H),
3.65ꢀ3.52 (m, 2H), 2.19 (ddd, J = 14.6, 12.0, 6.2 Hz, 1H), 2.02ꢀ1.84
(m, 2H), 1.74 (ddd, J = 14.6, 3.4, 2.2 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 159.2, 130.1, 129.8, 129.3, 127.8, 113.8, 77.2 (d, JCP = 6.3 Hz),
74.1 (d, JCP = 6.6 Hz), 72.8, 64.7, 62.9 (d, JCP = 6.4 Hz), 55.2, 35.9 (d,
JCP = 9.4 Hz), 34.9 (d, JCP = 5.9 Hz); HRMS calcd. for C16H21O6PK
(M þ K)þ 379.0713; found 379.0706 (TOF MS ESþ).
(4S,6R)-2-Methoxy-4-(2-((4-methoxybenzyl)oxy)ethyl)-6-
((S)-pent-4-en-2-yl)-1,3,2-dioxaphosphinane 2-Oxide (15).
To a stirring solution of HCO2NH4 (63 mg, 1.00 mmol) in degassed
DCE(4 mL) wasaddedPd(OAc)2 (12mg, 0.05mmol) andPh3P (66mg,
0.25 mmol) at rt, and the mixture was stirred for 15 min at rt under argon,
at which point a solution of acetate 14 (220 mg, 0.50 mmol) in degassed
DCE (2 mL) was added dropwise via cannula. The stirring solution was
equipped with a reflux condenser and placed into an oil bath at 90 °C for
1 h. The reaction mixture was cooled tortand washedwitha sat. NaHCO3
(6 mL) solution, and the aqueous layer was extracted with CH2Cl2 (3 ꢁ
10 mL). The combined organic layers were rinsed with brine (10 mL),
dried (Na2SO4), and concentrated under reduced pressure. Flash column
chromatography (1:1 EtOAc/hexane) afforded the desired compound 15
(180 mg, 94%) as a clear oil, and as an ∼1:1 mixture of diastereomers at
phosphorus; FTIR (neat): 3053, 2956, 2927, 2854, 12654, 1093, 1035,
970, 749, 703 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 8.5 Hz,
2H), 6.88 (d, J = 8.5 Hz, 2H), 5.81ꢀ5.70 (m, 1H), 5.10ꢀ5.02 (m, 2H),
4.82ꢀ4.63 (m, 1H), 4.48ꢀ4.38 (m, 2H), 4.37ꢀ4.21 (m, 1H), 3.81
(s, 3H), 3.78 (d, J = 7.4, Hz, 1.5H), 3.76 (d, J = 7.7 Hz, 1.5 H), 3.69ꢀ3.54
(m, 2H), 2.42ꢀ2.27 (m, 1H), 2.22ꢀ1.76 (m, 6H), 0.90 (d, J = 6.8 Hz,
1.5H), 0.86 (d, J = 6.8 Hz, 1.5H); HRMS calcd for C19H29O6PNa
(M þ Na)þ 407.1599; found 407.1612 (TOF MS ESþ).
(4R,6S)-4-((S)-But-3-en-2-yl)-2-methoxy-6-(2-((4-methoxy-
benzyl)oxy)ethyl)-1,3,2-dioxaphosphinane 2-Oxide (12).
Within a glovebox, CuCN (1.75 g, 19.51 mmol, dried overnight in a
vacuum oven at 60 °C/0.3 mmHg and stored in a glovebox) and LiCl
(1.65 g, 39.02 mmol, dried overnight in a vacuum oven at 60 °C/0.3
mmHg and stored in a glovebox) were added to a round-bottom flask
and sealed with a septum. The flask was removed from the glovebox
and placed under a balloon of argon. Anhydrous THF (20 mL) was
added to the mixture that was stirred for 20 min at rt and then cooled
to ꢀ30 °C. A solution of Me2Zn (16.2 mL, 1.2 M in toluene) was added
rapidly via dropwise addition, and the solution was stirred for 30 min
at ꢀ30 °C (solution turns deep green). After 30 min, phosphate 11
(1.32 g, 3.90 mmol) in anhydrous THF (6 mL) was cannulated drop-
wise (1 mL rinse) into the stirring reaction mixture, and the solution
was immediately removed from the bath and stirred at rt for 2 h. Upon
completion (monitored by TLC, baseline spot in EtOAc), the reaction
was cooled to 0 °C and slowly quenched with 10% aqueous HCl
(2 mL), followed by water (4 mL), and stirred at rt for 10 min, where
pepper-colored salts formed. The solution was filtered through a pad of
Celite and rinsed thoroughly with EtOAc. To the resulting biphasic
solution was added 10% aqueous HCl (3 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (2 ꢁ 25 mL),
and the combined organic layers were concentrated under reduced
pressure. The resulting oil was dissolved in MeOH (∼10 mL), where
TMSCHN2 (2 M in Et2O, ∼5 mL) was added dropwise, resulting in a
deep yellow solution. Excess TMSCHN2 was quenched via slow
dropwise addition of glacial acetic acid (3ꢀ4 drops), and the solution
was dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. Flash column chromatography (2:1 EtOAc/hexane) provided
title compound 12 (1.23 g, 85%) as a clear oil and as a ∼1:1 mixture of
diastereomers at phosphorus; FTIR (neat) 2925, 2852, 1265, 1093,
1033, 972, 749, 703 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 7.25 (d, J =
8.3 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H), 5.85ꢀ5.74 (m, 1H), 5.15ꢀ5.05
(m, 2H), 4.82ꢀ4.63 (m, 1H), 4.44 (s, 2H), 4.49ꢀ4.30 (m, 1H), 3.81 (s,
3H), 3.78 (d, J = 6.6 Hz, 1.5H), 3.76 (d, J = 6.6 Hz, 1.5H), 3.69ꢀ3.52
(m, 2H), 2.57ꢀ2.36 (m, 1H), 2.23ꢀ2.05 (m, 2H), 1.92ꢀ1.80 (m, 2H),
1.10 (d, J = 6.9 Hz, 1.5 H), 1.06 (d, J = 6.9 Hz, 1.5 H); HRMS calcd for
C18H27O6PK (M þ K)þ 409.1182; found 409.1188 (TOF MS ESþ).
(4S,E)-4-((4R,6S)-2-Methoxy-6-(2-((4-methoxybenzyl)oxy)-
ethyl)-2-oxido-1,3,2-dioxaphosphinan-4-yl)pent-2-en-1-yl
Acetate (14). The monocyclic phosphate 12 (1.0 g, 2.70 mmol) was
weighed into a round-bottom flask and dissolved in CH2Cl2 (degassed
10 min with Ar, 27.0 mL), followed by the addition of diacetate 13
(0.56 g, 3.24 mmol) and cat-C (168 mg, 0.27 mmol) under argon at rt.
The reaction mixture was heated at 45 °C for 1 h under a continuous
argon flow and, upon completion, as monitored by TLC, was con-
centrated under reduced pressure. Flash column chromatography (1:1
EtOAc/hexane) provided title compound 14 (0.99 g, 83%) as a clear oil
and as a ∼1:1 mixture of diastereomers at phosphorus; FTIR (neat) 3053,
2954, 2927, 2852, 1737, 1265, 1247, 1093, 1031, 972, 1031, 972, 749,
703 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 8.6 Hz, 2H), 6.88
(d, J = 8.6 Hz, 2H), 5.79ꢀ5.72 (m, 1H), 5.67ꢀ5.60 (m, 1H), 4.80ꢀ4.62
(m, 1H), 4.53 (t, J = 5.3 Hz, 2H), 4.47ꢀ4.29 (m, 3H), 3.81 (s, 3H), 3.77
(d, J = 7.4 Hz, 1.5 H), 3.75 (d, J = 7.4 Hz, 1.5 H), 3.68ꢀ3.53 (m, 2H),
2.59ꢀ3.38 (m, 1H), 2.23ꢀ2.04 (m, 2H), 2.07 (2s, 3H), 1.93ꢀ1.81 (m,
2H), 1.10 (d, J = 6.9 Hz, 1.5 H), 1.05 (d, J = 6.9 Hz, 1.5 H); HRMS calcd
for C21H31O8PK (M þ K)þ 481.1394; found 481.1390 (TOF MS ESþ).
(3S,5R,6S)-1-((4-Methoxybenzyl)oxy)-6-methylnon-8-ene-3,
5-diol (6). To a suspension of LiAlH4 (53 mg, 1.10 mmol) in anhydrous
Et2O (3 mL) was added dropwise a solution of 1:1 diastereomeric phos-
phate mixture 15 (170 mg, 0.45 mmol) in Et2O (2 mL) at 0 °C. The
reaction mixture was stirred at 0 °C for 1 h, quenched via slow sequential
addition of H2O (60 μL), 15% NaOH (60 μL), and H2O (180 μL), and
removed from the ice bath. After stirring for 30 min, 10% aqueous HCl
(5 mL) was added to the reaction mixture, and the layers were separated.
The aqueous layer was extracted with Et2O(3ꢁ 10 mL), and the combined
organiclayerswererinsedwithbrine(1ꢁ 10 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure. Flash column chromatography
(1:1 EtOAc/Hexane) afforded diol 6 (125 mg, 98% yield) as a viscous oil;
[R]D = þ15.16 (c = 1.20, CHCl3); FTIR (neat) 3412, 2921, 2866,1298,
1093, 975, 740, 703 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 8.6
Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.82 (dddd, J = 16.9, 10.2, 7.6, 6.6 Hz,
1H), 5.07ꢀ4.99 (m, 2H), 4.46 (s, 2H), 4.20ꢀ4.12 (m, 1H), 3.81 (s, 3H),
3.77ꢀ3.71 (m, 1H), 3.72 (td, J = 9.3, 4.7 Hz, 1H), 3.65 (td, J = 9.2, 3.8 Hz,
1H), 3.59 (br. s, 1H), 2.97 (br. s, 1H), 2.35ꢀ2.28 (m, 1H), 1.97ꢀ1.88 (m,
2H), 1.71ꢀ1.55 (m, 4H), 0.87 (d, J = 6.8 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 159.3, 137.5, 129.7, 129.3, 115.9, 113.8, 73.0, 72.3, 69.9, 69.2,
55.2, 39.0, 38.6, 37.2, 36.1, 15.1; HRMS calcd for C18H28O4Na (M þ Na)þ
331.1885; found 331.1877 (TOF MS ESþ).
(4S,5R,7S)-9-((4-Methoxybenzyl)oxy)-4-methyl-7-((triiso-
propylsilyl)oxy)non-1-en-5-ol (16). To a stirring solution of diol 6
(50 mg, 0.16 mmol) in CH2Cl2 (4 mL) was added 2,6-lutidine (70 mg,
0.65 mmol), and the mixture was cooled to ꢀ78 °C. TIPSOTf (100 mg,
0.32 mmol) was added dropwise, and the reaction mixture was stirred for
2 h and then allowed to slowly warm to 0 °C. After completion of the
reaction, as monitored by TLC, it was quenched with sat. NH4Cl, and the
layers were separated. The aqueous layer was extracted with CH2Cl2 (2 ꢁ
5 mL), dried (Na2SO4), and concentrated under reduced pressure. Flash
column chromatography (1:10 EtOAc/Hexane) afforded the desired silyl
ether 16 (64 mg, 86%) as a viscous oil; [R]D = þ12.88 (c = 1.35, CHCl3);
1
FTIR (neat) 3406, 2923, 2850, 1265, 1095, 740, 703 cmꢀ1; H NMR
(500 MHz, CDCl3) δ 7.24 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H),
5.78 (dddd, J = 16.9, 10.3, 7.5, 6.8 Hz, 1H), 5.06ꢀ4.95 (m, 2H), 4.41 (dd,
J = 39.1, 11.6 Hz, 2H), 4.36ꢀ4.31 (m, 1H), 3.83 (d, J = 0.9 Hz, 1H), 3.81
(s, 3H), 3.80ꢀ3.76 (m, 1H), 3.50ꢀ3.39 (m, 2H), 2.25ꢀ2.17 (m, 1H),
2.10ꢀ1.93 (m, 2H), 1.89ꢀ1.80 (m, 1H), 1.76ꢀ1.65 (m, 1H), 1.64ꢀ1.50
(m, 2H), 1.08 (s, 12H), 1.06 (s, 9H), 0.83 (d, J = 6.8 Hz, 3H); 13C NMR
(126 MHz, CDCl3) δ 159.2, 137.7, 130.3, 129.3, 129.2, 115.6, 113.7, 72.6,
71.6, 70.2, 66.3, 55.2, 38.9, 36.8, 36.3, 35.5, 18.1, 18.1, 17.7, 14.7, 12.3,
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ARTICLE
12.3; HRMS calcd for C27H48O4SiNa (M þ Na)þ 487.3220; found
487.3210 (TOF MS ESþ).
4.40 (s, 2H), 3.78 (s, 3H), 3.64 (ddd, J = 39.4, 15.7, 6.1 Hz, 2H), 3.58ꢀ3.51
(m, 3H), 3.37 (s, 3H), 2.11ꢀ1.98 (m, 3H), 1.97ꢀ1.88 (m, 1H), 1.88ꢀ1.70
(m, 3H), 0.89 (d, J = 6.7 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.7,
162.3, 159.1, 142.4, 137.7, 136.9, 134.0, 130.1, 129.3, 122.3, 116.12, 116.0,
115.5, 113.7, 112.7, 112.6, 96.5, 78.0, 72.8, 71.8, 66.4, 55.9, 55.2, 39.9, 37.5,
36.0, 35.2, 34.8, 13.5; HRMS calcd for C30H40O7Na (MþNa)þ 535.2672;
found 535.2627 (TOF MS ESþ).
(5R,7S)-9,9-Diisopropyl-7-(2-((4-methoxybenzyl)oxy)ethyl)-
10-methyl-5-((S)-pent-4-en-2-yl)-2,4,8-trioxa-9-silaundecane
(17). To a stirring solution of silyl ether 16 (60 mg, 0.129 mmol) in
anhydrous CH2Cl2 (5 mL), under argon, were added iPr2NEt (167 mg,
1.292 mmol) and MOMCl (52 mg, 0.646 mmol) at 0 °C. The reaction
was stirred at rt for 3ꢀ4 h. Upon completion (monitored by TLC), the re-
action was diluted with CH2Cl2 (5 mL) followed by a sat. NH4Cl solution
(10 mL), and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (2 ꢁ 10 mL), and the combined organic layers were washed
with brine (1 ꢁ 10 mL), dried(Na2SO4), filtered, and concentratedunder
reduced pressure. The crude reaction mixture was purified through flash
column chromatography (1:10 EtOAc/hexane) to afford MOM-ether 17
(60 mg, 92%) as a clear oil; [R]D = þ9.12 (c = 1.08, CHCl3); FTIR
(3S,5R,6S)-1-((4-Methoxybenzyl)oxy)-5-(methoxymethoxy)-
6-methylnon-8-en-3-yl 2-allyl-6-methoxybenzoate (20). To a
suspension of NaH (∼2 mg, 0.078 mmol, 60% w/v dispersion in mineral
oil) in anhydrous THF (1 mL) was added, dropwise, a solution of ester 19
(20 mg, 0.039) in anhydrous THF (2 mL). To this reaction mixture MeI
(22 mg, 0.156 mmol) was added, and stirring was continued for 1 h at rt.
The reaction mixture was quenched with cold water (2 mL), and the layers
were separated. The aqueous layer was extracted with EtOAc (3 ꢁ 5 mL),
and the combined organic layers were rinsed with brine (1 ꢁ 8 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. Flash column
chromatography (1:3 EtOAc/Hexane) afforded the methyl ether 20
(19 mg, 90%) as a viscous oil; [R]D = ꢀ1.6 (c = 0.50, CHCl3); FTIR
(neat) 2952, 2925, 2852, 1641, 1265, 1069, 1033, 748, 703 cmꢀ1; 1H
NMR (500 MHz, CDCl3) δ 7.31ꢀ7.27 (m, 3H), 6.88 (d, J = 8.7 Hz,
2H), 6.83 (d, J = 7.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 5.93 (dddd, J =
16.7, 10.2, 6.5, 6.5 Hz, 1H), 5.75 (dddd, J = 16.8, 10.2, 7.4, 6.5 Hz, 1H),
5.51ꢀ5.42 (m, 1H), 5.10ꢀ5.03 (m, 2H), 5.00ꢀ4.90 (m, 2H), 4.73 (dd,
J = 11.4, 6.8 Hz, 2H), 4.46 (dd, J = 25.3, 11.3 Hz, 2H), 3.81 (s, 3H), 3.80
(s, 3H), 3.73ꢀ3.69 (m, 1H), 3.66ꢀ3.56 (m, 2H), 3.41 (s, 3H), 3.36 (d, J =
6.4 Hz, 2H), 2.11ꢀ1.98 (m, 3H), 1.97ꢀ1.89 (m, 1H), 1.88ꢀ1.79 (m,
1H), 1.77ꢀ1.67 (m, 2H), 0.91 (d, J = 7.0 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 167.9, 159.1, 156.2, 138.1, 137.1, 136.4, 130.5, 130.2, 129.2,
124.1, 121.6, 116.4, 115.8, 113.7, 108.7, 97.0, 78.3, 72.7, 70.7, 55.8, 55.5,
55.3, 37.6, 37.2, 36.5, 35.3, 35.2, 13.7; HRMS calcd for C31H42O7Na
(M þ Na)þ 549.2833; found 549.28631(TOF MS ESþ).
1
(neat): 2923, 2850, 1460, 1265, 1097, 1039, 748, 703 cmꢀ1; H NMR
(500 MHz, CDCl3) δ 7.26 (d, J = 8.9 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H),
5.78 (dddd, J = 17.1, 10.2, 6.9, 6.4 Hz, 1H), 5.07ꢀ4.96 (m, 2H), 4.66 (dd,
J = 10.4, 6.8Hz, 2H), 4.43 (dd, J =14.8, 11.5Hz, 2H), 4.12ꢀ4.06 (m, 1H),
3.81 (s, 3H), 3.64 (ddd, J = 9.8, 6.6, 2.6 Hz, 1H), 3.57ꢀ3.52 (m, 2H), 3.36
(s, 3H), 2.15ꢀ2.08 (m, 1H), 1.94ꢀ1.80 (m, 3H), 1.67ꢀ1.60 (m, 2H),
1.52 (ddd, J = 14.2, 7.4, 3.4 Hz, 1H), 1.06 (br. s, 18H), 1.06ꢀ1.04 (m,
3H), 0.89 (d, J = 6.5 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 159.0,
137.5, 130.7, 129.2, 115.7, 113.7, 96.6, 79.9, 72.6, 68.1, 66.5, 55.7, 55.3,
38.3, 38.1, 37.1, 36.5, 18.3, 18.3, 14.2, 12.9; HRMS: calcd for C29H52O5S-
iNa (M þ Na)þ 531.3482; found 531.3502 (TOF MS ESþ).
(3S,5R,6S)-1-((4-Methoxybenzyl)oxy)-5-(methoxymethoxy)-
6-methylnon-8-en-3-ol (18). A solution of protected triol 17 (52 mg,
0.110 mmol) in anhydrous THF (2 mL) was treated with TBAF (1 M in
THF, 0.3 mL) at 0 °C and stirred for 2 h at rt. After completion of the re-
action, as monitored by TLC, the reaction mixture was concentrated under
reduced pressure. The crude product was purified through flash column
chromatography (1:6 EtOAc/hexane) to afford alcohol 18 (34 mg, 95%) as
a viscous oil; [R]D = þ38.6 (c = 1.00, CHCl3); FTIR (neat) 3412, 2921,
2856, 1298, 1093, 975, 749, 703 cmꢀ1;1H NMR (500 MHz, CDCl3) δ7.25
(d, J = 8.6 Hz, 2H), 6.92ꢀ6.87 (d, J = 8.6 Hz, 2H), 5.78 (ddt, J = 17.0, 10.1,
7.0 Hz, 1H), 5.05ꢀ4.99 (m, 2H), 4.69 (dd, J = 10.1, 6.6 Hz, 2H), 4.45 (s,
2H), 4.05ꢀ3.96 (m, 1H), 3.81 (s, 3H), 3.75ꢀ3.60 (m, 3H), 3.41 (s, 3H),
3.31 (d, J = 3.4 Hz, 1H), 2.19ꢀ2.12 (m, 1H), 1.89ꢀ1.81 (m, 2H),
1.81ꢀ1.68 (m, 2H), 1.52 (dddd, J = 32.1, 14.2, 9.6, 2.8 Hz, 2H), 0.88 (d, J =
6.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 159.2, 137.2, 130.2, 129.3,
115.9, 113.8, 96.9, 79.0, 72.8, 68.3, 66.8, 55.9, 55.2, 37.6, 37.4, 37.0, 36.5,
14.2; HRMS calcd for C20H32O5Na (MþNa)þ 375.2147; found 375.2146
(TOF MS ESþ).
(3S,5R,6S,E)-14-Methoxy-3-(2-((4-methoxybenzyl)oxy)-
ethyl)-5-(methoxymethoxy)-6-methyl-3,4,5,6,7,10-hexahydro-
1H-benzo[c][1]oxacyclododecin-1-one (3). Grubbs catalyst
(Cy3P)2Cl2RudCHPh (∼3 mg, 10 mol %, cat-A) was added to a
solution of methyl ether 20 (14 mg, 0.026 mmol) in degassed, anhydrous
CH2Cl2 (5 mL) atrt under argon. The stirring solutionwas equipped with
a reflux condenser and placed into an oil bath at 40 °C for 1 h. After
completion of the reaction, as monitored by TLC, the reaction mixture
was concentrated under reduced pressure. Flash column chromatography
(1:4 EtOAc/Hexane) afforded the major E-isomer 3 (11 mg, 82%) as a
viscous oil (containing a small amount of Z-isomer, the E/Z ratio was 10:1
asdeterminedby1H NMR ofthecrude reaction); [R]D = ꢀ41.7(c =0.35,
CHCl3); FTIR (neat) 2942, 2911, 2850, 1649, 1266, 1239, 1064, 1033,
908, 748, 702 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 8.8 Hz,
2H), 7.23 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.4 Hz,
1H), 6.77 (d, J = 7.7 Hz, 1H), 5.53ꢀ5.45 (m, 2H), 5.35 (ddt, J = 15.2, 9.5,
2.1 Hz, 1H), 4.85 (dd, J = 46.3, 6.7 Hz, 2H), 4.48 (s, 2H), 4.16 (dd, J = 9.3,
3.6 Hz, 1H), 3.81 (s, 3H), 3.76ꢀ3.70 (m, 1H), 3.72 (s, 3H), 3.66 (t, J = 6.8
Hz, 2H), 3.44 (s, 3H), 3.33 (ddd, J = 14.0, 4.1, 2.1 Hz, 1H), 2.31 (d, J =
13.3 Hz, 1H), 2.13 (ddd, J = 18.8, 12.2, 6.2 Hz, 1H), 2.08ꢀ1.98 (m, 1H),
1.91 (dtd, J = 11.6, 7.4, 4.1 Hz, 1H), 1.82ꢀ1.65 (m, 2H), 1.46 (dd, J =
15.5, 9.4 Hz, 1H), 0.87 (d, J = 6.8 Hz, 3H); 13C NMR (126 MHz, CDCl3)
δ 168.2, 159.1, 156.4, 139.1, 131.4, 130.7, 129.9, 129.0, 128.5, 124.5, 122.8,
113.7, 109.8, 96.8, 79.2, 72.6, 72.2, 66.6, 55.6, 55.3, 55.3, 37.7, 37.7, 36.4,
35.7, 34.0, 13.4; HRMS calcd for C29H38O7Na (M þ Na)þ 521.2515;
found 521.2525 (TOF MS ESþ).
(3S,5R,6S)-1-((4-Methoxybenzyl)oxy)-5-(methoxymethoxy)-
6-methylnon-8-en-3-yl 2-allyl-6-hydroxybenzoate (19). To a
suspension of NaH (24 mg, 0.852 mmol, 60% w/v dispersion in mineral
oil) in anhydrous THF (2 mL), under argon, was added, dropwise, a solu-
tion of alcohol 18 (30 mg, 0.085) in anhydrous THF (1 mL) at 0 °C. The
reaction mixture was stirred for 15 min at 0 °C. A solution of benzodiox-
inone 5 (37 mg, 0.170 mmol) in THF (1 mL) was added dropwise via
cannula to the mixture, and the reaction was warmed to rt and stirred for 6 h.
The reaction was quenched with saturated NH4Cl (5 mL), and the layers
were separated. The aqueous layer was extracted with EtOAc (3 ꢁ 5 mL),
and the combined organic layers were rinsed with brine (1 ꢁ 10 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. Flash column
chromatography (1:4 EtOAc/Hexane) afforded ester 19 (29 mg, 66%) as a
viscous oil, along with recovered starting material (9 mg); [R]D = þ12.3
(c = 1.00, CHCl3) FTIR (neat) 3435, 3053, 2956, 2925, 2854, 1646, 1265,
1033, 748, 703 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 11.17 (s, 1H), 7.32
(t, J = 7.9 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 6.88 (dd, J = 8.3, 1.1 Hz, 1H),
6.82 (d, J = 8.8 Hz, 2H), 6.72 (dd, J = 7.4, 1.1 Hz, 1H), 5.97 (dddd, J = 16.9,
10.2, 6.1, 6.1 Hz, 1H), 5.72 (dddd, J = 17.0, 10.1, 7.0, 7.0 Hz, 1H),
5.62ꢀ5.56 (m, 1H), 5.03ꢀ4.90 (m, 4H), 4.63 (dd, J = 41.5, 6.9 Hz, 2H),
(3S,5R,6S)-5-Hydroxy-1-((4-methoxybenzyl)oxy)-6-meth-
ylnon-8-en-3-yl 2-allyl-6-hydroxybenzoate (21a). To a solu-
tion of diol 6 (50 mg, 0.16 mmol) in anhydrous THF (2 mL) was added,
dropwise, NaHMDS (1 M in THF, 1.3 mL) at ꢀ20 °C, and the reaction
mixture was stirred for 15 min at ꢀ20 °C. A solution of benzodioxinone
5 (42 mg, 0.14 mmol) in THF (1 mL) was added dropwise via cannula
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The Journal of Organic Chemistry
ARTICLE
to the reaction mixture, and the combined mixture was warmed to 0 °C
and stirred for 6 h. The reaction was quenched with saturated NH4Cl,
and the layers were separated. The aqueous layer was extracted with
EtOAc (3 ꢁ 5 mL), and the combined organic layers were rinsed with
brine (1 ꢁ 10 mL), dried (Na2SO4), filtered, and concentrated under
reduced pressure. Flash column chromatography (1:5 EtOAc/Hexane)
yielded both isomers 21a (32.8 mg) and 21b (9.2 mg) as viscous oils
(65% overall yield); [R]D = ꢀ10.0 (c = 0.25, CHCl3); FTIR (neat)
(3S,5R,6S,E)-3-(2-((4-Methoxybenzyl)oxy)ethyl)-5,14-bis-
(methoxymethoxy)-6-methyl-3,4,5,6,7,10-hexahydro-1H-
benzo[c][1]oxacyclododecin-1-one (4). Grubbs catalyst (Cy3P)2Cl2-
RudCHPh (∼3 mg, 10 mol %, cat-A) was added to a solution of
compound 22 (15 mg, 0.027 mmol) in degassed, anhydrous CH2Cl2
(5 mL) at rt under argon. The stirring solution was equipped with a reflux
condenser and placed into an oil bath at 40 °C for 1 h. After completion of
the reaction, as monitored by TLC, the reaction mixture was concentrated
under reduced pressure. Flash column chromatography (1:5 EtOAc/
Hexane) afforded macrolide 4 (12 mg, 84%) as a viscous oil (a small
amount of Z-isomer was observed; the E/Z ratio was 9:1 as determined by
1H NMR of the crude reaction); [R]D = ꢀ29.6 (c = 0.65, CHCl3); FTIR
(neat): 2952, 2921, 2850, 1639, 1263, 1249, 1064, 908, 736, 702 cmꢀ1; 1H
NMR (500 MHz, CDCl3) δ 7.27 (d, J = 8.6 Hz, 2H), 7.21 (dd, J = 8.3, 7.7
Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 7.6
Hz, 1H), 5.53ꢀ5.46 (m, 2H), 5.39ꢀ5.31 (m, 1H), 5.07 (s, 2H), 4.85 (dd,
J = 44.1, 6.8 Hz, 2H), 4.47 (s, 2H), 4.14 (dd, J = 9.3, 3.6 Hz, 1H), 3.81 (s,
3H), 3.73 (dd, J = 16.4, 9.5 Hz, 1H), 3.69ꢀ3.64 (m, 2H), 3.44 (s, 3H),
3.40 (s, 3H), 3.34 (ddt, J = 16.4, 4.5, 2.3 Hz, 1H), 2.35ꢀ2.28 (m, 1H),
2.19ꢀ2.09 (m, 1H), 2.07ꢀ1.99 (m, 1H), 1.96ꢀ1.89 (m, 1H), 1.80ꢀ1.67
(m, 2H), 1.48 (dd, J = 15.4, 9.4 Hz, 1H), 0.88 (d, J = 6.8 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 168.0, 159.1, 154.2, 139.1, 131.3, 130.6,
129.9, 129.0, 128.5, 125.3, 123.9, 113.7, 112.8, 96.9, 94.4, 79.4, 72.6, 72.2,
66.5, 56.0, 55.6, 55.3., 37.7, 37.7, 36.4, 35.5, 34.0, 13.4; HRMS calcd for
C30H40O8Na (M þ Na)þ 551.2621; found 551.2605 (TOF MS ESþ).
1
3435, 3053, 2956, 2925, 2854, 1656, 1265, 748, 703 cmꢀ1; H NMR
(500 MHz, CDCl3) δ 11.05 (s, 1H), 7.31(dd, J = 8.2, 7.6 Hz, 1H), 7.17
(d, J = 8.6, Hz, 2H), 6.87 (dd, J = 8.2, 1.1 Hz, 1H), 6.79 (d, J = 8.6 Hz,
2H), 6.71(dd, J = 7.5, 1.1 Hz, 1H), 5.95 (dddd, J = 16.9, 10.2, 6.0, 6.0 Hz,
1H), 5.76 (dddd, J = 16.9, 10.2, 7.6, 6.6 Hz, 1H), 5.66ꢀ5.60 (m, 1H),
5.01ꢀ4.93 (m, 3H), 4.89ꢀ4.83 (m, 1H), 4.38 (dd, J = 23.2, 11.5 Hz,
2H), 3.75 (s, 3H), 3.66 (dd, J = 15.7, 5.9 Hz, 1H), 3.55 (dd, J = 15.7, 5.9
Hz, 1H), 3.53ꢀ3.47 (m, 2H), 3.41ꢀ3.34 (m, 1H), 2.66 (d, J = 4.4 Hz,
1H), 2.27ꢀ2.21 (m, 1H), 2.10ꢀ1.94 (m, 2H), 1.91ꢀ1.78 (m, 2H),
1.71ꢀ1.64 (m, 1H), 1.62ꢀ1.57 (m, 1H), 0.84 (d, J = 6.8 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 171.4, 162.6, 159.8, 142.6, 137.7, 137.2,
134.4, 129.9, 129.4, 122.7, 116.4, 116.8, 115.4, 113.7, 112.2, 72.8, 71.8,
70.7, 66.7, 55.2, 40.0, 39.1, 38.6, 37.0, 35.1, 15.6; HRMS calcd for
C28H36O6Na (M þ Na)þ 491.2410; found 491.2420 (TOF MS ESþ).
(4S,5R,7S)-7-Hydroxy-9-((4-methoxybenzyl)oxy)-4-meth-
ylnon-1-en-5-yl 2-allyl-6-hydroxybenzoate (21b). [R]D = þ2.0
(c = 0.25, CHCl3); FTIR (neat): 3439, 3046, 2950, 2931, 2867, 1661,
1243, 742, 729, 703 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 11.26 (s, 1H),
7.35 (dd, J = 8.1, 7.6 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 6.91 (dd, J = 7.6, 1.1
Hz, 1H), 6.83 (d, J = 8.2 Hz, 2H), 6.76 (dd, J = 7.5, 1.1 Hz, 1H),
6.03ꢀ5.84 (m, 1H), 5.84ꢀ5.71 (m, 1H), 5.51ꢀ5.43 (m, 1H), 5.08ꢀ4.95
(m, 3H), 4.93ꢀ4.86 (m, 1H), 4.38 (dd, J = 21.1, 12.2 Hz, 2H), 3.79 (s,
3H), 3.78ꢀ3.76 (m, 1H), 3.68ꢀ3.50 (m, 3H), 3.31ꢀ3.27 (m, 1H),
2.31ꢀ2.23 (m, 1H), 2.04ꢀ1.90 (m, 2H), 1.87ꢀ1.65 (m, 4H), 0.97 (d,
J = 6.7 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 171.4, 162.9, 159.2,
142.4, 137.6, 136.1, 134.3, 132.5, 129.3, 122.6, 116.8, 116.3, 115.5, 113.8,
112.1, 76.6, 73.0, 68.0, 66.5, 55.6, 39.9, 38.5, 37.1, 36.9, 36.7, 15.2;
HRMS calcd for C28H36O6Na (M þ Na)þ 491.2410; found 491.2415
(TOF MS ESþ).
’ ASSOCIATED CONTENT
S
Supporting Information. Spectroscopicdata ofnew com-
b
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: phanson@ku.edu.
(3S,5R,6S)-1-((4-Methoxybenzyl)oxy)-5-(methoxymethoxy)-
6-methylnon-8-en-3-yl 2-allyl-6-(methoxymethoxy)benzoate
(22). To a solution of ester 21a (25 mg, 0.053 mmol) in anhydrous
DCE (5 mL), under argon, was added iPr2NEt (69 mg, 0.53 mmol) and
MOMCl (43 mg g, 0.53 mmol) at rt. The stirring solution was equipped
with a reflux condenser and placed into an oil bath at 90 °C for 3ꢀ4 h.
Upon completion (monitored by TLC), the reaction was diluted with
CH2Cl2 (5 mL), followed by a saturated NH4Cl solution (6 mL), and the
layers were separated. The aqueous layer was extracted with CH2Cl2
(2 ꢁ 10 mL), and the combined organic layers were washed with brine
(1 ꢁ 10 mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude reaction mixture was purified through flash column
chromatography (1:4 EtOAc/hexane) to afford title compound 22
(25 mg, 86%) as a clear oil; [R]D = þ5.27 (c = 0.55, CHCl3); FTIR
(neat): 2952, 2925, 2852, 1641, 1265, 1033, 748, 703 cmꢀ1; 1H NMR
(500 MHz, CDCl3) δ 7.30ꢀ7.24 (m, 3H), 7.04 (d, J = 7.9 Hz, 1H),
6.90ꢀ6.86 (m, 3H), 5.94 (dddd, J = 16.7, 10.2, 6.6, 6.6 Hz, 1H), 5.73
(dddd, J = 16.9, 10.2, 7.5, 6.6 Hz, 1H), 5.49ꢀ5.42 (m, 1H), 5.16 (dd, J =
26.3, 6.9 Hz, 2H), 5.10ꢀ5.03 (m, 2H), 4.99ꢀ4.90 (m, 2H), 4.72 (dd, J =
12.8, 6.9 Hz, 2H), 4.46 (dd, J = 21.6, 11.3 Hz, 2H), 3.81 (s, 3H),
3.70ꢀ3.57 (m, 3H), 3.45 (s, 3H), 3.41 (s, 3H), 3.37 (d, J = 6.5 Hz, 2H),
2.13ꢀ1.97 (m, 3H), 1.95ꢀ1.77 (m, 2H), 1.76ꢀ1.71 (m, 2H), 0.90 (d, J =
6.7 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 167.7, 159.1, 153.8, 138.1,
137.1, 136.3, 130.45, 130.2, 129.2, 124.9, 122.6, 116.5, 115.9, 113.7,
112.2, 96.8, 94.4, 78.2, 72.7, 70.8, 66.5, 56.0, 55.8, 55.7, 37.6, 37.2, 36.5,
35.4, 35.1, 13.7; HRMS calcd for C32H44O8K (M þ K)þ 595.2673;
found 595.2653 (TOF MS ESþ).
’ ACKNOWLEDGMENT
This investigation was generously supported by funds pro-
vided by the National Institute of General Medical Sciences
(NIH RO1 GM077309). The authors thank Dr. Justin Douglas
and Sarah Neuenswander for assistance with NMR measure-
ments and Dr. Todd Williams for HRMS analysis. The authors
also thank Materia, Inc. for supplying metathesis catalyst and
helpful suggestions.
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