A formal synthesis of (-)-cyanolide a featuring a stereoselective mukaiyama aldol reaction and oxocarbenium reduction

Article abstract of DOI:10.1021/jo201210u

The formal synthesis of the marine natural product (-)-cyanolide A is presented. The synthetic strategy is centered on two acyclic diastereoselective reactions and a single cyclic reaction with modest to excellent dr based on an initial stereocenter. Most

Full text of DOI:10.1021/jo201210u

NOTE
pubs.acs.org/joc
A Formal Synthesis of (À)-Cyanolide A Featuring a Stereoselective
Mukaiyama Aldol Reaction and Oxocarbenium Reduction
Robert J. Sharpe and Michael P. Jennings*
Department of Chemistry, 250 Hackberry Lane, The University of Alabama, Tuscaloosa, Alabama 35487-0336, United States
S Supporting Information
b
ABSTRACT: The formal synthesis of the marine natural
product (À)-cyanolide A is presented. The synthetic strategy
is centered on two acyclic diastereoselective reactions and a
single cyclic reaction with modest to excellent dr based on an
initial stereocenter. Most notable is a highly stereoselective oxo-
carbenium reduction based on a “mismatched” reactive con-
former to afford the β-C-glycoside subunit leading to an efficient
synthesis of the diolide aglycon in 12 overall steps.
Scheme 1. Structural Similarity between Cyanolide A and
Clavosolide A
arine-based organisms continue to provide synthetic or-
ganic chemists challenging, intriguing, and biologically
M
relevant natural product targets. As disclosed in 2010 by Gerwick
and co-workers, cyanolide A (1) is a dimeric 16-membered
macrolide that was isolated from the extracts of a Papua New
Guinea collection of Lyngbya bouillonii.1 Cyanolide A has been
shown to be a highly potent molluscicidal agent against the snail
vector Biomphalaria glabrata with an LC50 = 1.2 μM. Regrettably,
nearly 1 billion people worldwide are either infected with or at
risk of infection of schistosomiasis.2 This prevalent parasitic
infection can cause a host of health problems ranging from
bladder cancer to kidney malfunction and ultimately death.3 One
of the major challenges of eradicating schistosomiasis lies in the
complex lifecycle of the flatworm and its symbiotic nature with
the mammalian and aquatic snail host. Thus, one leading theory
on controlling the rate of schistosomiasis is to arrest the cell cycle
of the host snail with an antimolluscicidal compound. Fortu-
nately, 1 has great potential to combat this type of infection
because of its high potency as an antimolluscicidal agent.
This highly functionalized 16-membered dimeric macrocycle
has attracted moderate interest within the synthetic community
because of its biological activity and similarity to the clavosolide
family of natural products as highlighted in Scheme 1.4 The
efforts of the Hong group confirmed the relative and absolute
stereochemistry of 1 through total synthesis by featuring an
elegant sequential allylic oxidation followed by intramolecular
oxy-Michael addition to the corresponding α,β-unsaturated
aldehyde intermediate as the key step.5 Ensuing dimerization
and bis-glycosylation afforded the natural cyanolide A (1). In
addition to the biological relevance, the polyfunctionality of
the monomeric subunit resident in 1 and its close structural rela-
tionship to clavosolide A made it an attractive target to further
investigate a “mismatched” oxocarbenium cation formation/
reduction protocol.6
of such compounds. Generally, the leading strategy for the syn-
thesis of natural products centers on a single asymmetric induc-
tion followed by a series of diastereoselective reactions until the
desired target is attained. While this tactic is a laudable goal,
diastereoselective control of acyclic reactions tends to lag behind
their cyclic counterparts. In this paper, we underscore the above-
mentioned strategy by highlighting two acyclic and a single cyclic
diastereoselective reaction with modest to excellent dr based on
an initial stereocenter en route to the formal synthesis of 1.
The retrosynthetic analysis of 1 followed the previous dis-
connection of Hong in that the carbohydrate moiety would be
attached at the last step as shown in Scheme 2.5 Completion of
the dimerized diol 2 would be obtained via a tandem Yamaguchi
esterificationÀmacrolactonization reaction process of the hydroxyl
As isolated natural products become more structurally com-
plex, the further development and understanding of known
reaction processes is essential for the stereoselective construction
Received: June 10, 2011
Published: August 24, 2011
r
2011 American Chemical Society
8027
dx.doi.org/10.1021/jo201210u J. Org. Chem. 2011, 76, 8027–8032
|

The Journal of Organic Chemistry
NOTE
Scheme 2. Retrosynthetic Analysis of (À)-Cyanolide A
Scheme 3. Synthesis of the β-Hydroxy Ester 12
gem-dimethyl silyl ketene acetal 11. Thus, we initially attempted
the union of 11 and 5 utilizing TiCl4 as the Lewis acid promoter
based on the 1,3-anti-chelation control model, but unfortunately,
only starting material decomposition was observed.10 Although
acid monomer 3. Thus, seco acid 3 would be derived from a
functionalization of the alkylation product of lactone 4 followed by
a stereoselective mismatched oxocarbenium cation formation/
reduction sequence to afford the necessary β-C-glycoside pre-
cursor. We envisaged the generation of lactone 4 from a sequential
acetal deprotection/acid catalyzed cyclization event in which,
in turn, the requisite stereocenter would be produced from a
1,3-directed Mukaiyama aldol reaction between the appropriate
silyl ketene acetal and aldehyde 5. Thus, the required aldehyde 5
could, in principle, be derived in three steps from 6 by means
of a Ru-catalyzed cross-metathesis with an appropriate acrylate
followed by an intramolecular oxy-Michael addition to set the
second stereocenter and final partial DIBAL reduction of the
ester moiety.
BF3 OEt2 will only allow for chelation to the aldehyde carbonyl
3
via an open transition state, we were encouraged by Evans’ report
based on their electrostatic model of modest to high levels of dr
for 1,3-anti-products during a Mukaiyama aldol reaction with
silyl enol ether nucleophiles.11 In accordance with their model,
the addition of 11 to aldehyde 5 readily proceeded with BF3
3
OEt2, via the presumed transition state shown in Scheme 3 to
provide aldol adduct 12 in 64% with a modest dr of 4.2:1 for the
desired 1,3-anti-product.
With aldol adduct 12 in hand, the focus was shifted to com-
pletion of the monomeric subunit via a stereoselective oxocar-
benium reduction to forge the β-C-glycoside moiety as deli-
neated in Scheme 4. Hence, treatment of hydroxy ester 12 with
MOMCl and DIPEA afforded acetal 13 in 78% yield, analogous
to our previous efforts with clavosolide A.6 Conversion of the
Mukayiama aldol adduct 13 into the desired lactone 4 was
initiated by transforming 13 to the diol by means of hydro-
genolysis of the benzylidene acetal followed by acid catalyzed
lactonization. Along this line, treatment of 13 with H2 and
Pearlman’s catalyst [Pd(OH)2] at rt in MeOH led to the for-
mation of the corresponding diol, which was used immediately
without purification. Subsequent lactonization was accomplished
under standard ester hydrolysis conditions by treating the
crude diol with aqueous trifluoroacetic acid (TFA) in THF.
The hydroxy lactone 4 was obtained in 73% yield from 13.
With the synthesis of lactone 4 complete, our attention shifted
toward the construction of the β-C-glycoside subunit. Thus,
alkylation of lactone 4 with allylmagnesium bromide afforded the
intermediate hemiketal 14, which underwent tandem stereose-
lective oxocarbenium cation formation/reduction with TFA and
Et3SiH to afford the β-C-glycoside (as determined by NOE) 17
With this retrosynthetic plan in mind, the initial focus was
placed on the synthesis of the β-hydroxy ester 12. As shown in
Scheme 3, treatment of the previously reported homoallylic
alcohol 6 (prepared in one step via the asymmetric allylboration
of propanal)7 with 2-ethylhexyl acrylate (7) in the presence of
Grubbs’ second-generation catalyst (8) under the conditions as
described by O’Doherty diastereoselectively provided the δ-
hydroxy-(E)-α,β-unsaturated ester 9 in 72% yield.8 It is worth
noting that methyl acrylate in place of 7 worked equally well by
TLC analysis; however, isolation and purification were trouble-
some due to the low molecular weight of the desired product. An
ensuing tandem hemiketal formation/intramolecular hetero-
Michael addition utilizing PhCHO and KO-t-Bu to 9 over 3 h
at 0 °C afforded the syn-benzylidine acetal 10 in 60% yield and as
1
a single diastereomer as assessed by H NMR analysis.9 Partial
reduction of the ester moiety resident in 10 with DIBAL to the
requisite aldehyde proceeded at À78 °C and was complete
within 20 min by TLC analysis to furnish 5 in 94% yield and
set the stage for the directed Mukaiyama aldol reaction with the
8028
dx.doi.org/10.1021/jo201210u |J. Org. Chem. 2011, 76, 8027–8032

The Journal of Organic Chemistry
NOTE
Scheme 4. Synthesis of the β-C-Glycoside 17
Scheme 5. Synthesis of 2 via a Yamaguchi Dimerization
in 56% yield over the two-step sequence from 4. Of the two
possible reactive conformers (15 versus 16), and based on the
isolated β-C-glycoside, the proposed conformer 16 places all of
the substituents at C3 and C5 in the pseudoequatorial positions.
In a variety of past projects from our laboratory, stereoselective
endocyclic oxocarbenium reductions have placed the C3 hydro-
xyl moiety in the axial position and the C5 substituent in the
pseudoequatorial geometry.12 Typically, these oxocarbenium
formation/reduction reactions are complete at À78 f À40 °C
within 0.25À0.5 h and provide the desired β-C-glycoside with
>20:1 dr. On the basis of Woerpel’s observations and our prior
investigations, these C3 axial and C5 pseudoequatorial oxocarbe-
nium conformations represent a “matched” geometry from a
reactive conformer perspective. However, the reactive oxocarbe-
nium conformer 16 places the C3 and C5 substituents in the
pseudoequatorial positions.13 Interestingly, the stereoselective
oxocarbenium formation/reduction reaction required >12 h
for completion at À20 °C as also seen in the synthesis of
clavosolide A. Hence, it is once again suggested that 16 repre-
sents a “mismatched” reactive conformer that nonetheless al-
lowed for a highly stereoselective oxocarbenium reduction, albeit
with extended reaction time. It is worth noting that the yield is
∼10% lower over the three steps from lactone 4 than it was for an
identical sequence during the synthesis of clavosolide A. We
speculate that this is due to the gem-dimethyl substituent α to the
lactone carbonyl of 4, thus providing more steric hindrance for
nucleophilic attack of the Grignard reagent.
accomplished under the previously reported Yamaguchi macro-
lactonization conditions to afford the MOM-protected aglycon
20 in a modest 45% yield.6,15 Final deprotection of the two
MOM acetals was accomplished utilizing LiBF4 in aq MeCN
furnishing aglycon 2 in a 68% yield, thus constituting a formal
synthesis of 1. The spectral data (1H NMR, 500 MHz; 13C
NMR, 125 MHz), optical rotation, and HRMS data of synthetic
2 were in complete agreement with those previously
reported.4cÀe,5 The final diastereoselective glycosylation of
2 with thioacetal 21 and TMSOTf could be carried out in
accordance with the Hong report for the total synthesis of 1.5
In summary, an extremely efficient formal synthesis of 1 has
been successfully achieved in 12 steps. The described tactic
underscores a strictly diastereoselective strategy which incorpo-
rates two acyclic and a single cyclic reaction with modest to excel-
lent dr based on the initial stereocenter of alcohol 6. Additionally,
we have observed a highly stereoselective oxocarbenium reduc-
tion based on a “mismatched” reactive conformer to afford the
β-C-glycoside subunit leading to an efficient synthesis of 2.
With the functionalized β-C-glycoside 17 in hand, our focus
turned toward completion of the formal synthesis of 1 as
described in Scheme 5. Consequently, standard ozonolysis of
the olefin moiety resident in 17 followed by a PPh3 reductive
workup provided aldehyde 18 in 66% yield. Subsequently, a
LindgrenÀKrausÀPinnick oxidation provided the necessary seco
acid 3 in virtually quantitative yield which was then used without
further purification.14 Dimerization of the monomeric acid 3 was
’ EXPERIMENTAL SECTION
(5R,E)-2-Ethylhexyl 5-hydroxyhept-2-enoate (9). To a stir-
red solution of 6 (3.00 g, 29.9 mmol, 1.00 equiv) in anhydrous benzene
(150 mL) under an atmosphere of Ar at rt was added 2-ethylhexyl
acrylate (11.0 g, 59.9 mmol, 2.00 equiv) dropwise. To the resulting
solution was added Grubbs’ second-generation catalyst (0.509 g 0.599
mmol, 0.020 equiv), and the solution was allowed to stir for 48 h at rt.
8029
dx.doi.org/10.1021/jo201210u |J. Org. Chem. 2011, 76, 8027–8032

The Journal of Organic Chemistry
NOTE
The reaction was then concentrated under reduced pressure. Subse-
quent flash chromatography (silica, 7% EtOAc/hexanes) afforded 9 as a
brown, viscous oil (5.52 g, 72%): TLC Rf = 0.77 in 35% EtOAc/hexanes;
[α]23D = À5.6 (c 0.055, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 6.97
(m, 1H), 5.92 (dt, J = 15.8, 1.3 Hz, 1H), 4.05 (m, 2H), 3.70 (m, 1H),
2.42 (m, 1H), 2.33 (m, 1H), 1.55 (m, 4H), 1.37 (m, 2H), 1.30 (m, 6H),
0.97 (t, J = 7.6 Hz, 3H), 0.90 (m, 6H); 13C NMR (125 MHz, CDCl3) δ
166.9, 145.3, 124.3, 72.3, 67.2, 40.1, 39.2, 30.8, 30.3, 29.3, 24.2, 23.3,
14.4, 11.4, 10.2; IR (neat) cmÀ1 3443, 2934, 1713, 1457, 737; HRMS
(EI) calcd for C15H28O3 [M À OH] 239.2011, found 239.2019.
2-Ethylhexyl 2-((4R,6R)-6-Ethyl-2-phenyl-1,3-dioxan-4-yl)-
acetate (10). Ester 9 (1.93 g, 7.53 mmol, 1.00 equiv) was dissolved in
anhydrous THF (75.0 mL) under Ar and cooled to 0 °C. To this solution
were added benzaldehyde (0.890 g, 8.28 mmol, 1.10 equiv) and KO-t-Bu
(0.0840 g, 0.753 mmol, 0.100 equiv) sequentially. This addition was
repeated three times for benzaldehyde and 11 times for KO-t-Bu in
15 min intervals upon which the reaction was quenched via the addition
of a pH 7.00 phosphate buffer solution (30.0 mL). The resulting mixture
was warmed to rt and stirred vigorously until a distinct separation of
layers was observed. The layers were partitioned with H2O and Et2O in a
separatory funnel, and the aqueous layer was extracted with Et2O (3 Â
25 mL). The combinedorganic extracts were dried over Na2SO4, filtered,
and concentrated in vacuo to yield the crude product. Subsequent
flash chromatography (silica, 1% EtOAc/Hexanes) afforded 10 as a
yellow, viscous oil (1.63 g, 60%): TLC Rf = 0.74 in 15% EtOAc/hexanes;
[α]23D = À2.6 (c 0.057, CH2Cl2); 1H NMR (360 MHz, CDCl3) δ 7.55
(d, J = 6.4 Hz, 2H), 7.39 (m, 3H), 5.61 (s, 1H), 4.36 (m, 1H), 4.09 (m,
2H), 3.83 (m, 1H), 2.69 (dq, J = 7.3, 5.9 Hz, 2H), 1.77 (m, 2H), 1.63 (m,
2H), 1.45 (m, 3H), 1.34 (s, 6H), 1.06 (t, J = 7.5 Hz, 3H), 0.93 (m, 6H);
13C NMR (125 MHz, CDCl3) δ 171.4, 139.0, 128.9, 128.5, 126.5, 101.0,
78.3, 73.7, 67.4, 41.6, 39.1, 36.5, 30.8, 29.3, 29.2, 24.1, 23.0, 14.4, 11.3,
9.8; IR (neat) cmÀ1 2941, 2869, 1731, 1458, 754, 700; HRMS (EI) calcd
for C22H34O4 362.2457, found 362.2471.
layer was extracted with CHCl3 (3 Â 25 mL). The combined organics
were dried (Na2SO4), filtered, and concentrated to yield the crude β-
hydroxy ester. Subsequent flash chromatography (silica, 10% EtOAc/
hexanes) afforded 12 as a clear viscous oil as a separable 4.2:1 mixture of
diastereomers (1.08 g, 64%): TLC Rf = 0.81 in 37% EtOAc/hexanes;
[α]23D = À11.3 (c 0.026, CH2Cl2); 1H NMR (360 MHz, CDCl3 δ 7.50
(m, 2H), 7.34 (m, 3H), 5.54 (s, 1H), 4.18 (m, 1H) 4.16 (q, J = 6.6 Hz,
2H), 4.07 (m, 1H), 3.71 (m, 1H), 2.93 (d, J = 5.9 Hz, 1H), 1.71 (m, 2H),
1.56 (m, 4H), 1.26 (t, J = 7.3 Hz, 3H), 1.20 (s, 3H), 1.18 (s, 3H), 1.00 (t,
J = 7.5 Hz, 3H); 13C NMR (125 MHz,CDCl3) δ 178.0, 139.3, 128.8,
128.4, 126.4, 100.8, 78.5, 74.3, 72.7, 61.0, 47.0, 38.3, 37.0, 29.2, 22.5,
20.7, 14.5, 9.8; IR (CH2Cl2) cmÀ1 2972, 2875, 1723, 754, 703; HRMS
(EI) calcd for C20H30O5 350.2093, found 350.2094.
(3S)-Ethyl 4-((4R,6R)-6-Ethyl-2-phenyl-1,3-dioxan-4-yl)-
3-(methoxymethoxy)-2,2-dimethylbutanoate (13). To a stir-
red solution of 12 (0.720 g, 2.06 mmol, 1.00 equiv) in anhydrous
CH2Cl2 (7.00 mL) under Ar at 0 °C was added diisopropylethylamine
(0.090 g, 0.720 mmol, 5.00 equiv). To the resulting solution was added
MOMCl (0.030 g, 0.357 mmol, 2.50 equiv) dropwise, and the reaction
was allowed to warm to rt and stirred until the starting material was
consumed as indicated by TLC analysis (∼36 h). The reaction was then
quenched via the dropwise addition of saturated aqueous NaHCO3 and
partitioned between CH2Cl2, and the aqueous layer was extracted with
CH2Cl2 (3 Â 15 mL). The combined organics were dried (MgSO4),
filtered, and concentrated in vacuo to yield the crude protected alcohol.
Subsequent flash chromatography (silica, 7% EtOAc/hexanes) afforded
13 as a yellow viscous oil (0.630 g, 78%): TLC Rf1= 0.92 in 37% EtOAc/
hexanes; [α]23 = À13.9 (c 0.034, CH2Cl2); H NMR (360 MHz,
D
CDCl3) δ 7.52 (m, 2H), 7.35 (m, 3H), 5.52 (s, 1H), 4.69 (d, J = 1.1 Hz,
2H), 4.11 (m, 4H), 3.38 (s, 3H), 1.64 (m, 6H), 1.40 (m, 1H), 1.22 (m,
6H), 1.13 (s, 3H), 1.00 (t, J = 7.5, 3H); 13C NMR (125 MHz, CDCl3) δ
176.8, 139.4, 128.6, 128.3, 126.3, 100.5, 99.1, 81.0, 78.5, 73.3, 60.7, 56.3,
47.5, 38.3, 37.4, 29.1, 21.5, 21.1, 14.3, 9.8; IR (CH2Cl2) cmÀ1 2947,
1729, 1467, 922, 700; HRMS (EI) calcd for C22H34O6 394.2355, found
394.2360.
2-((4R,6R)-6-Ethyl-2-phenyl-1,3-dioxan-4-yl)acetaldehyde
(5). To stirred solution of 10 (1.97 g, 5.44 mmol, 1.00 equiv) in anhy-
drous CH2Cl2 (27.2 mL) at À78 °C under Ar was added DIBAL-H as a
1.0 M solution in toluene (5.63 mL, 5.63 mmol, 1.20 equiv), dropwise.
The mixture was allowed to stir at À78 °C until the starting material was
consumed as indicated by TLC analysis (∼20 min) upon which the
reactionwas quenched via the addition of chilledacetone (48.0 mL). The
resulting mixture was allowed to stir for 10 min, at which time the
mixture was warmed to rt. To the mixture was added a 20% aqueous
solution of sodium potassium tartrate (45.0 mL), and the aqueous layer
was extracted with Et2O (3 Â 30 mL). The combined organics were
dried (Na2SO4), filtered, and concentrated. Subsequent flash chroma-
tography (silica, 7% EtOAc/hexanes) afforded 5 as a clear, viscous oil
(4S,6R)-6-((R)-2-Hydroxybutyl)-4-(methoxymethoxy)-3,3-
dimethyltetrahydro-2H-pyran-2-one (4). To a solution of 13
(0.530 g, 1.34 mmol, 1.00 equiv) in MeOH (20.0 mL) at rt was added
Pd(OH)2 (0.530 g). The mixture was then subjected to an atmosphere
of H2 until the starting material was consumed as indicated by TLC
analysis (∼3 h). The mixture was subsequently filtered over Celite and
concentrated in vacuo to afford the crude syn-diol, which was used
without further purification.
To a solution of the crude diol (0.411 g, 1.34 mmol, 1.00 equiv) in a
solution of THF (6.10 mL) and H2O (0.620 mL) was added TFA
(15.0 μL, 0.201 mmol, 0.150 equiv), and the resulting mixture was refluxed
for 24 h at 60 °C. The reaction was cooled to rt and quenched via the
dropwise addition of saturated aqueous NaHCO3. The mixture was
partitioned between EtOAc and H2O, and the aqueous layer was
extracted with EtOAc (3 Â 12 mL). The combined organics were dried
(MgSO4), filtered, and concentrated in vacuo to yield the crude lactone.
Subsequent flash chromatography (silica, 47% EtOAc/hexanes) af-
forded 4 as a clear, viscous oil (0.260 g, 73%): TLC Rf = 0.14 in 37%
EtOAc/hexanes; [α]23D = +7.0 (c 0.030, CH2Cl2); 1H NMR (360 MHz,
CDCl3) δ 4.74 (d, J = 7.0 Hz, 1H), 4.63 (d, J = 7.0 Hz, 1H), 4.44 (m,
1H), 3.73 (m, 2H), 3.38 (s, 3H), 2.19 (m, 2H), 1.88 (m, 2H), 1.74 (m,
1H), 1.46 (m, 2H), 1.35 (s, 3H), 1.25 (s, 3H), 0.94 (t, J = 7.3 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 176.8, 96.2, 76.0, 70.7, 56.1, 44.4, 43.2,
32.1, 30.7, 23.9, 21.5, 10.0. IR (CH2Cl2) cmÀ1 2938, 1729, 1264, 1145,
1039, 737; HRMS (EI) calcd for C13H24O5 [M À H] 259.1545, found
259.1554.
(1.19 g, 94%): TLC Rf = 0.30 in 10% EtOAc/hexanes; [α]23 = +1.2
D
(c0.049, CH2Cl2); 1H NMR (360 MHz, CDCl3) δ9.86 (t, J = 1.8 Hz, 1H),
7.49 (m, 2H), 7.35 (m, 3H), 5.58 (s, 1H), 4.40 (m, 1H), 3.79 (m, 1H),
2.87 (ddd, J = 16.8, 7.3, 2.0 Hz, 1H), 2.68 (ddd, J = 16.8, 5.2, 1.6 Hz, 1H),
1.71 (m, 2H), 1.60 (m, 1H), 1.47 (m, 1H), 1.00 (t, J = 7.5, 3H); 13C
NMR (125 MHz, CDCl3) δ 200.8, 138.8, 129.0, 128.5, 126.4, 101.0,
78.3, 72.3, 49.8, 36.6, 29.1, 9.8; IR (neat) cmÀ1 2962, 2873, 2729, 1723,
1345, 760, 697; HRMS (EI) calcd for C14H18O3 234.1256, found
234.1253.
(3S)-Ethyl 4-((4S,6R)-6-Ethyl-2-phenyl-1,3-dioxan-4-yl)-3-
hydroxy-2,2-dimethylbutanoate (12). To a solution of 5 (1.13 g,
4.82 mmol, 1.00 equiv) in anhydrous CH2Cl2 (28.4 mL) at À78 °C
was added silyl ketene acetal 11 (1.13 g, 5.98 mmol, 1.24 equiv) followed
by BF3 OEt2 (0.85 g, 5.98 mmol, 1.24 equiv) dropwise. The resulting
3
mixture was allowed to stir until the starting material was consumed as
indicated by TLC analysis (∼30 min) and was subsequently quenched
via addition of saturated aqueous NaHCO3 (15.0 mL). The reaction was
warmed to rt and partitioned between CHCl3 and H2O, and the aqueous
(R)-1-((2R,4S,6S)-6-Allyl-4-(methoxymethoxy)-5,5-dimeth-
yltetrahydro-2H-pyran-2-yl)butan-2-ol (17). To a solution of 4
(0.160 g, 1.00 mmol, 1.00 equiv) in anhydrous THF (10.0 mL) at
8030
dx.doi.org/10.1021/jo201210u |J. Org. Chem. 2011, 76, 8027–8032

The Journal of Organic Chemistry
NOTE
À78 °C under Ar was added allylmagnesium bromide (0.640 mL, 1.0 M
in Et2O, 0.640 mmol, 2.80 equiv) dropwise over a period of 30 min. The
resulting solution was allowed to stir at À78 °C until the starting material
was consumed as indicated by TLC analysis (∼5 min), at which time the
reaction was quenched via saturated aqueous NH4Cl (5.00 mL). The
layers were partitioned between EtOAc and H2O, and the aqueous layer
was extracted with EtOAc (3 Â 15 mL). The combined organics were
dried (MgSO4), filtered, and concentrated in vacuo to afford the crude
hemiketal as a clear viscous oil, which was carried forward without further
purification.
(3 Â 5 mL). The combined organics were dried (MgSO4), filtered, and
concentrated in vacuo to yield 3 as a clear viscous oil, which was judged
pure via withoutfurtherpurification. (0.071 g, 99%): TLCRf = 0.35 in 60%
EtOAc/hexanes; [α]23D = À8.1 (c 0.026, CH2Cl2); 1H NMR (500 MHz,
CDCl3) 4.71 (d, J = 6.6 Hz, 1H), 4.60 (d, J = 6.6 Hz, 1H), 3.90 (m, 1H),
3.67 (m, 1H), 3.56 (s, 1H), 3.35 (m, 3H), 2.46 (m, 2H), 1.81 (m, 1H),
1.54 (m, 5H), 1.25 (m, 3H), 0.90 (m, 9H); 13C NMR (125 MHz, CDCl3)
δ 173.9, 96.2, 81.4, 81.0, 78.0, 74.2, 55.9, 41.2, 38.5, 35.2, 29.9, 22.8, 13.6,
9.7; IR (CH2Cl2) cmÀ1 2939, 1730, 1150, 1099, 1038; HRMS (EI) calcd
for C15H28O6 [M À HOH] 286.1780, found 286.1775.
The crude hemiketal (0.302 g, 1.00 mmol, 1.00 equiv) was subse-
quently dissolved in CH2Cl2 under Ar and cooled to À50 °C, at which
time TFA (0.456 g, 4.00 mmol, 4.00 equiv) was added dropwise
followed immediately by Et3SiH (1.05 g, 9.00 mmol, 9.00 equiv)
dropwise. The resulting mixture was warmed to À15 °C over the course
of ∼1 h and stirred until the reaction was complete as indicated by TLC
analysis (∼14 h.). The reaction was then quenched via addition of
saturated aqueous NaHCO3 (3 mL), and the mixture was partitioned
between EtOAc and H2O. The aqueous layer was extracted with EtOAc
(3 Â 15 mL), and the combined organics were dried (MgSO4), filtered,
and concentrated in vacuo to yield the crude β-C-glycoside as a pale
yellow, viscous, oil. Subsequent flash chromatography (silica, 12% EtOAc/
hexanes) afforded 17 as a clear, viscous oil (0.160 g, 56%): TLC Rf =0.45in
27% EtOAc/hexanes; [α]23D = +2.5 (c 0.004, CH2Cl2); 1H NMR (360
MHz, CDCl3) δ 5.80 (m, 1H), 5.09 (m, 2H), 4.72 (d, J = 7.0 Hz, 1H), 4.60
(d, J = 7.0 Hz, 1H), 3.87 (s, 1H), 3.72 (m, 1H), 3.57 (m, 1H), 3.37 (s, 3H),
3.28 (dd, J = 11.6, 4.8 Hz, 1H), 3.09 (dd, J = 10.4, 2.3 Hz, 1H), 2.27 (m,
2H), 1.78 (m, 1H), 1.50 (m, 5H), 0.91 (m, 9H); 13C NMR (125 MHz,
CDCl3) δ 136.4, 117.6, 96.2, 84.2, 81.4, 78.2, 73.9, 55.9, 41.9, 38.8, 35.4,
34.0, 30.5, 22.9, 13.7, 10.1; IR (CH2Cl2) cmÀ1 2936, 2879, 1150, 1091,
1032, 913; HRMS (EI) calcd for C16H30O4 [M À C2H5O2] 225.1855,
found 225.1858.
2-((2S,4S,6R)-6-((R)-2-Hydroxybutyl)-4-(methoxymethoxy)-
3,3-dimethyltetrahydro-2H-pyran-2-yl)acetaldehyde (18).
To a solution of 17 (0.100 g, 0.35 mmol, 1.00 equiv) dissolved in CH2-
Cl2 (7.00 mL) and MeOH (0.160 mL) was added 5 drops of anhydrous
pyridine. The resulting mixture was cooled to À78 °C, and O3 was
bubbled through the solution until the starting material was consumed as
indicated by TLC analysis (∼30 min.). The solution was then sparged
with O2, and the reaction was quenched via portionwise addition of PPh3
(0.121 g, 0.46 mmol, 3.00 equiv) and stirred at rt for 4 h. The resulting
mixture was concentrated in vacuo to yield the crude aldehyde as a clear,
viscous oil. Subsequent flash chromatography (silica, 32% EtOAc/
(1S,5R,7R,9S,11S,15R,17R,19S)-5,15-Diethyl-9,19-bis(meth-
oxymethoxy)-10,10,20,20-tetramethyl-4,14,21,22-tetraoxa-
tricyclo[15.3.117,11]docosane-3,13-dione (20). To a stirred so-
lution of 3 (0.071 g, 0.233 mmol, 1.00 equiv) in anhydrous THF
(1.60 mL) under Ar was added Et3N (0.033 g, 0.330 mmol, 1.40 equiv)
followed by 2,4,6-trichlorobenzoyl chloride (0.0680 g, 0.280 mmol,
1.20 equiv) dropwise, and then the mixture was allowed to stir at room
temperature for 2.5 h. The resulting mixture was diluted with anhydrous
toluene (12.2 mL) and added dropwise over 5 h to a refluxing solution of
DMAP (0.043 g, 0.350 mmol, 5.00 equiv) in toluene (46.0 mL) at
120 °C. After the addition was complete, the auxiliary flask was washed
with toluene (2.00 mL), and the resulting rinse was added dropwise to
the reaction mixture over the course of 0.5 h. The resulting mixture
was refluxed for 14 h, cooled to rt, and concentrated in vacuo to yield
the crude diolide and as a pale yellow, viscous oil. Subsequent flash
chromatography (silica, 20% EtOAc/hexanes) afforded 20 as a clear,
viscous oil (0.030 g, 45%): TLC Rf = 0.26 in 20% EtOAc/hexanes;
[α]23D = À6.3 (c 0.011, CH2Cl2); 1H NMR (360 MHz, CDCl3) δ 4.90
(m, 2H), 4.73 (d, J = 6.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H), 3.38 (m, 9H),
2.34 (m, 4H), 1.88 (m, 3H), 1.59 (m, 6H), 1.25 (m, 6H), 0.90 (m, 18H);
13C NMR (125 MHz, CDCl3) δ 172.0, 96.2, 81.5, 80.9, 75.4, 74.2, 55.9,
40.9, 38.5, 35.6, 35.2, 28.5, 22.8, 13.7, 9.8; IR (CH2Cl2) cmÀ1 2962,
2879, 2362, 1736, 1150, 1096, 1040; HRMS (EI) calcd for C30H52O10
572.3560, found 572.3548.
Aglycon Dimer 2. To a stirred solution of 20 (0.030 g, 0.052 mmol,
1.00 equiv) in CH3CN (1.02 mL) and H2O (5.00 μL) was added LiBF4
(1.04 mL, 1.0 M in CH3CN, 1.04 mmol, 20.0 equiv), and the resulting
mixture was refluxed at 70 °C until the starting material was consumed as
observed by TLC analysis (∼40 min). The reaction was cooled to rt and
subsequently quenched via addition of saturated aqueous NaHCO3
(1.0 mL). The mixture was partitioned between EtOAc and H2O, and
the aqueous layer was extracted with EtOAc (3 Â 5 mL). The combined
organics were dried (MgSO4), filtered, and concentrated to yield the
crude diol as a clear, viscous oil. Subsequent flash chromatography
(silica, 50% EtOAc/hexanes) afforded 2 as a clear, viscous oil (0.017 g,
68%): TLC Rf = 0.28 in 60% EtOAc/hexanes; [α]23D = À13.6 (c 0.009,
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 4.90 (dd, 14.6, 6.7 Hz, 2H),
3.46 (m, 4H), 3.39 (m, 2H), 2.41 (dd, J = 15.6, 1.1, 2H), 2.28 (dd, J =
15.7, 9.1, 2H), 1.86 (m, 4H), 1.58 (m, 8H), 1.34 (dd, J = 12.3, 11.4 Hz,
2H), 0.93 (s, 6H), 0.87 (t, J = 7.3 Hz, 6H), 0.83 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 172.4, 81.0, 75.7, 75.3, 74.0, 41.3, 39.0, 37.6, 35.7, 28.5,
22.6, 12.9, 9.9; IR (CH2Cl2) cmÀ1 2965, 2873, 1733, 1200, 741; HRMS
(EI) calcd for C26H44O8 484.3036, found 484.3048.
hexanes) afforded 18 as a clear viscous oil (0.067 g, 66%): TLC Rf =
1
0.22 in 32% EtOAc/hexanes; [α]23 = À1.6 (c 0.018, CH2Cl2); H
D
NMR (360 MHz, CDCl3) δ 9.78 (t, J = 1.6 Hz, 1H), 4.71 (d, J = 7.0 Hz,
1H), 4.59 (d, J = 7.0 Hz, 1H), 3.69 (m, 3H), 3.36 (s, 3H), 3.32 (m, 1H),
3.04 (s, 1H), 2.54 (m, 2H), 1.83 (m, 1H), 1.52 (m, 5H), 0.90 (m, 9H);
13C NMR (125 MHz, CDCl3) δ 201.0, 96.2, 81.0, 79.1, 73.2, 55.9, 44.0,
42.4, 38.4, 35.1, 30.5, 22.9, 13.8, 10.1; IR (CH2Cl2) cmÀ1 2933, 1727,
1600, 1147, 1093, 1035; HRMS (EI) calcd for C15H28O5 [M À C2H5]
259.1545, found 259.1541.
2-((2S,4S,6R)-6-((R)-2-Hydroxybutyl)-4-(methoxymethoxy)-
3,3-dimethyltetrahydro-2H-pyran-2-yl)acetic Acid (3). To a
stirred solution of 18 (0.067 g, 0.232 mmol, 1.00 equiv) in t-BuOH
(3.05 mL) and H2O (1.02 mL) was added 2-methyl-2-butene (1.63 g,
23.23 mmol, 100.00 equiv) followed by NaH2PO4 (0.278 g, 2.32 mmol,
10.0 equiv), and the mixture was cooled to À5 °C. To this mixture was
addedNaClO2 (0.047 g, 0.87 mmol, 6.00 equiv)asa 1.40 Msolution of3:1
t-BuOH/H2O (0.370 mL), and the reaction was allowed to stir until the
starting material was consumed as indicated by TLC analysis (∼30 min).
The reaction was subsequently quenched via the addition of saturated
aqueous NH4Cl (1.0 mL). The resulting mixture was partitioned be-
tween EtOAc and H2O, and the aqueous layer was extracted with EtOAc
’ ASSOCIATED CONTENT
S
Supporting Information. Spectroscopic data for all the
b
reported compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jenningm@bama.ua.edu.
8031
dx.doi.org/10.1021/jo201210u |J. Org. Chem. 2011, 76, 8027–8032

The Journal of Organic Chemistry
NOTE
’ ACKNOWLEDGMENT
Support for this project was provided by the National Science
Foundation CAREER program under CHE-0845011. R.J.S. is
the 2011 American Institute of Chemists recipient within the
undergraduate program at the University of Alabama.
’ REFERENCES
(1) Pereira, A. R.; McCue, C. F.; Gerwick, W. H J. Nat. Prod. 2010,
73, 217.
(2) (a) Steinmann, P.; Keiser, J.; Bos, R.; Tanner, M.; Utzinger
J. Lancet Infect. Dis. 2006, 6, 411. (b) Chitsulo, L.; Engels, D.; Montresor,
A.; Savioli, L. Acta Trop. 2000, 77, 41.
(3) Gryseels, B.; Polman, K.; Clerinx, J.; Kestens, L. Lancet 2006,
368, 1106.
(4) (a) Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2002, 65, 386.
(b) Erickson, K. L.; Gustafson, K. R.; Pannell, L. K.; Beutler, J. A.; Boyd,
M. R. J. Nat. Prod. 2002, 65, 1303. (c) Hajare, A. K.; Ravikumar, V.;
Khaleel, S.; Bhuniya, D.; Reddy, D. S. J. Org. Chem. 2011, 76, 963.
(d) Yang, Z.; Xie, X.; Jing, P.; Zhao, G.; Zheng, J.; Zhao, C.; She, X. Org.
Biomol. Chem. 2011, 9, 984. (e) Pabbaraja, S.; Satyanarayana, K.;
Ganganna, B.; Yadav, J. S. J. Org. Chem. 2011, 76, 1922. (f) Gesinski,
M. R.; Rychnovsky, S. D. J. Am. Chem. Soc. 2011, 133, 9727.
(5) Kim, H.; Hong, J. Org. Lett. 2010, 12, 2880.
(6) Carrick, J. D.; Jennings, M. P. Org. Lett. 2009, 11, 769.
(7) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432.
(8) (a) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 1049.
(b) Smith, C. M.; O’Doherty, G. A. Org. Lett. 2003, 5, 1959. (c) Guo, H.;
Mortensen, M. S.; O’Doherty, G. A. Org. Lett. 2008, 10, 3149.
(9) (a) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993,
58, 2446. (b) Rotulo-Sims, D.; Prunet, J. Org. Lett. 2007, 9, 4147.
(10) (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.
(b) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462.
(11) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322.
(12) (a) Ding, F.; Jennings, M. P. Org. Lett. 2005, 7, 2321.
(b) Sawant, K. B.; Jennings, M. P. J. Org. Chem. 2006, 71, 7911.
(c) Sawant, K. B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2006, 47,
939. (d) Sawant, K. B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2007,
48, 5177. (e) Ding, F.; Jennings, M. P. J. Org. Chem. 2008, 73, 5965.
(f) Martinez-Solorio, D.; Jennings, M. P. J. Org. Chem. 2010, 75, 4095.
(13) (a) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am.
Chem. Soc. 2000, 122, 168. (b) Ayala, L.; Lucero, C. G.; Romero, J. A. C.;
Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521.
(14) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888. (b) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
(c) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825. (d) Pinnick,
H. W.; Childers, W. E.; Bal, B. S. Tetrahedron 1981, 37, 2091.
(15) Yamaguchi, M. A.; Katsuki, T.; Sacki, H.; Hirata, K.; Inanaga, J.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
8032
dx.doi.org/10.1021/jo201210u |J. Org. Chem. 2011, 76, 8027–8032