Synthesis of the C3-14 fragment of palmerolide A using a chiral pool based strategy

Article abstract of DOI:10.1016/j.tet.2009.12.007

Palmerolide A, a potent and selective inhibitor of melanoma cell growth, is a macrocylic polyketide isolated from the Antarctic tunicate Synoicum adareanum. Palmerolide A targets transmembrane proton pumps, the vacuolar-ATPases, and induces autophagy, but

Full text of DOI:10.1016/j.tet.2009.12.007

Tetrahedron 66 (2010) 1557–1562
Contents lists available at ScienceDirect
Tetrahedron
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Synthesis of the C3–14 fragment of palmerolide A using a chiral pool based
strategy
*
Matthew D. Lebar, Bill J. Baker
Department of Chemistry and Center for Molecular Diversity in Drug Design, Discovery and Delivery, University of South Florida, 4202 E. Fowler Ave CHE205, Tampa, FL 33620, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 October 2009
Received in revised form 25 November 2009
Accepted 2 December 2009
Available online 11 December 2009
Palmerolide A, a potent and selective inhibitor of melanoma cell growth, is a macrocylic polyketide
isolated from the Antarctic tunicate Synoicum adareanum. Palmerolide A targets transmembrane proton
pumps, the vacuolar-ATPases, and induces autophagy, but in a manner independent of HIF-1a activation.
Herein we report a synthesis of the C3–14 fragment of palmerolide A using readily available polyols as
chiral building blocks for entry into structure/activity studies of the macrocycle.
Ó 2009 Published by Elsevier Ltd.
Keywords:
Tunicate
Macrolide
Melanoma
1. Introduction
compared to synthetic analogs generated from commercially
available sugar derivatives 4 and 5, resulting in the reassignment of
The palmerolides are a family of macrocylic polyketides found in
the abundant Antarctic tunicate Synoicum adareanum collected at
the National Science Foundation’s Palmer Station, on the Antarctic
peninsula.1 The major metabolite, palmerolide A (1), displays
18 nM inhibition of UACC-66 melanoma and includes among its
biochemical targets the pH regulatory vacuolar-ATPase (V-ATPase),
for which it is a potent inhibitor (IC50¼2 nM). V-ATPases are largely
responsible for cellular and organellular pH regulation but have
been implicated in cancer treatment2 due in part to the low pH
requirement and concomitant overexpression of V-ATPases of some
cancer cell types.3 In ongoing studies at the National Cancer In-
stitute at Frederick (Anne Monks, personal communication), pal-
merolide A induced markers of autophagy and the transcription
the C7, 10, and 11 configuration of palmerolide A.5
factor Hypoxia Induction Factor-1a (HIF-1a), but the mechanism
underlying palmerolide A-induced cell death in human tumor cells
remains unclear. Palmerolide A remains of interest for development
due, in contrast to other V-ATPase inhibitors such as bafilomycin,4
to its lack of neurotoxicity at therapeutic levels.
The original1 stereochemical assignment of palmerolide A was
based on derivitization and 2D NMR techniques, leading to sub-
sequent degradation studies of the natural product.5 The degra-
dation took advantage of the fact that reductive ozonolysis
(Scheme 1) of palmerolide A yielded, among other products, polyols
2 and 3. Polyols 2 and 3, derived from palmerolide A, were
Scheme 1. Polyol targets (2, 3) generated from ozonolysis of palmerolide A (1).
Total synthesis of ent-palmerolide A by De Brabander6 followed
by total synthesis of the natural enantiomer by Nicolaou7 con-
firmed that C7, 10, and 11 were indeed mis-assigned in the original
paper. Several partial syntheses of palmerolide A have since been
reported.8 With the correct absolute configuration of the core
polyol fragment determined, our efforts were directed toward the
* Corresponding author. Tel.: þ1 813 974 1967; fax: þ1 813 974 1733.
E-mail address: bjbaker@cas.usf.edu (B.J. Baker).
0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.12.007

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M.D. Lebar, B.J. Baker / Tetrahedron 66 (2010) 1557–1562
reconstruction of palmerolide A based on our degredative polyols.
The utility of this synthetic approach is reflected in the availability
of a wide variety of chiral polyols, derived from sugars, which
would lead to isomers, homologs and higher-oxygenated de-
rivatives for structure/activity (SAR) or structure/property (SPR)
studies.
refluxing conditions11 yielded a thioether intermediate, which
could then be oxidized with catalytic amounts of sodium tung-
state, phenylphosphonic acid, methyltrioctylammonium hydro-
gensulfate and an excess of 30% hydrogen peroxide12 to generate
sulfone 6.
Turning our attention to aldehyde 7, comprising C9–C14, prep-
aration was achieved in five steps from commercially available ketal
5 (Scheme 4). Monobenzylated13 ketal 5 was oxidized and the
subsequent aldehyde underwent Wittig olefination to an in-
separable mixture of E/Z isomers (12). E-12 could be obtained ex-
clusively using HWE conditions.
2. Results and discussion
We envisioned (Scheme 2) reconstructing the ozonolysis prod-
ucts, or alternate polyols, utilizing any number of olefination
methods and aimed for the palmerolide A C8/C-9 construction
based on the Julia–Kocienski protocol,9 which has previously been
used to prepare trans-olefins bearing allylic alkoxy groups.10
Compostella et al.10 demonstrate that Julia–Kocienski olefination is
useful in constructing trans-olefins with an
a
-alkoxy aldehyde and
-elimination ob-
an aliphatic sulfone or an -alkoxy sulfone (no
b
b
served) and aliphatic aldehyde, but to our knowledge no examples
exist in which both coupling components contain alkoxy sub-
stituents. Applying Julia–Kocienski methodology to our polyols, we
envisioned the E-alkene at C8-C9 could be formed from sulfone 6,
which could be derived from polyol 2, by coupling with aldehyde 7,
similarly derived from polyol 3.
Scheme 4. Preparation of aldehyde 7 and alkene 16.
Hydrogenation of both isomers reduced the olefin and depro-
tected the benzyl ether, setting up treatment with Dess–Martin
periodinane (DMP) to yield the desired aldehyde (7), which could
be used for alternate methods (vis 16, see below).
Attempts at coupling 6 and 7 using Julia–Kocienski methodol-
ogy were not successful in our hands, yielding low recoveries of
Scheme 2. Julia–Kocienski path to polyol coupling.
unreacted starting material with no evidence of b-elimination of
the TBS ether in 6.
The synthesis of triol 2 was modified to generate sulfone 6
(C3–C8) from alcohol 95 (Scheme 3). Anticipating an olefin ring
closing metathesis reaction to form the macrolide portion of
palmerolide A, intermediate terminal alkene 10 was required.
Dess–Martin oxidation of the primary alcohol 9 followed by
Wittig olefination and hydrolysis yielded the desired alkene 10.
Monotosylation followed by silylation of the free secondary al-
cohol led to sulfone precursor 11. Treating tosylate 11 with 1-
phenyl-1H-tetrazole-5-thiol and potassium carbonate under
A route to join fragments derived from 2 and 3 was devised
utilizing olefin cross metathesis.14 We chose Grubbs second gen-
eration catalyst because Type II/Type III cross couplings are pre-
dicted to produce moderate to high yields with little to no
homodimerization.15 The new route required each fragment ter-
minate in an olefin. The synthesis of a fragment bearing the pal-
merolide A (1) C3–8 centers (e.g., 6) was modified to produce
olefin-metathesis substrate 15 (Scheme 5). Benzylation followed by
acid hydrolysis of intermediate 9 resulted in the formation of diol
Scheme 3. Preparation of sulfone 6.
Scheme 5. Preparation of olefin 15.

M.D. Lebar, B.J. Baker / Tetrahedron 66 (2010) 1557–1562
1559
13. A one pot protecting group manipulation produced secondary
acetate 14. Dess–Martin oxidation and Wittig olefination resulted
in the formation of terminal olefin 15. The fragment bearing the
palmerolide A (1) C9–14 segment, 16 (Scheme 4), was derived from
aldehyde 7 by a Wittig reaction.
4.1.1. Preparation of (S)-hept-6-ene-1,2-diol (10). To 10 mL dry DCM
at ꢀ60 ꢁC was added oxalyl chloride (787 mg, 6.20 mmol, 0.525 mL,
2.0 equiv). After stirring for 5 min, DMSO (605 mg, 7.75 mmol,
0.55 mL, 2.5 equiv) was added. After stirring 2 min, 9 (540 mg,
3.10 mmol, 1 equiv) dissolved in 3 mL dry DCM was added over
a 5 min period. After stirring for an additional 10 min at ꢀ60 ꢁC,
TEA (1.88 g, 18.6 mmol, 2.6 mL, 6 equiv) was added. The mixture
was then warmed to rt and partitioned between EtOAc and water.
The organic layer was collected. The aqueous layer was washed 2ꢂ
with aliquots of EtOAc. The organic layers were combined, dried
over anhydrous MgSO4, and concentrated to afford the aldehyde
(S)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)butanal (488 mg, 2.83 mmol,
Combination of olefins 15 and 16 (Scheme 6) using Grubbs
second generation catalyst proceeded smoothly to generate the
desired E isomer, as predicted, in moderate yields (17, C3–14 of
palmerolide A) with no homodimers nor unreacted starting
material. Steric bulk at both allylic positions in the product may
explain why Z-17 was not observed. One cannot rule out the
possibility of E/Z isomerisation via secondary metathesis of 17,
which could also explain selective E-isomer formation. The fact
that no homodimers were found and only the E-isomer of 17 was
isolated suggests 15 and 16 may be reacting in a selective type II/
type III fashion as postulated by Grubbs et al.15 However, due to
the moderate yield of 17 and no evidence of either homodimer, it
is unclear of which olefin type (II or III) 15 and 16 should be
considered.
91%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d (multiplicity, J
(Hz), integration): 1.28 (s, 3H),1.34 (s, 3H),1.58 (m, 4H), 2.44 (dt, 7.3,
1.6, 2H), 3.45 (t, 7.1, 1H), 3.97 (t, 7.1, 1H), 4.0 (m, 1H), 9.71 (t, 1.6, 1H);
13C NMR (100 MHz, CDCl3)
109.1, 202.4.
d: 18.4, 25.9, 27.1, 33.1, 43.8, 69.5, 76.2,
To a stirring slurry of Ph3PCH3Br (1.95 g, 5.46 mmol, 2.0 equiv)
in dry THF (50 mL) at 0 ꢁC was added KHMDS (0.5 M in toluene,
10.92 mL, 5.46 mmol, 2.0 equiv) over a 10 min period. The mixture
was warmed to rt and stirred for 30 min. The mixture was cooled to
0 ꢁC and (S)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)butanal (470 mg,
2.72 mmol, 1.0 equiv) dissolved in 10 mL dry THF was added over
a 10 min period. The mixture stirred at 0 ꢁC for 1.5 h. Methanol
(0.6 mL) was added to quench the reaction. The mixture was di-
luted with Et2O and filtered through Celite. The filtrate was
concentrated and chromatographed by silica gel MPLC (eluting at
10–12% EtOAc in hexanes) to afford (S)-2,2-dimethyl-4-(pent-4-
enyl)-1,3-dioxolane as a colorless oil (260 mg, 1.53 mmol, 56%). 1H
NMR (400 MHz, CDCl3)
d (multiplicity, J (Hz), integration): 1.29 (s,
3H), 1.34 (s, 3H), 1.45 (m, 2H), 1.55 (m, 2H), 2.02 (dt, 6.8, 1.4, 2H),
3.44 (t, 7.4,1H), 3.96 (dt, 7.4, 5.8,1H), 3.99 (m,1H), 4.89 (m,1H), 4.94
(m, 1H), 5.73 (ddt, 17.2, 6.8, 3.5, 1H); 13C NMR (100 MHz, CDCl3)
25.1, 25.8, 27.1, 33.1, 33.7, 69.6, 76.2, 108.9, 115.0, 138.8.
d:
(S)-2,2-dimethyl-4-(pent-4-enyl)-1,3-dioxolane (233 mg, 1.37
mmol) was stirred in 5 mL 50% AcOH:H2O in a flask open to air for
Scheme 6. Construction of palmerolide A fragment C3–14.
2 h at rt. The solvent was then removed under a stream of air to
20
yield diol 10 as a colorless oil (164 mg, 1.26 mmol, 92%). [
(c 1.0, CHCl3); IR (neat)
NMR (400 MHz, CDCl3)
a]
ꢀ6.5
D
n
(cmꢀ1): 3365, 3079, 2935, 1070, 1039; 1H
(multiplicity, J (Hz), integration): 1.44
3. Conclusion
d
(m, 4H), 1.68 (br s, 1H), 2.03 (m, 2H), 2.07 (br s, 1H), 3.37 (dd, 10.8,
7.7, 1H), 3.59 (dd, 10.8, 3.0, 1H), 3.65 (m 1H), 4.93 (m, 2H), 5.74 (ddt,
In summary, we constructed 17, the C3–14 portion of palmer-
olide A, from commercially available chiral building blocks 4 and 5.
The total synthesis of palmerolide A based on this chiral pool ap-
proach is ongoing and when completed should offer a facile route
to a multitude of derivatives for use in SAR and SPR studies.
17.0, 6.6, 3.5, 1H); 13C NMR (100 MHz, CDCl3)
d: 24.9, 32.7, 33.7, 67.0,
72.3, 115.0, 138.7; ESI HRMS [MþNH4]þ calcd for [C7H18O2N]þ:
148.1332, found 148.1328.
4.1.2. Preparation of (S)-2-(tert-butyldimethyl silyloxy)hept-6-enyl
4-methylbenzenesulfonate (11). To a solution of tosyl chloride
(265 mg, 1.39 mmol, 1.1 equiv) and DMAP (15 mg, 0.13 mmol,
0.1 equiv) in 9 mL dry DCM and stirring at 0 ꢁC was added 10
(164 mg, 1.26 mmol, 1.0 equiv) dissolved in 1 mL dry DCM. The
solution stirred for 5 min, then TEA (141 mg, 0.2 mL, 1.39 mmol,
1.1 equiv) was added. The solution stirred at 0 ꢁC for 4 h and then rt
for 4 h. The solution was poured into a flask containing 20 mL ice,
20 mL H2O and 10 mL 2 N HCl. The resulting mixture was extracted
2ꢂ with 50 mL aliquots of DCM. The combined organic layers were
dried over anhydrous MgSO4 and concentrated under reduced
pressure. The crude concentrate was chromatographed by silica gel
MPLC to afford the monotosylated alcohol as a colorless oil (315 mg,
1.11 mmol, 88%). To the monotosylated alcohol (150 mg, 0.53 mmol,
1.0 equiv) in 5 mL dry DCM under stirring at 0 ꢁC was added 2,6-
lutidine (169 mg, 0.18 mL, 1.58 mmol, 3.0 equiv) then tert-butyldi-
methylsilyl trifluoromethanesulfonate (TBS-OTf, 348 mg, 0.30 mL,
1.32 mmol, 2.5 equiv). The mixture stirred for 2 h and was parti-
tioned between DCM/H2O. The organic layer was collected. The
aqueous layer was extracted 2ꢂ with aliquots of DCM. The
4. Experimental
4.1. General
Unless otherwise stated, all experiments were performed under
an atmosphere of nitrogen in oven-dried glassware equipped with
a magnetic stir bar and a rubber septum. All solvents used were
reagent grade. Anhydrous DCM was obtained by distillation from
CaH. Anhydrous THF was obtained by distillation from sodium/
benzophenone. All other chemicals were purchased from Sigma–
Aldrich and were used as received. Products were chromato-
graphed on
a Teledyne Isco Combiflash Companion MPLC
instrument using normal phase silica gel cartridges purchased from
Teledyne Isco. Melting points were recorded on an Electrothermal
Mel-Temp 3.0 instrument. IR spectra were recorded on a Nicolet
Avatar 320 spectrometer with a Smart Miracle accessory. HRMS
data was obtained on an Agilent LC/MSD TOF electrospray ioniza-
tion mass spectrometer. 1H and 13C NMR spectra were recorded on
a Varian 400 MHz using CDCl3.

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M.D. Lebar, B.J. Baker / Tetrahedron 66 (2010) 1557–1562
combined organic extracts were dried over anhydrous MgSO4,
concentrated under reduced pressure, and subjected to silica gel
(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (342
mg, 1.35 mmol, 1.0 equiv) dissolved in 5 mL dry DCM followed by
pyridine (534 mg, 0.54 mL, 6.75 mmol, 5.0 equiv). After 30 min at
rt, the mixture was quenched by addition of satd NaHCO3 (50 mL)
and 1 M Na2S2O3 solution (50 mL). This mixture was allowed to stir
until both layers were clear and was then partitioned between
EtOAc and water. The aqueous layer was extracted 2ꢂ with aliquots
of EtOAc. The combined organic layers were dried over anhydrous
MgSO4 and concentrated to yield the crude aldehyde (360 mg). A
slurry of (Ethoxycarbonylmethyl)triphenyl phosphonium bromide
(683 mg, 1.59 mmol, 1.1 equiv) and NaH (38 mg, 1.59 mmol,
1.1 equiv) in 50 mL dry THF at rt stirred for 4 h. The crude aldehyde
(360 mg, w1.44 mmol, 1 equiv) dissolved in 5 mL dry THF was then
added. The mixture stirred for 6 h and was then partitioned with
Et2O/H2O. The organic layer was collected. The aqueous layer was
extracted 2ꢂ with aliquots of Et2O. The combined organic layers
were dried over anhydrous MgSO4 and concentrated under reduced
pressure. The concentrate was chromatographed by silica gel MPLC
(eluting at 15% EtOAc/hexane) to afford a mixture of isomers of
conjugate ester 12 (298 mg, 0.93 mmol, 69%, two steps) as a color-
less oil. The E-isomer could be formed exclusively by substituting
MPLC to yield 11 as a colorless oil (215 mg, 0.53 mmol, quantita-
20
tive). [
a
]
ꢀ6.0 (c 0.4, CHCl3); IR (neat)
n
(cmꢀ1): 3079, 2952, 2857,
D
1170; 1H NMR (400 MHz, CDCl3)
d (multiplicity, J (Hz), integration):
0.01 (s, 3H), 0.02 (s, 3H), 0.83 (s, 9H), 1.39 (m, 4H), 2.00 (dt, 6.6, 6.6,
2H), 2.45 (s, 3H), 3.85 (m, 2H), 3.85 (m, 1H), 4.96 (m, 2H), 5.74 (ddt,
17.0, 6.6, 3.2, 1H) 7.34 (d, 8.0, 2H), 7.79 (d, 8.0, 2H); 13C NMR
(100 MHz, CDCl3)
d
: ꢀ4.8, ꢀ4.6, 21.6, 24.0, 25.7 (3C), 26.9, 33.4, 33.6,
69.8, 73.1, 114.7, 127.9 (2C), 129.8 (2C), 133.0, 138.3, 144.7; ESI HRMS
[MþH]þ calcd for [C20H35O4SSi]þ: 399.2020, found 399.2032.
4.1.3. Preparation of (S)-5-(2-(tert-butyldimethyl silyloxy) hept-6-
enylsulfonyl)-1-phenyl-1H-tetrazole (6). To 1-phenyl-1H-tetrazole-
5-thiol (288 mg, 1.62 mmol, 3.0 equiv) and potassium carbonate
(K2CO3, 372 mg, 2.60 mmol, 5 equiv) was added 11 (215 mg,
0.54 mmol, 1.0 equiv) dissolved in 5 mL dry acetone. The stirring
mixture refluxed for 20 h and was cooled to rt, and partitioned
between Et2O/H2O. The aqueous layer was extracted 2ꢂ with ali-
quots of Et2O. The combined organic extracts were dried over an-
hydrous MgSO4, concentrated under reduced pressure, and
subjected to silica gel MPLC to afford the thioether intermediate as
white needles (mp 35–36 ꢁC, 174 mg, 0.430 mmol, 80%). To the
thioether intermediate (103 mg, 0.254 mmol, 1.0 equiv) in 2 mL
(Ethoxycarbonylmethyl)triphenyl phosphonium bromide with
20
triethylphosphonoacetate (60%, two steps). E-12: [
a
]
ꢀ23.4 (c 1.0,
D
CHCl3); IR (neat)
(400 MHz, CDCl3)
n
(cmꢀ1): 2988, 1722, 1654, 1090; 1H NMR
(multiplicity, J (Hz), integration): 1.29 (t, 6.9,
EtOAc was added H2O2 (86
0.762 mmol, 3.0 equiv), sodium tungstate (Na2WO4$2H2O,170
a 5 mg/mL solution in EtOAc, 0.85 mg, 0.00254 mmol, 0.01 equiv),
phenylphosphonic acid (80 L of a 5 mg/mL solution in EtOAc,
0.4 mg, 0.00254 mmol, 0.01 equiv), and methyltrioctylammonium
hydrogensulfate (Oct3MeNHSO4, 240 L of a 5 mg/mL solution,
mL
30% solution, 26 mg H2O2,
d
mL of
3H), 1.44 (s, 3H), 1.45 (s, 3H), 3.63 (d, 4.7, 2H), 3.96 (dt, 8.4, 4.7, 1H),
4.20 (q, 6.9, 2H), 4.43 (ddd, 8.4, 5.6, 1.7, 1H), 4.60 (s, 2H), 6.09 (dd,
15.7, 1.7, 1H), 6.89 (dd, 15.7, 5.6, 1H), 7.34 (m, 5H). 13C NMR
m
(100 MHz, CDCl3) d: 14.3, 26.8, 27.1, 60.7, 69.5, 73.8, 77.6, 79.7, 110.3,
m
122.7, 127.8 (2C), 127.9, 128.6 (2C), 137.9, 144.2, 166.1. ESI HRMS
1.2 mg, 0.00254 mmol, 0.01 equiv). After 40 h the reaction was not
yet complete via TLC so another aliquot of sodium tungstate
(0.01 equiv), phenylphosphonic acid (0.01 equiv), Oct3MeNHSO4
(0.01 equiv), and (H2O2 3.0 equiv) was added. This mixture stirred
another 60 h and was partitioned between EtOAc and H2O. The
organic layer was dried over anhydrous MgSO4, concentrated and
chromatographed via silica gel MPLC afford a mixture of di-
astereomers of the partially oxidized sulfoxide (20 mg, 0.05 mmol,
[MþNa]þ calcd for [C18H24O5Na]þ: 343.1516, found 343.1510.
4.1.5. Preparation of ethyl 3-((4S,5R)-5-formyl-2,2-dimethyl-1,3-di-
oxolan-4-yl)propanoate (7). To activated 10% Pd/C (50 mg) was
added 12 (278 mg, 0.87 mmol) dissolved in 10 mL EtOH. A balloon
containing H2 gas was affixed to the flask. The mixture stirred for
12 h at rt, was diluted with EtOAc, and filtered through Celite. The
filtrate was concentrated to afford ethyl 3-((4S,5S)-5-(hydrox-
ymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propanoate as a colorless
20%) as well as desired sulfone 6 as a white solid (mp 62–64 ꢁC,
20
48 mg, 0.110 mmol, 43%). [
n
a
]
D
þ15.6 (c 0.4, CHCl3); IR (neat)
oil (194 mg, 0.84 mmol, 96%). 1H NMR (400 MHz, CDCl3)
d (multi-
plicity, J (Hz), integration): 1.23 (t, 7.2, 3H), 1.37 (s, 3H), 1.38 (s, 3H),
1.60 (br s, 1H), 1.83, (m, 1H), 1.94 (m, 1H), 2.46 (m, 2H), 3.61 (m, 1H),
3.75 (m, 1H), 3.78 (m, 1H), 3.89 (dt, 7.7, 3.6, 1H), 4.12 (q, 7.2, 2H); 13C
(cmꢀ1): 3073, 2950, 2934, 2858, 1345, 1254, 1157; 1H NMR
(400 MHz, CDCl3)
d (multiplicity, J (Hz), integration): 0.03 (s, 3H),
0.06 (s, 3H), 0.84 (s, 9H), 1.48 (m, 2H), 1.67 (m, 2H), 2.10 (dt, 7.0, 7.0,
2H), 3.86 (dd, 14.9, 4.6, 1H), 4.00 (dd, 14.9, 6.6z, 1H), 4.48 (m, 1H),
5.00 (m, 2H), 5.77 (ddt, 16.9, 6.9, 3.9, 1H), 7.64 (m, 5H); 13C NMR
NMR (100 MHz, CDCl3)
81.2, 109.2, 173.4.
d: 14.4, 27.2, 27.5, 28.2, 30.9, 60.6, 62.0, 76.3,
(100 MHz, CDCl3)
d
: ꢀ4.7,ꢀ4.1, 18.1, 23.6, 25.8 (3C), 33.6, 37.1, 62.1,
To a stirring solution of Dess–Martin periodinane (424 mg,
1.02 mmol, 1.2 equiv) in 10 mL dry DCM at rt was added ethyl 3-
((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl) prop-
anoate (198 mg, 0.85 mmol, 1.0 equiv) then pyridine (336 mg,
0.35 mL, 5.0 equiv). The solution stirred for 1 h and was then
quenched with 5 mL 1 M Na2S2O3 and 5 mL satd NaHCO3 solution.
The mixture stirred until both layers were no longer cloudy. The
organic layer was concentrated then repartitioned in EtOAc/H2O.
The organic layer was collected, dried over anhydrous MgSO4, and
66.6, 115.4, 125.3 (2C), 129.9 (2C), 131.6, 133.3, 138.1, 154.4; ESI
HRMS [MþH]þ calcd for [C20H33N4O3SSi]þ: 437.2037, found
437.2024.
4.1.4. Preparation of ethyl 3-((4S,5S)-5-(benzyloxy methyl)-2,2-di-
methyl-1,3-dioxolan-4-yl)acrylate (12). A mixture of (þ)-2,3-O-iso-
propylidene-L-threitol (5, 500 mg, 3.08 mmol, 1.0 equiv), benzyl
bromide (580 mg, 3.39 mmol, 1.1 equiv), and silver oxide (Ag2O,
1.07 g, 4.62 mmol, 1.5 equiv) in dry toluene was stirred at rt for 8 h.
The mixture was filtered through a plug of silica and concentrated.
The resulting residue was chromatographed on silica (eluting at
35–42% EtOAc in hexanes) to yield ((4S,5S)-5-(benzyloxymethyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)methanol (598 mg, 2.38 mmol,
concentrated to yield 7 as a colorless oil (150 mg, 0.65 mmol, 76%).
[a
]
ꢀ7.4 (c 1.0, CHCl3); IR (neat)
n
(cmꢀ1): 2985, 2938, 1731, 1073;
d (multiplicity, J (Hz), integration): 1.19
20
D
1H NMR (400 MHz, CDCl3)
(t, 7.3, 3H), 1.34 (s, 6H), 1.95 (m, 2H), 2.42 (m, 2H), 3.91 (dt, 1H), 4.04
(m, 1H), 4.07 (q, 7.3, 2H), 9.67 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
:
77%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
J (Hz), integration): 1.35 (s, 6H), 2.15 (br s,1H), 3.49 (dd, 9.9, 5.5,1H),
d
(multiplicity,
14.3, 26.4, 27.2, 28.7, 30.4, 60.7, 76.1, 84.7, 110.1, 172.9, 201.1; ESI
HRMS [MþH]þ calcd for [C11H19O5]þ: 231.1227, found 231.1221.
3.63 (m, 3H), 3.88 (m, 1H), 3.99 (m, 1H), 4.52 (s, 2H), 7.25 (m, 5H);
13C NMR (100 MHz, CDCl3)
128.0, 128.1, 128.7, 137.8.
d: 27.1, 62.6, 70.6, 73.9, 76.8, 79.9, 109.5,
4.1.6. Preparation of (S)-6-(benzyloxy)hexane-1,2-diol (13). To
a stirring solution of 9 (215 mg, 1.25 mmol, 1.0 equiv) in 5 mL dry
THF at rt was added NaH (33 mg, 1.37 mmol, 1.1 equiv) in one
portion. The mixture bubbled vigorously for 5 min. After gas
To
a stirring slurry of Dess–Martin periodinane (630 mg,
1.49 mmol, 1.1 equiv) in 100 mL dry DCM was added ((4S,5S)-5-

M.D. Lebar, B.J. Baker / Tetrahedron 66 (2010) 1557–1562
1561
evolution had subsided, benzyl bromide (257 mg, 1.5 mmol,
1.2 equiv) was added. The mixture stirred for 20 h and was parti-
tioned between Et2O/H2O. The organic layer was collected. The
aqueous layer was extracted 2ꢂ with aliquots of Et2O. The com-
bined organic layers were dried over anhydrous MgSO4 and con-
centrated. The crude residue was chromatographed by silica gel
MPLC (eluting at 12–14% EtOAc/hexane) to afford the benzylated
intermediate as a colorless oil (142 mg, 0.54 mmol, 43%). The
benzylated intermediate was stirred in 2 mL 50% AcOH:H2O in
1.61 (m, 4H), 2.04 (s, 3H), 3.44 (t, 6.6, 2H), 4.48 (s, 2H), 5.14
(dd, 10.6, 1.0, 1H), 5.21 (m, 2H), 5.75 (ddd, 17.3, 10.5, 6.4, 1H), 7.27
(m, 1H), 7.31 (m, 4H); 13C NMR (100 MHz, CDCl3)
d: 21.4, 22.0, 29.7,
34.2, 70.3, 73.1, 74.9, 116.8, 127.7, 127.8 (2C), 128.5 (2C), 136.7,
133.8, 170.7; ESI HRMS [MþNa]þ calcd for [C16H22O3Na]þ:
285.1461, found 285.1463.
4.1.9. Preparation of ethyl 3-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-diox-
olan-4-yl)propanoate (16). To
a stirring slurry of Ph3PMeBr
a flask opened to air for 3 h. The mixture was then concentrated to
(414 mg, 1.16 mmol, 2.0 equiv) in 10 mL dry THF at 0 ꢁC was added
dropwise KHMDS (0.5 M in toluene, 2.32 mL, 1.16 mmol, 2.0 equiv).
The mixture was warmed to rt and stirred for 30 min. The mixture
20
afford 13 as a colorless oil (125 mg, 0.47 mmol, 94%). [
1.0, CHCl3); IR (neat)
1H NMR (400 MHz, CDCl3)
a
]
D
ꢀ3.3 (c
n
(cmꢀ1): 3382, 2938, 2867, 1456, 1096, 1029;
(multiplicity, J (Hz), integration): 1.44
d
was then cooled back down to 0 ꢁC. Aldehyde
7 (150 mg,
(m, 2H), 1.59 (m, 4H), 1.91 (br s, 1H), 2.14 (br s, 1H), 3.41 (dd, 11.1, 7.6,
1H), 3.47 (t, 6.4, 2H), 3.62 (dd, 11.1, 3.0, 1H), 3.69 (m, 1H), 4.49 (s,
0.65 mmol, 1.0 equiv) dissolved in 3 mL dry THF was then added
dropwise. The reaction was then partitioned between Et2O and
H2O. The aqueous layer was extracted 2ꢂ with aliquots of Et2O. The
combined organic layers were dried over anhydrous MgSO4 and
concentrated. The crude residue was chromatographed by silica gel
2H), 7.27 (m, 1H), 7.32 (m, 4H); 13C NMR (100 MHz, CDCl3)
d: 22.4,
29.7, 33.0, 67.0, 70.3, 72.4, 73.1, 127.8, 127.9 (2C), 128.6 (2C), 138.8;
ESI HRMS [MþH]þ calcd for [C13H21O3]þ: 225.1485, found 225.1481.
MPLC (eluting at 12–16% EtOAc/hexanes) to afford 16 as a colorless
20
4.1.7. Preparation of (S)-6-(benzyloxy)-1-hydroxyhexan-2-yl acetate
(14). To a stirring solution of 13 (100 mg, 0.45 mmol, 1.0 equiv) in
oil (91 mg, 0.40 mmol, 62%). [
n
a
]
ꢀ2.3 (c 0.7, CHCl3); IR (neat)
D
(cmꢀ1): 3082, 2985, 1741, 1167, 1073; 1H NMR (400 MHz, CDCl3)
(multiplicity, J (Hz), integration): 1.25 (t, 7.3, 3H), 1.39 (s, 3H), 1.40
3 mL dry THF at rt was added TEA (54 mg, 71
1.2 equiv) followed by chlorotrimethylsilane (53 mg, 63
0.49 mmol, 1.1 equiv) dropwise. After stirring 25 min, the mixture
was diluted with 3 mL dry DCM. Additional TEA (162 mg, 213 L,
mL, 0.54 mmol,
d
mL,
(s, 3H), 1.83 (m, 1H), 1.96 (m, 1H), 2.45 (m, 2H), 3.69 (dt, 8.3, 3.7, 1H),
4.00 (dd, 8.3, 1.4, 1H), 4.13 (q, 7.3, 2H), 5.26 (dd, 10.2, 1.4z, 1H), 5.38
(dd, 17.4, 1.4 Hz, 1H), 5.80 (ddd, 17.4, 10.2, 7.0, 1H); 13C NMR
m
0.16 mmol, 3.6 equiv) followed by DMAP (5 mg, 0.045 mmol,
0.1 equiv) was added. Acetic anhydride (137 mg, 1.34 mmol,
3.0 equiv) was added to the stirring solution dropwise. The solution
stirred for 1 h then was partitioned between Et2O/2 N HCl. The
organic layer was collected. The aqueous layer was extracted
2ꢂ with aliquots of Et2O. The combined organic layers were dried
over anhydrous MgSO4 and concentrated. The crude residue was
chromatographed by silica gel MPLC (eluting at 45–65% EtOAc/
(100 MHz, CDCl3) d: 14.4, 27.0, 27.1, 27.4, 30.9, 60.6, 79.8, 82.6, 109.0,
119.3, 135.2, 173.3; ESI HRMS [MþNa]þ calcd for [C12H20O4Na]þ:
251.1254, found 251.1256.
4.1.10. Preparation of ethyl 3-((4S,5S)-5-((S,E)-3-acetoxy-7-(benzy-
loxy)hept-1-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propanoate
(17). To a solution of 15 (20 mg, 0.076 mmol, 1.0 equiv) and 16
(17 mg, 0.076 mmol, 1.0 equiv) in dry DCM under stirring at rt was
added Grubbs second generation catalyst (7 mg, 0.008 mmol,
0.1 equiv). The solution stirred for 48 h then was concentrated and
chromatographed by silica gel MPLC (eluting at 25–30% EtOAc/
hexanes) to afford 14 as a colorless oil (66 mg, 0.249 mmol, 56%).
20
Starting material (24%) was also recovered. [
IR (neat)
(400 MHz, CDCl3)
a
]
ꢀ1.0 (c 1.0, CHCl3);
D
n
(cmꢀ1): 3452, 2941, 2864, 1735, 1241, 1096; 1H NMR
(multiplicity, J (Hz), integration): 1.42 (m, 2H),
d
hexanes) to afford the E isomer 17 as a colorless oil, which solidified
20
1.60 (m, 4H), 2.07 (s, 3H), 3.45 (t, 6.3, 2H), 3.61 (dd, 11.5, 6.3, 1H),
3.70 (dd, 11.5, 2.5, 1H), 4.48 (s, 2H), 4.89 (m, 1H), 7.27 (m, 1H), 7.32
when placed in freezer (14 mg, 0.03 mmol, 40%). [
CHCl3); IR (neat)
1093, 1079, 1022; 1H NMR (400 MHz, CDCl3)
a
]
ꢀ15.6 (c 0.36,
D
n
(cmꢀ1): 3032, 2988, 2931, 2867, 1738, 1372, 1241,
(multiplicity, J (Hz),
(m, 5H); 13C NMR (100 MHz, CDCl3)
d
: 21.3, 22.3, 29.7, 30.4, 65.0,
d
70.2, 73.2, 75.7, 127.7, 127.8 (2C), 128.6 (2C), 138.7, 171.6; ESI HRMS
integration): 1.22 (t, 7.1, 3H), 1.36 (s, 6H), 1.38 (m, 2H), 1.59 (m, 4H),
1.84 (m, 2H), 2.02 (s, 3H), 2.41 (m, 2H), 3.43 (t, 6.5, 2H), 3.64 (dt, 7.7,
4.0, 1H), 3.97 (dt, 7.7, 7.2, 1H), 4.10 (q, 7.1, 2H), 4.47, (s, 2H), 5.24
(d, 6.7, 1H), 5.60 (dd, 15.6, 7.2, 1H), 5.68 (dd, 15.6, 6.7, 1H), 7.25 (m,
[MþH]þ calcd for [C15H23O4]þ: 267.1591, found 267.1594.
4.1.8. Preparation of (S)-7-(benzyloxy)hept-1-en-3-yl acetate (15).
To a stirring solution of 14 (66 mg, 0.248 mmol, 1.0 equiv) in 5 mL
dry DCM at 0 ꢁC was added Dess–Martin periodinane (158 mg,
0.372 mmol, 1.5 equiv) in one portion. The mixture was warmed to
rt and stirred for 45 min. Saturated NaHCO3 (5 mL) and 1.0 M
Na2S2O3 (5 mL) was added. The mixture stirred for 5 min then was
partitioned between Et2O/H2O. The organic layer was collected,
dried over anhydrous MgSO4 and concentrated under reduced
pressure to yield the aldehyde intermediate as a colorless oil
1H), 7.31 (m, 4H); 13C NMR (100 MHz, CDCl3)
d: 14.4, 21.4, 22.0, 27.0,
27.1, 27.4, 29.7, 30.8, 34.3, 60.6, 70.2, 73.1, 73.7, 79.9, 81.5, 109.1,
127.7, 127.8 (2C), 128.5 (2C), 129.7, 133.2, 138.7, 170.4, 173.3; ESI
HRMS [MþNa]þ calcd for [C26H38O7Na]þ: 485.2510, found
485.2524.
Acknowledgements
(65 mg, 0.248 mmol, 100%). To
a
mixture of ethyl-
We would like to thank the National Science Foundation’s Office
of Polar Programs for financial support (OPP-0442857 and ANT-
0838776).
triphenylphosphonium bromide (89 mg, 0.25 mmol, 1.1 equiv) in
5 mL dry THF at 0 ꢁC was added KHMDS (0.5 M in toluene, 0.5 mL,
0.25 mmol, 1.1 equiv) dropwise. After 10 min stirring at 0 ꢁC, the
aldehyde intermediate (60 mg, 0.227 mmol, 1.0 equiv) dissolved
in 2 mL dry THF was added dropwise. After 5 min the reaction was
partitioned between Et2O/H2O. The organic layer was collected.
The aqueous layer was extracted 2ꢂ with aliquots of Et2O. The
combined organic layers were dried over anhydrous MgSO4 and
concentrated. The crude residue was chromatographed by silica
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2009.12.007.
References and notes
gel MPLC (eluting at 10–13% EtOAc/hexanes) to afford 15 as a col-
20
orless oil (37 mg, 0.141 mmol, 62%). [
(neat)
(400 MHz, CDCl3)
a
]
ꢀ2.9 (c 0.6, CHCl3); IR
D
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