Syntheses of (-)-cryptocaryolone and (-)-cryptocaryolone diacetate via a diastereoselective oxy-Michael addition and oxocarbenium allylation

Article abstract of DOI:10.1021/jo301122b

The total syntheses of both (-)-cryptocaryolone and (-)-cryptocaryolone diacetate is presented herein. The usage of a diastereoselective oxy-Michael addition/benzylidene acetal formation coupled with a selective axial oxocarbenium allylation allowed for the preparation of the α-C-glycoside moiety present in the bicyclic bridged structure. In addition, the syn-1,3-diol of the linear portion was installed via a Wacker oxidation followed by a subsequent directed reduction of the appropriate homoallylic alcohol precursor.

Full text of DOI:10.1021/jo301122b

Article
pubs.acs.org/joc
Syntheses of (−)-Cryptocaryolone and (−)-Cryptocaryolone Diacetate
via a Diastereoselective Oxy-Michael Addition and Oxocarbenium
Allylation
Aymara M. M. Albury and Michael P. Jennings*
Department of Chemistry, The University of Alabama, 250 Hackberry Lane, Tuscaloosa, Alabama 35487-0336, United States
S
* Supporting Information
ABSTRACT: The total syntheses of both (−)-cryptocaryo-
lone and (−)-cryptocaryolone diacetate is presented herein.
The usage of a diastereoselective oxy-Michael addition/
benzylidene acetal formation coupled with a selective axial
oxocarbenium allylation allowed for the preparation of the α-
C-glycoside moiety present in the bicyclic bridged structure. In
addition, the syn-1,3-diol of the linear portion was installed via
a Wacker oxidation followed by a subsequent directed reduction of the appropriate homoallylic alcohol precursor.
pulmonary diseases, and a variety of other bacterial and fungal
infections, comprised both 1 and 2, in addition to a few other
structurally related compounds.
INTRODUCTION
■
Natural product extracts borne from terrestrial plant sources
have been the source of discovery for numerous biologically
active compounds for many years within a diverse array of
therapeutic areas.1 Along this line, cryptocaryolone (1) and
cryptocaryolone diacetate (2) are two dioxabicyclo[3.3.1]-
nonan-3-one derivatives2 that were obtained from the bark
extract of Cryptocarya latifolia, as shown in Figure 1.3 Isolation
Not surprisingly, there has been modest interest with respect
to the synthesis of both 1 and 2 (and other related bicyclic
lactones) due to their somewhat unusual core.4−7 Within this
paper, we will describe a distinct synthetic approach to the
preparation of both of these molecules via a highly
diastereoselective oxy-Michael addition/benzylic acetal forma-
tion followed by an oxocarbenium allylation in order to
generate the bicyclic core.
RESULTS AND DISCUSSION
■
Retrosynthetic Analysis of Cryptocaryolone (1) and
Cryptocaryolone Diacetate (2). Most synthetic approaches
to cryptocaryolone and related natural products (i.e., leiocarpin
A and polyrhacitide A and B) have relied on an intramolecular
oxy-Michael addition of an alcohol onto an α,β-unsaturated
ester under either basic or acidic conditions for the creation of
the polycyclic ester nucleus.4−7 However, our retrosynthesis
plan centered on forming the bicyclic ester core early in the
synthetic sequence via an oxocarbenium allylation followed by
intramolecular esterification. Thus, the late-stage installation of
the syn-1,3-diol resident in both 1 and 2 would be accomplished
via a directed reduction of the β-hydroxy ketone 3 as shown in
Scheme 1. It was envisioned that the β-hydroxy ketone 3 would
be obtained via a Wacker oxidation of the TES protected
homoallylic alcohol precursor 4. The usage of the Brown
allylation protocol would allow for the conversion of the
aldehyde generated from the oxidation of primary alcohol 5, to
furnish the homoallylic alcohol 4 with good/excellent levels of
diastereoselectivity. Working further back, Yamaguchi lactoni-
Figure 1. Structures of selected natural products containing a bridged
bicyclic lactone core.
and structural determination of these molecules was disclosed
by Horn in 1995 in which the relative and absolute
stereochemistry was not determined after an inquisition to
determine the molecular source of the bark extract’s biological
activity.3 Their studies revealed that the extract, which has been
used for the treatment of headaches, morning sickness, cancer,
Received: May 31, 2012
© XXXX American Chemical Society
A
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Scheme 1. Retrosynthetic Analysis of (−)-Cryptocaryolone (1) and (−)-Cryptocaryolone Diacetate (2)
Scheme 2. Synthesis of Oxocarbenium Precursor 14
zation and TBDPS deprotection would allow for the
preparation of the primary alcohol 5 from the hydroxy-
carboxylic acid compound 6. The acid 6 can be derived from
the functionalization of the allylated α-C-glycoside segment by
way of a bis-oxidation of the olefin moiety, which can be
generated from the lactone 7 through a highly diastereose-
lective oxocarbenium allylation process. It was envisioned that
lactone 7 would be generated from a sequential acetal
deprotection/acid-catalyzed cyclization of the benzylidene
acetal 8. The lactone precursor 8 would be diastereoselectively
prepared from the intramolecular oxy-Michael addition of
benzaldehyde to the δ-hydroxy-(E)-α,β-unsaturated methyl
ester, which would be generated by means of a Ru-catalyzed
cross-metathesis of homoallylic alcohol 9 with methyl acrylate
as reported previously by O’Doherty.4a
With this retrosynthetic plan in mind, our initial focus was to
prepare acetate 14, the precursor for the oxocarbenium
allylation. As shown in Scheme 2, treatment of the previously
reported TBDPS monoprotected homoallylic alcohol 98
(prepared by an asymmetric allylboration of 3-((tert-
butyldiphenylsilyl)oxy)propanal) with methyl acrylate (10) in
the presence of Grubbs’ second-generation catalyst (11) under
standard olefin cross-metathesis conditions provided the δ-
hydroxy-(E)-α,β-unsaturated methyl ester 12 in 83% yield as a
single diastereomer.4a,9,10 Following the Evans-acetal formation
protocol, the δ-hydroxy enoate 12 was converted to the syn-
B
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Scheme 3. Synthesis of Carboxylic Acid Intermediate 20 via an Oxocarbenium Allylation Process
Scheme 4. Synthesis of Homoallylic Alcohol 4 via Asymmetric Allylboration
benzylidene acetal 8 by addition of PhCHO and KOtBu over 2
HOAc followed by cyclization/transesterfication led to the
formation of the hydroxy lactone 13 in 71% yield. Protection of
the free hydroxyl group resident in 13 was achieved using
standard silylating conditions (TBSCl and imidazole) and
1
h in 67% yield as a single diastereomer, as determined by H
NMR analysis.11 Subsequent hydrogenolysis of 10 in the
presence of H2 and Pearlman’s catalyst [Pd(OH)2] at rt in
C
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Scheme 5. Synthesis of (−)-Cryptocaryolone (1) and (−)-Cryptocaryolone Diacetate (2)
provided the TBS protected β-hydroxy lactone 7. Partial
reduction of the carbonyl moiety of 7 with DIBAL-H at −78 °C
resulted in the formation of a diastereomeric mixture of lactols.
Ensuing treatment of the lactol mixture (as a 4:1 ratio of
epimers) in the presence of acetic anhydride and pyridine
afforded intermediate 14 in 87% yield over two steps from 7.12
With intermediate 14 in hand, we shifted our focus to the
preparation of the α-C-glycoside subunit, by means of a
stereoselective oxocarbenium allylation. As the result of
previous synthetic endeavors, we were confident that our
approach would allow for the preparation of the intended target
with high levels of stereoselectivity in good to excellent yields.13
With this in mind, the treatment of acetate 14 with BF3·OEt2 at
−78 °C presumably generated the oxocarbenium cation, which
existed as two possible reactive conformers, 16 and 17, as
shown in Scheme 3. Conformer 16 maintains the C5 alkyl
substituent in the pseudo axial position and the C3 silyloxy
substituent in the equatorial position. Conversely, conformer
17 places the C5 substituent in the pseudo equatorial position
and the C3 silyloxy substituent in the axial position.
On the basis of our previous observations and in accordance
with Woerpel’s reports, we predicted that 17 would be the
“matched” conformer, and axial nucleophilic addition of
allyltrimethylsilane (15) would stereoselectively furnish 18 via
a chairlike transition state.14 As expected, the α-C-glycoside 18
was isolated with a very high dr (>20:1) as a single
stereoisomer in 89% yield. Ensuing ozonolysis of the olefin
moiety resident in 18 followed by a reductive quench with PPh3
provided aldehyde 19 in 87% yield. Subsequently, further
oxidation of aldehyde 19 was accomplished by utilizing the
Lindgren−Kraus−Pinnick protocol to afford the carboxylic acid
20 in virtually quantitative yield (99%).15
20 was accomplished using a THF/HCOOH/H2O (6:3:1)
mixture at 0 °C to provide the hydroxy acid 6 in 77% yield.
Ensuing exposure of 6 to standard Yamaguchi lactonization
conditions afforded the TBDPS protected 2,6-
dioxabicyclo[3.3.1]nonan-3-one compound 22 in 88% yield.16
Cleavage of the TBDPS ether presented a bit of a challenge,
due to the delicate nature of the bicyclic bridged moiety.
However, the use of a HF·pyridine buffered with additional
pyridine at 0 °C readily allowed for desilylation and provided
the primary alcohol 5 in 77% yield. Subsequent oxidation of the
primary alcohol moiety of 5 was achieved by using NaHCO3
buffered Dess−Martin periodinane (23) and afforded aldehyde
24 in 64% yield.17 A mismatched asymmetric allylboration of
aldehyde 24 with Brown’s (−)-Ipc2Ballyl reagent followed by
basic oxidation (NaOH and H2O2) furnished homoallylic
alcohol 4 in a modest 62% yield with a 6:1 dr (as determined by
1H NMR of the crude reaction mixture) for the desired
stereoisomer.18
In order to accomplish the syntheses of both 1 and 2,
homoallylic alcohol 4 must be converted to TES protected
counterpart 25 followed by Wacker oxidation of the terminal
alkene and final directed syn-reduction to provide the diol
stereochemistry as shown in Scheme 5.
Thus, the treatment of 4 with TESCl, DMAP, and imidazole
provided the silyl ether in 84% yield and set the stage for the
oxidation of the terminal alkene resident in 25. Ensuing
exposure of 25 to the standard Wacker oxidation procedure as
described by Smith and co-workers [PdCl2 and Cu(OAc)2
under an atmosphere of O2] converted the olefin moiety into
methyl ketone 26 in 66% yield.19 Subsequent desilylation of 26
using p-TsOH in a 1:1 MeOH/CH2Cl2 solution at 0 °C
afforded the β-hydroxy methyl ketone 3 in 80% yield. The
utilization of a chelation-controlled reduction by means of
Et2BOMe and NaBH4 allowed for the conversion of the β-
hydroxy ketone moiety of 3 to the 1,3-syn diol and thus the
completion of 1 in 92% yield and a dr of >20:1 as determined
With carboxylic acid 20 in hand, our next challenge was to
complete the bicyclic bridged structure and prepare the
homoallylic alcohol precursor required for the preparation of
the 1,3-syn diol moiety as delineated in Scheme 4. Selective
removal of the TBS protecting group resident in carboxylic acid
20
1
by H NMR. Finally, treatment of 1 with Ac2O and pyridine
D
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[α]23D = −82.0 (c 0.92, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.66
(m, 4H), 7.36 (m, 11H), 5.54 (s, 1H), 4.32 (m, 1H), 4.14 (m, 1H),
3.92 (m, 1H), 3.77 (m, 1H), 3.71 (s, 3H), 2.73 (dd, J = 15.5, 7.3 Hz,
1H), 2.51 (dd, J = 15.5, 6.0 Hz, 1H), 1.84 (m, 2H), 1.71 (dt, J = 12.9,
2.5 Hz, 1H), 1.46 (dt, J = 12.9, 11.4 Hz, 1H), 1.06 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 171.2, 138.5, 135.5, 133.8, 133.7, 129.6, 129.6,
128.5, 128.1, 127.6, 127.6, 126.1, 100.5, 73.3, 73.2, 59.5, 51.7, 40.8,
38.7, 36.7, 31.6, 26.9, 23.1; IR (neat) cm−1 2958, 2859, 1741, 1475,
741, 703; HRMS (EI) calcd for C31H38O5Si [M − C4H9] 461.1784,
found 461.1784.
afforded 2 in 91% yield. The spectral data (1H NMR, 500 MHz;
13C NMR, 125 MHz), optical rotations ([α]23 −21.1, c 0.52,
D
CH2Cl2 for 1 and ([α]23 −32.7, c 0.31, CH2Cl2 for 2) and
D
HRMS data of synthetic 1 and 2 were in agreement with the
natural samples.3,4 It is worth mentioning that our rotational
data is very similar to She’s values (in CH2Cl2);4c however, they
are lower than that of the disclosure paper (−128 and −145 for
1 and 2, in CHCl3).3
(4S,6S)-6-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)-4-hydroxyte-
trahydro-2H-pyran-2-one (13). To a solution of 8 (3.50 g, 6.75
mmol, 1.00 equiv) in acetic acid (100 mL) at rt was added Pd(OH)2
(3.5 g). The mixture was then subjected to an atmosphere of H2 and
allowed to stir for 16 h. The catalyst was filtered off through Celite,
and the filtrate was concentrated to leave a crude residue. The residue
was purified by flash chromatography (38% EtOAc/hexanes) to afford
13 as a white solid (1.91 g, 71%): TLC Rf = 0.43 in 50% EtOAc/
CONCLUSION
■
In summary, both (−)-cryptocaryolone and (−)-cryptocar-
yolone diacetate were prepared in an efficient diastereoselective
manner using an oxy-Michael addition followed by a stereo-
selective oxocarbenium allylation process. The late stage
installation of the syn-1,3-polyol moieties resident in 1 and 2
also allow for the synthesis of additional natural products that
possess the dioxabicyclo[3.3.1]nonan-3-one structure, such as
ent- polyrhacitide A and B from a common intermediate.
hexanes; [α]23 = −84.2 (c 0.57, CH2Cl2); 1H NMR (500 MHz,
D
CDCl3) δ 7.66 (m, 4H), 7.40 (m, 6H), 4.93 (m, 1H), 4.32 (m, 1H),
3.88 (m, 1H), 3.81 (m, 1H), 2.69 (dd, J = 17.7, 5.0 Hz, 1H), 2.59
(ddd, J = 17.7, 3.8, 1.6 Hz, 1H), 2.31 (br s, 1H), 1.96 (m, 2H), 1.84
(m, 1H), 1.75 (ddd, J = 14.5, 11.4, 3.5 Hz, 1H), 1.06 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 170.8, 135.4, 135.4, 133.5, 133.4, 129.6,
127.6, 73.2, 62.3, 59.5, 38.5, 38.2, 35.9, 26.8, 19.1; IR (neat) cm−1
3398, 2859, 1706, 1252, 950, 826; HRMS (EI) calcd for C23H30O4Si
[M − C4H9] 341.1209, found 341.1208.
(4S,6S)-4-((tert-Butyldimethylsilyl)oxy)-6-(2-((tert-
butyldiphenylsilyl)oxy)ethyl)tetrahydro-2H-pyran-2-one (7).
To a stirred solution of 13 (3.83 g, 9.62 mmol, 1.00 equiv) in
anhydrous DMF (24.0 mL) under Ar at 0 °C were added imidazole
(1.96 g, 28.9 mmol, 3.00 equiv), DMAP (0.118 g, 0.962 mmol, 0.10
equiv), and tert-butyldimethylsilyl chloride (1.74 g, 11.5 mmol, 1.2
equiv) sequentially. The mixture was allowed to warm to rt and stir
overnight. The mixture was then diluted with water and extracted by
EtOAc. The aqueous layer was washed with EtOAc (3 × 25 mL). The
combined organic layers were washed with water (3 × 20 mL), then
dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by flash chromatography (10% EtOAc/
EXPERIMENTAL SECTION
■
General Procedure. All of the reactions were performed under an
inert atmosphere of Ar in flame-dried glassware. All starting materials
and solvents were commercially available and were used without
further purification. Deuterated chloroform (CDCl3) was stored over
molecular sieves (4 Å). The NMR spectra were recorded on a 500
1
MHz spectrometer. H and 13C NMR spectra were obtained using
either CDCl3 or C6D6 as the solvent with chloroform (CHCl3, 7.26
ppm) or benzene (C6H6, 7.15 ppm) as the internal standard. High-
resolution mass spectra were recorded on an EBE sector instrument
using electron ionization (EI) at 70 eV. Column chromatography was
performed using 60−200 μm silica gel. Analytical thin layer
chromatography was performed on silica-coated glass plates with F-
254 indicator. Visualization was accomplished by UV light (254 nm),
KMnO4, or ceric sulfate-PMA stain. Compound 9 has been previously
reported.8
(R,E)-Methyl 7-((tert-butyldiphenylsilyl)oxy)-5-hydroxyhept-
2-enoate (12). To a flame-dried round-bottom flask with a solution
of 9 (2.80 g, 7.91 mmol, 1.00 equiv) in anhydrous CH2Cl2 (160 mL)
under an atmosphere of Ar at rt was added methyl acrylate (9.27 mL,
103 mmol, 13.0 equiv) dropwise. To the resulting solution was added
Grubbs’ second-generation catalyst (0.335 g, 0.395 mmol, 0.05 equiv).
The solution was allowed to stir for 16 h at rt. The reaction was then
concentrated under reduced pressure and purified by flash
chromatography (15% EtOAc/hexanes) to afford 12 as a brown
hexanes) to afford 7 as a yellow, viscous oil (4.45 g, 89%): TLC Rf =
1
0.37 in 20% EtOAc/hexanes; [α]23 = +13.3 (c 0.60, CH2Cl2); H
D
NMR (500 MHz, CDCl3) δ 7.69 (m, 4H), 7.41 (m, 6H), 5.05 (m,
1H), 4.33 (m, 1H), 3.94 (m, 1H), 3.81 (m, 1H), 2.60 (m, 2H), 1.93
(m, 2H), 1.85 (m, 1H), 1.73 (ddd, J = 13.9, 11.7, 2.5 Hz, 1H), 1.08 (s,
9H), 0.91 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 170.0, 135.4, 135.3, 133.5, 133.3, 129.5, 129.5, 127.6, 127.5,
72.9, 63.5, 59.4, 39.2, 38.4, 36.7, 26.7, 25.6, 19.0, 17.8, −5.0, −4.9; IR
(neat) cm−1 2932, 2857, 1738, 1472, 1253, 1087, 835; HRMS (EI)
calcd for C29H44O4Si2 [ M − C4H9] 455.2074, found 455.2091.
(4S,6S)-4-((tert-Butyldimethylsilyl)oxy)-6-(2-((tert-
butyldiphenylsilyl)oxy)ethyl)tetrahydro-2H-pyran-2-yl Acetate
(14). To a solution of 7 (4.45 g, 8.69 mmol, 1.00 equiv) in anhydrous
CH2Cl2 (54.0 mL), under an atmosphere of Ar, was added DIBAL-H
(1.0 M in toluene, 10.9 mL, 1.25 equiv) at −78 °C. The reaction was
stirred until there was no sign of starting material on TLC (4 h). The
reaction was then quenched with an aqueous solution of saturated
NaHCO3, diluted with CH2Cl2, and warmed to rt with magnetic
stirring. After the solution was washed with aqueous NH4Cl, the
organic layer was separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were dried over
MgSO4 and filtered, and the solvent was evaporated to yield the crude
lactol. The product was dissolved in anhydrous CH2Cl2 (54.0 mL). To
this solution were added pyridine (1.05 mL, 13.0 mmol, 1.50 equiv),
Ac2O (1.44 mL, 15.2 mmol, 1.75 equiv), and DMAP (0.106 g, 0.869
mmol, 0.100 equiv). The mixture was stirred at rt for 16 h, at which
time the reaction was quenched with aqueous NaHCO3. The aqueous
layer was extracted with CH2Cl2 (3 × 30 mL). The organic layers were
dried over MgSO4, filtered, and concentrated under vacuum. The
crude product was purified by flash chromatography (5% EtOAc/
hexanes) to afford 14 as a colorless oil (4.21 g, 87%): TLC Rf = 0.57 in
viscous oil (2.70 g, 83%): TLC Rf = 0.240 in 20% EtOAc/hexanes;
[α]23 = +6.0 (c 1.17, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.67
1
D
(m, 4H), 7.43 (m, 6H), 7.01 (ddd, J = 15.8, 7.6, 7.3 Hz, 1H), 5.91
(ddd, J = 15.8, 1.6, 1.3 Hz, 1H), 4.07 (m, 1H), 3.86 (m, 2H), 3.73 (s,
3H), 3.41 (d, J = 2.8 Hz, 1H), 2.41 (m, 2H), 1.75 (m, 1H), 1.67 (m,
1H), 1.05 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 166.7, 145.5,
135.5, 132.8, 129.9, 127.8, 123.2, 70.5, 63.2, 51.4, 40.2, 37.9, 26.8, 18.9;
IR (neat) cm−1 3501, 2945, 1722, 1654, 823; HRMS (EI) calcd for
C24H32O4Si [M − C4H9] 355.1366, found 355.1355.
Methyl-2-((2S,4S,6S)-6-(2-((tert-butyldiphenylsilyl)oxy)-
ethyl)-2-phenyl-1,3-dioxan-4-yl)acetate (8). Ester 12 (4.39 g,
10.7 mmol, 1.00 equiv) was dissolved in anhydrous THF (110 mL)
under Ar and cooled to 0 °C. To this stirred solution were added
benzaldehyde (1.20 mL, 11.7 mmol, 1.10 equiv) and KO-t-Bu (0.119
g, 1.06 mmol, 0.10 equiv) sequentially. This addition was repeated four
times for benzaldehyde and eight times for KO-t-Bu in 15 min
intervals. The reaction was allowed to warm to rt and then quenched
with pH 7 buffer solution (60 mL). The layers were separated, and
extraction of the aqueous layer was done with Et2O (3 × 50 mL). The
combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified by
flash chromatography (8% EtOAc/hexanes) to afford 8 as a yellow
viscous oil (3.70 g, 67%): TLC Rf = 0.38 in 10% EtOAc/hexanes;
E
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1
10% EtOAc/hexanes; [α]23 = +1.7 (c 0.58, CH2Cl2); H NMR (500
(s, 6H); 13C NMR (125 MHz, CDCl3) δ 173.6, 135.6, 135.5, 133.9,
133.7, 129.6, 127.6, 67.2, 66.6, 64.6, 60.4, 39.7, 38.8, 38.5, 35.7, 26.9,
25.8, 19.2, 18.0, −4.7; IR (neat) cm−1 3250, 2957, 2890, 1712, 1468,
1257, 910; HRMS (EI) calcd for C31H48O5Si2 [ M − C4H9] 499.2336,
found 499.2328.
D
MHz, CDCl3) δ 7.67 (m, 4H), 7.39 (m, 6H), 6.07 (dd, J = 9.8, 2.2 Hz,
1H), 4.30 (m, 2H), 3.82 (m, 1H), 3.72 (m, 1H), 2.09 (s, 3H), 1.85 (m,
1H), 1.80 (m, 1H), 1.70 (m, 1H), 1.61 (m, 2H), 1.46 (m, 1H), 1.04 (s,
9H), 0.91 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 168.9, 135.6, 135.5, 134.0, 133.8, 129.5, 127.6, 92.1, 68.6,
65.6, 60.0, 38.7, 38.6, 38.0, 26.8, 25.7, 21.2, 19.2, 17.9, −5.0, −4.9; IR
(neat) cm−1 2954, 2857, 1745, 1428, 1231, 1039, 773; HRMS (EI)
calcd for C31H48O5Si2 [ M − C4H9] 499.2336, found 499.2346.
(2-((2S,4R,6S)-6-Allyl-4-((tert-butyldimethylsilyl)oxy)-
tetrahydro-2H-pyran-2-yl)ethoxy)(tert-butyl)diphenylsilane
(18). Acetate 14 (4.21 g, 7.57 mmol, 1.00 equiv) and allyltrimethylsi-
lane (3.02 mL, 18.9 mmol, 2.50 equiv) were dissolved in anhydrous
CH2Cl2 (76 mL) under an atmosphere of Ar. Upon cooling to −78
°C, BF3·OEt2 (1.89 mL, 15.1 mmol, 2.00 equiv) was added dropwise
via syringe. Upon completion of the reaction, as monitored by TLC
(0.5 h), the light yellow solution was quenched with a saturated
solution of NaHCO3 at −78 °C, and the reaction was allowed to warm
to rt. The mixture was then extracted with CH2Cl2 (3 × 30 mL), and
the combined organic layers were washed with brine. After drying with
anhydrous Na2SO4 and evaporation of solvent, the crude product was
purified by flash chromatography (5% EtOAc/hexanes) to afford 18 as
a colorless oil (3.64 g, 89%): TLC Rf = 0.68 in 10% EtOAc/hexanes;
[α]23D = −14.0 (c 0.57, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.72
(m, 4H), 7.42 (m, 6H), 5.78 (m, 1H), 5.06 (d, J = 17.3 Hz, 1H), 4.99
(d, J = 10.1 Hz, 1H), 4.30 (m, 1H), 3.98 (m, 1H), 3.81 (m, 1H), 3.73
(m, 1H), 3.54 (m, 1H), 2.42 (m, 1H), 2.23 (m, 1H), 1.96 (m, 1H),
1.81 (ddd, J = 12.9, 3.8, 3.5 Hz, 1H), 1.67 (dd, J = 6.6, 4.7 Hz, 2H),
1.32 (m, 2H), 1.09 (s, 9H), 0.93 (s, 9H), 0.09 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 135.6, 135.5, 135.3, 133.9, 133.7, 129.5, 127.6, 116.5,
69.1, 67.7, 65.3, 60.8, 39.9, 39.8, 38.9, 35.2, 26.8, 25.8, 19.1, 18.1, −4.6,
−4.7; IR (neat) cm−1 2954, 2854, 1645, 1428, 1109, 700; HRMS (EI)
calcd for C32H50O3Si2 [ M − C4H9] 481.2594, found 481.2601.
2-((2R,4S,6S)-4-((tert-Butyldimethylsilyl)oxy-6-(2-((tert-
butyldiphenylsilyl)oxy)ethyl)tetrahydro-2H-pyran-2-yl)-
acetaldehyde (19). A solution of 18 (3.64 g, 6.76 mmol, 1.00 equiv)
dissolved in CH2Cl2 (68.0 mL) was cooled to −78 °C, and O3 was
bubbled through the solution until the starting material was consumed
as indicated by TLC analysis (0.5 h). The solution was then purged
with O2, and the reaction was quenched via portionwise addition of
PPh3 (5.32 g, 20.3 mmol, 3.0 equiv) and stirred for 4 h. The resulting
mixture was concentrated in vacuo to yield the crude aldehyde as a
yellow solid. Purification by flash chromatography (5% EtOAc/
hexanes) afforded 19 as a white solid (3.19 g, 87%): TLC Rf = 0.57 in
15% EtOAc/hexanes; [α]23D = −4.8 (c 0.62, CH2Cl2); 1H NMR (500
MHz, CDCl3) δ 9.69 (s, 1H), 7.70 (m, 4H), 7.41 (m, 6H), 4.31 (m,
1H), 4.16 (m, 1H), 4.05 (m, 1H), 3.80 (m, 1H), 3.72 (m, 1H), 2.84
(ddd, J = 16.7, 8.2, 2.2 Hz, 1H), 2.60 (ddd, J = 16.7, 5.0, 1.6 Hz, 1H),
1.89 (m, 2H), 1.67 (m, 3H), 1.43 (m, 1H), 1.09 (s, 9H), 0.93 (s, 9H),
0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 201.2,
135.5, 133.8, 133.6, 129.5, 127.6, 127.5, 66.4, 65.3, 64.8, 60.4, 48.7,
38.9, 38.6, 35.8, 26.8, 25.8, 19.1, 17.9, −4.8; IR (neat) cm−1 2950,
2857, 1726, 1105, 1035, 869; HRMS (EI) calcd for C31H48O4Si2 [ M
− C4H9] 483.2387, found 483.2403.
2-((2R,4S,6S)-6-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)-4-hy-
droxytetrahydro-2H-pyran-2-yl)acetic Acid (6). A solution of acid
20 (3.25 g, 5.83 mmol, 1.00 equiv) in 512 mL of a mixture of THF/
HCOOH/H2O (6:3:1) was stirred at 0 °C for 3 h. The mixture was
neutralized with a saturated solution of NaHCO3 (400 mL) and
partitioned between 200 mL of EtOAc and 200 mL of brine. The
combined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. Purification by flash chromatography (48%
EtOAc/2% AcOH/50% hexanes) afforded 6 as a colorless viscous oil
(2.01 g, 77%): TLC Rf = 0.39 in 48% EtOAc/2% AcOH/50% hexanes;
[α]23D = −23.1 (c 0.74, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.72
(m, 4H), 7.42 (m, 6H), 4.38 (br s, 1H), 3.99 (m, 2H), 3.83 (m, 1H),
3.76 (m, 1H), 2.63 (dd, J = 15.8, 7.6 Hz, 1H), 2.51 (dd, J = 15.8, 5.7
Hz, 1H), 2.00 (m, 2H), 1.84 (br d, J = 12.6 Hz, 1H), 1.69 (m, 2H),
1.33 (m, 1H), 1.10 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 175.6,
135.4, 135.3, 133.7, 133.6, 129.5, 129.4, 127.5, 127.4, 68.9, 65.4, 64.0,
60.3, 40.4, 39.5, 37.4, 34.2, 26.7, 19.0; IR (neat) cm−1 3432, 2854,
1723, 1429, 933, 822, 747; HRMS (EI) calcd for C25H34O5Si [ M −
C4H9 − H2O] 367.1366, found 367.1371.
(1S,5R,7S)-7-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)-2,6-
dioxabicyclo[3.3.1]nonan-3-one (22). To a solution of hydrox-
yacid 6 (0.500 g, 1.13 mmol, 1.00 equiv) in THF (23 mL), under an
atmosphere of Ar, cooled to 0 °C were added Et3N (0.954 mL, 6.85
mmol, 6.06 equiv) and 2,4,6-trichlorobenzoyl chloride (0.689 mL, 4.41
mmol, 3.90 equiv). After being stirred at rt for 4 h, the reaction
mixture was diluted with toluene (28.0 mL). This mixture was then
added dropwise, over 6.5 h, into a solution of DMAP (4.14 g, 33.9
mmol, 30.0 equiv) in toluene (226 mL) at 100 °C and allowed to stir
overnight. The reaction was then cooled to rt and washed successively
with 0.5 M HCl solution (100 mL), saturated aqueous NaHCO3
solution (100 mL), and then brine (100 mL). The organic layer was
dried over Na2SO4, filtered, concentrated under vacuum, and then
purified by flash chromatography (30% EtOAc/hexanes) to afford 22
as a colorless viscous oil (0.420 g, 88%): TLC Rf = 0.37 in 30%
1
EtOAc/hexanes; [α]23 = −13.5 (c 0.41, CH2Cl2); H NMR (500
D
MHz, CDCl3) δ 7.67 (m, 4H), 7.38 (m, 6H), 4.80 (bs, 1H), 4.26 (bs,
1H), 4.05 (m, 1H), 3.82 (m, 1H), 3.74 (m, 1H), 2.79 (bd, J = 19.2 Hz,
1H), 2.71 (dd, J = 19.2, 5.0 Hz, 1H), 1.99 (bd, J = 11.0 Hz, 1H), 1.91
(bd, J = 13.9 Hz, 1H), 1.84 (bd, J = 13.6 Hz, 1H), 1.74 (m, 2H), 1.54
(ddd, J = 13.6, 11.7, 2.2 Hz, 1H), 1.07 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 169.0, 135.2, 133.5, 129.3, 127.4, 72.7, 65.6, 62.2, 59.5, 38.4,
36.8, 36.2, 29.5, 26.6, 18.9; IR (neat) cm−1 3070, 2926, 2858, 1734,
1472, 1242, 1088, 703; HRMS (EI) calcd for C25H32O4Si [ M −
C4H9] 367.1362, found 367.1364.
(1S,5R,7S)-7-(2-Hydroxyethyl)-2,6-dioxabicyclo[3.3.1]nonan-
3-one (5). To a stirred solution of 22 (0.533 g, 1.26 mmol, 1.00
equiv) in THF (13.0 mL) at 0 °C in a polyethylene bottle was added
HF·pyridine stock solution (HF·Py/Py/THF (1:2:5)) (4.76 mL). The
resulting mixture was stirred at 0 °C for 40 min and then allowed to
warm to rt and stirred for an additional 4 h. The reaction was then
quenched by slow addition of a saturated solution of NaHCO3, and
the resulting mixture was stirred for 10 min at rt. The mixture was then
diluted with CHCl3, and the layers were separated. The aqueous layer
was extracted by CHCl3 (3 × 15), and the combined organic layers
were washed with brine, dried over Na2SO4, filtered, and concentrated
in vacuo. The crude product was purified by flash chromatography (5%
2-((2R,4S,6S)-4-((tert-Butyldimethylsilyl)oxy-6-(2-((tert-
butyldiphenylsilyl)oxy)ethyl)tetrahydro-2H-pyran-2-yl)acetic
Acid (20). To a solution of aldehyde 19 (3.19 g, 5.89 mmol, 1.00
equiv) in THF (59.0 mL) and t-BuOH (59.0 mL) was added 2-
methyl-2-butene (6.23 mL, 58.9 mmol, 10.0 equiv) under vigorous
stirring. NaClO2 (2.66 g, 29.5 mmol, 5.00 equiv) and NaH2PO4 (3.53
g, 29.5 mmol, 5.00 equiv) were dissolved in water (19.6 mL), and the
aqueous solution was added to the mixture, which was stirred at rt for
3.5 h. Once complete by TLC analysis, the mixture was diluted with
water and extracted with CH2Cl2, followed by evaporation of the
organic layer in vacuo to afford the acid 20 without further purification.
MeOH/CH2Cl2) to afford 5 as a colorless oil (0.180 g, 77%); TLC Rf
1
= 0.25 in 6% MeOH/CH2Cl2; [α]23 = −37.5 (c 1.65, CH2Cl2); H
D
NMR (500 MHz, CDCl3) δ 4.88 (br s, 1H), 4.37 (br s, 1H), 3.99 (m,
1H), 3.74 (t, J = 5.4 Hz, 2H), 2.89 (bd, J = 19.2 Hz, 1H), 2.78 (dd, J =
19.2, 5.4 Hz, 1H), 2.43 (bs, 1H), 2.02 (m, 2H), 1.93 (m, 1H), 1.75 (m,
2H), 1.65 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 169.5, 72.7, 65.9,
65.5, 60.3, 37.7, 36.9, 36.4, 29.6; IR (neat) cm−1 3410, 2954, 1719,
1084, 780; HRMS (EI) calcd for C9H14O4 [ M ] 186.0892, found
186.0894, calcd for C9H14O4 [ M − H2O ] 168.0786, found 168.0785.
(3.25 g, 99%): TLC Rf = 0.31 in 15% EtOAc/hexanes; [α]23 = −5.2
D
(c 0.95, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.66 (m, 4H), 7.39
(m, 6H), 4.34 (m, 1H), 4.02 (m, 2H), 3.77 (m, 1H), 3.69 (m, 1H),
2.79 (dd, J = 15.8, 8.5 Hz, 1H), 2.56 (dd, J = 15.8, 4.8 Hz, 1H), 1.87
(m, 2H), 1.65 (m, 2H), 1.46 (m, 2H), 1.04 (s, 9H), 0.88 (s, 9H), 0.05
F
dx.doi.org/10.1021/jo301122b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2-((1R,3R,5S)-7-Oxo-2,6-dioxabicyclo[3.3.1]nonan-3-yl)-
acetaldehyde (24). To a solution of alcohol 5 (0.213 g, 1.14 mmol,
1.00 equiv) in CH2Cl2 (143 mL) at rt was added NaHCO3 (0.480 g,
5.72 mmol, 5.00 equiv) followed by DMP (0.581 g, 1.37 mmol, 1.20
equiv). The resulting mixture was stirred for 2 h before being
quenched with NaHCO3 (70 mL, satd aq) and Na2S2O3 (70 mL, satd
aq). The layers were separated, the aqueous layer was extracted with
CHCl3 (3 × 100 mL), and the combined organic layers were dried
over Na2SO4 and concentrated in vacuo. Flash column chromatog-
raphy (65% EtOAc/hexanes) was used to purify aldehyde 24 as a
colorless oil (0.134 g, 64%); TLC Rf = 0.30 in 80% EtOAc/hexanes;
[α]23D = −1.6 (c 6.70, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 9.69
(dd, J = 2.8, 1.6 Hz, 1H), 4.87 (m, 1H), 4.31 (m, 2H), 2.85 (d, J = 19.2
Hz, 1H), 2.76 (dd, J = 19.2, 5.4 Hz, 1H), 2.56 (ddd, J = 16.4, 7.9, 2.8
Hz, 1H), 2.49 (ddd, J = 16.4, 4.1, 1.3 Hz, 1H), 2.05 (m, 1H), 1.97 (m,
1H), 1.90 (m, 1H), 1.62 (ddd, J = 13.9, 11.7, 2.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 199.7, 169.1, 72.4, 65.9, 65.7, 61.4, 48.7, 36.2,
29.2; IR (neat) cm−1 2958, 1723, 1384, 1198, 1065, 734; HRMS (EI)
calcd for C9H12O4 [ M + H] 185.0814, found 185.0817.
(1S,5R,7S)-7-((S)-2-Hydroxypent-4-en-1-yl)-2,6-dioxabicyclo-
[3.3.1]nonan-3-one (4). To a flame-dried round-bottom flask under
Ar, allylMgBr (1.0 M in Et2O, 1.22 mL) was added dropwise into a
solution of (−)-Ipc2BOMe (0.411 g, 1.30 mmol, 1.80 equiv) in
anhydrous Et2O (3.26 mL) at 0 °C. The reaction was allowed to stir at
rt for 1 h before being cooled to −78 °C. The aldehyde 24 (0.134 g,
0.730 mmol, 1.00 equiv) was dissolved in THF (1.00 mL), added
dropwise into the borane solution and allowed to stir for 1 h, then
allowed to warm to rt slowly over the course of 1 h. A solution of pH 7
buffer (0.575 mL) was added followed by slow addition of 30% H2O2
solution (1.07 mL). The mixture was refluxed at 35 °C for 3 h. After
cooling to rt, the biphasic solution was separated, and the aqueous
layer was extracted with CHCl3 (3 × 10 mL). The organic layers were
combined, dried over MgSO4, and concentrated under pressure. The
crude product was purified by flash chromatography (65% EtOAc/
H2O (7:1) (2.73 mL) was placed under an atmosphere of O2 and
stirred at rt for 24 h. The reaction was then diluted with Et2O and
water. The aqueous layer was extracted with Et2O (3 × 5 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under vacuum. The crude product was then purified
by flash chromatography (40% EtOAc/hexanes) to afford 26 as a
colorless oil (0.064 g, 66%); TLC Rf = 0.21 in 35% EtOAc/hexanes;
[α]23D = −18.3 (c 0.49, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 4.86
(br s, 1H), 4.31 (m, 2H), 3.88 (m, 1H), 2.83 (br d, J = 19.2 Hz, 1H),
2.75 (dd, J = 19.2, 5.0 Hz, 1H), 2.59 (d, J = 6.3 Hz, 2H), 2.13 (s, 3H),
1.98 (m, 2H), 1.88 (m, 1H), 1.75 (ddd, J = 14.2, 7.9, 4.7 Hz, 1H), 1.57
(m, 2H), 0.91 (t, J = 7.9 Hz, 9H), 0.55 (q, J = 7.9 Hz, 6H). 13C NMR
(125 MHz, CDCl3) δ 207.5, 169.4, 72.9, 65.6, 65.4, 62.3, 50.6, 43.3,
37.2, 36.4, 31.5, 29.7, 6.8, 4.9; IR (neat) cm−1 2952, 2878, 1731, 1074,
1007, 742; HRMS (EI) calcd for C18H32O5Si [ M − C2H5] 327.1628
found 327.1633, calcd for C18H32O5Si [ M + H] 357.2097, found
357.2104.
(1S,5R,7S)-7-((R)-2-Hydroxy-4-oxopentyl)-2,6-dioxabicyclo-
[3.3.1]nonan-3-one (3). To a solution of 26 (0.0580 g, 0.163 mmol,
1.00 equiv) in a 1:1 MeOH/DCM (2.71 mL) at 0 °C was added p-
TsOH (0.00300 g, 0.0163 mmol, 0.10 equiv). The resulting solution
was stirred at 0 °C for 2 h. The reaction was then quenched with
saturated aqueous NaHCO3 (5 mL), and the solution was extracted
with CHCl3 (3 × 5 mL). The combined organic extracts were dried
over MgSO4 and concentrated in vacuo, and the residue was purified
by column chromatography (2% MeOH/CH2Cl2) to afford 3 as a
colorless oil (0.0310 g, 80%); TLC Rf = 0.11 in 80% EtOAc/hexanes;
[α]23D = −22.2 (c 1.57, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 4.88
(m, 1H), 4.37 (m, 1H), 4.24 (m, 1H), 4.02 (m, 1H), 3.41 (d, J = 1.9
Hz, 1H), 2.88 (bd, J = 19.2 Hz, 1H), 2.79 (dd, J = 19.2, 5.4 Hz, 1H),
2.62 (dd, J = 16.7, 7.9 Hz, 1H), 2.55 (dd, J = 17.0, 4.4 Hz, 1H), 2.17
(s, 3H), 2.03 (m, 2H), 1.93 (m, 1H), 1.68 (m, 1H), 1.63 (m, 2H). 13C
NMR (125 MHz, CDCl3) δ 208.3, 169.2, 72.6, 66.4, 65.9, 65.5, 50.2,
41.8, 36.9, 36.4, 30.8, 29.5; IR (neat) cm−1 3172, 2955, 2881, 1712,
1351, 1063, 785; HRMS (EI) calcd for C12H18O5 [ M − H2O]
224.1049, found 224.1051, calcd for C12H18O5 [ M + H] 243.1232,
found 243.1232.
hexanes) to afford 4 as a colorless viscous oil (0.102 g, 62%); TLC Rf =
1
0.16 in 70% EtOAc/hexanes; [α]23 = −28.1 (c 3.20, CH2Cl2); H
D
NMR (500 MHz, CDCl3) δ 5.78 (m, 1H), 5.06 (m, 2H), 4.85 (m,
1H), 4.37 (br s, 1H), 3.98 (m, 1H), 3.83 (m, 1H), 3.17 (br s, 1H),
2.86 (br d, J = 19.2 Hz, 1H), 2.78 (dd, J = 19.2, 5.4 Hz 1H), 2.19 (m,
2H), 2.00 (m, 2H), 1.92 (m, 1H), 1.61 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 169.2, 134.4, 117.5, 72.5, 70.3, 66.6, 65.9, 41.9, 41.7, 37.1,
36.3, 29.4; IR (neat) cm−1 3456, 2946, 1730, 1639, 1339, 1198, 1077,
913; HRMS (EI) calcd for C12H18O4 [ M + H] 227.1283 found
227.1275, calcd for C12H18O4 [ M − OH] 209.1178, found 209.1178.
(1S,5R,7S)-7-((S)-2-((Triethylsilyl)oxy)pent-4-en-1yl)-2,6-
dioxabicyclo[3.3.1]nonan-3-one (25). To a solution of alcohol 4
(0.0740 g, 0.327 mmol, 1.00 equiv), imidazole (0.084 g, 1.24 mmol,
3.77 equiv, and DMAP (0.011 g, 0.093 mmol, 0.280 equiv) in DMF
(1.50 mL) at 0 °C was added chlorotriethylsilane (0.103 g, 0.681
mmol, 2.10 equiv) dropwise. The reaction mixture was allowed to stir
at rt for 16 h. It was then poured into a saturated NaHCO3 solution
(15 mL) and extracted with EtOAc (3 × 15 mL). The combined
organic layers were washed with water (3 × 10 mL) and brine, dried
over MgSO4, and filtered, and the solvent was removed under
pressure. The crude oil was purified by flash chromatography (25%
EtOAc/hexanes) to afford 25 as a colorless oil (0.0930 g, 84%); TLC
Rf = 0.21 in 20% EtOAc/hexanes; [α]23D = −7.7 (c 4.66, CH2Cl2); 1H
NMR (500 MHz, CDCl3) δ 5.79 (m, 1H), 5.04 (m, 2H), 4.86 (m,
1H), 4.32 (br s, 1H), 3.89 (m, 2H), 2.83 (br d, J = 19.2 Hz, 1H), 2.75
(dd, J = 19.2, 5.0 Hz, 1H), 2.23 (m, 2H), 2.00 (m, 2H), 1.89 (m, 1H),
1.73 (m, 1H), 1.55 (m, 2H), 0.94 (t, J = 8.2 Hz, 9H), 0.57 (q, J = 8.2
Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 169.4, 134.6, 117.2, 72.9,
68.2, 65.7, 62.8, 42.9, 41.7, 37.2, 36.4, 29.8, 6.8, 5.0; IR (neat) cm−1
2956, 2876, 1735, 1640, 1237, 1078, 1003, 727; HRMS (EI) calcd for
C18H32O4Si [ M + H] 341.2148 found 341.2136, calcd for C18H32O4Si
[ M − C2H5] 311.1679, found 311.678.
(−)-Cryptocaryolone (1). To a solution of 3 (0.0150 g, 0.0640
mmol, 1.00 equiv) in THF (0.508 mL) cooled to −78 °C was added
diethylmethoxyborane (1.0 M in THF, 0.0700 mL, 0.0700 mmol, 1.10
equiv) followed by MeOH (0.129 mL). The reaction mixture was then
stirred for 30 min, after which solid NaBH4 (0.00300 g, 0.0700 mmol,
1.10 equiv) was added in three portions. The mixture was allowed to
stir for 2 h at −78 °C before being quenched with a mixture of pH 7
phosphate buffer (0.0920 mL), methanol (0.138 mL), and 30% H2O2
(0.0460 mL). This mixture was allowed to warm to rt and stirred at rt
for 18 h. The organic solvent was evaporated in vacuo, and the aqueous
layer was extracted with CHCl3 (3 × 5 mL). The combined organic
layers were washed with brine and dried over anhydrous Na2SO4.
Evaporation of the solvent in vacuo gave the crude product, which was
purified by flash chromatography (2% MeOH/CH2Cl2) to give 1 as a
colorless oil (0.014 g, 94%); TLC Rf = 0.21 in 6% MeOH/CH2Cl2;
1
[α]23 = −21.1 (c 0.52, CH2Cl2); H NMR (500 MHz, C6D6) δ 4.05
D
(m, 2H), 3.63 (m, 4H), 3.33 (br s, 1H), 2.40 (br d, J = 19.2 Hz, 1H),
2.01 (dd, J = 19.2, 5.4 Hz, 1H), 1.50 (m, 1H), 1.37 (m, 3H), 1.23 (d, J
= 6.0 Hz, 3H), 1.13 (dt, J = 13.9, 2.2 Hz, 1H), 1.03 (m, 2H), 0.88 (m,
1H); 13C NMR (125 MHz, C6D6) δ 167.7, 72.5, 71.8, 68.2, 66.8, 66.0,
45.7, 43.1, 37.2, 36.4, 29.1, 24.2; IR (neat) cm−1 3424, 2923, 2853,
1721, 1339, 1072; HRMS (EI) calcd for C12H20O5 [ M + H] 245.1389,
found 245.1391.
(−)-Crytpocaryolone Diacetate (2). To a solution of 1 (5.00 mg,
0.0200 mmol, 1.00 equiv) in CH2Cl2 (1.30 mL) at 0 °C were added
pyridine (0.00900 mL, 0.111 mmol, 5.40 equiv), Ac2O (0.00800 mL,
0.0820 mmol, 4.00 equiv), and DMAP (1.00 mg, 0.010 mmol, 0.50
equiv). The reaction was allowed to stir overnight and then was
quenched with solid NaHCO3. The solvent was removed in vacuo, and
the product was purified by column chromatography (50% EtOAc/
(1S,5R,7S)-7-((R)-4-Oxo-2-((triethylsilyl)oxy)pentyl)-2,6-
dioxabicyclo[3.3.1]nonan-3-one (26). A suspension of 25 (0.0930
g, 0.273 mmol, 1.00 equiv), PdCl2 (0.00500 g,0.0273 mmol, 0.100
equiv), and Cu(OAc)2 (0.0100 g, 0.0546 mmol, 0.200 equiv) in DMF/
hexanes) to afford 2 as a colorless oil (0.00600 g, 91%); TLC Rf = 0.25
1
in 70% EtOAc/hexanes; [α]23 = −32.7 (c 0.31, CH2Cl2); H NMR
D
(500 MHz, CDCl3) δ 5.08 (m, 1H), 4.95 (m, 1H), 4.87 (m, 1H), 4.32
G
dx.doi.org/10.1021/jo301122b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(br s, 1H), 3.88 (m, 1H), 2.86 (br d, J = 19.2 Hz, 1H), 2.76 (dd, J =
19.2, 5.4 Hz, 1H), 2.03 (s, 3H), 2.02 (s, 3H), 1.90 (m, 3H), 1.69 (m,
2H), 1.57 (m, 3H), 1.22 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 170.5, 170.4, 169.5, 72.8, 68.3, 67.9, 65.8, 63.1, 39.9, 39.7,
36.9, 36.2, 29.6, 21.3, 21.2, 20.1; IR (neat) cm−1 3449, 2927, 2853,
1735, 1374, 1240, 1020, 785; HRMS (EI) calcd for C16H24O7 [ M +
H] 329.1600, found 329.1606, calcd for C16H24O7 [ M − CH3CO2]
269.1389, found 269.1384.
(13) (a) Sawant, K. B.; Jennings, M. P. J. Org. Chem. 2006, 71, 7911.
(b) Mueller Hendrix, A. J.; Jennings, M. P. Tetrahedron Lett. 2010, 51,
4260. (c) Martinez-Solorio, D.; Belmore, K. A.; Jennings, M. P. J. Org.
Chem. 2011, 76, 3898.
(14) (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.
(15) (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) Bal, B. S.;
Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
(16) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full spectroscopic characterization (1H and 13C NMR) data for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(18) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432.
(19) Smith, A. B., III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett.
1998, 39, 8765.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jenningm@bama.ua.edu.
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(20) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Support for this project was provided by the University of
Alabama and the National Science Foundation CAREER
program under CHE-0845011.
REFERENCES
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(1) Cragg, G. M.; Newman, D. J. Pure Appl. Chem. 2005, 77, 7.
(2) (a) Mu, Q.; Tang, W.; Li, C.; Lu, Y.; Sun, H.; Zheng, H.; Hao, X.;
Zheng, Q.; Lou, B. Heterocycles 1999, 51, 2969. (b) Takeda, Y.; Okada,
Y.; Masuda, T.; Hirata, E.; Shinzato, T.; Takushi, A.; Yu, Q.; Otsuka,
H. Chem. Pharm. Bull. 2000, 48, 752. (c) Jiang, Z.-H.; Yang, Q.-X.;
Tanaka, T.; Kouno, I. J. Nat. Prod. 2008, 71, 724.
(3) Drewes, S. E.; Sehlapelo, B. M.; Horn, M. M.; Scott-Shaw, R.;
Sandor, P. Phytochemistry 1995, 40, 1427.
(4) For syntheses of cryptocaryolone and cryptocaryolone diacetate,
see: (a) Smith, C. M.; O’Doherty, G. A. Org. Lett. 2003, 5, 1959.
(b) Tosaki, S.-y.; Horiuchi, Y.; Nemoto, T.; Ohshima, T.; Shibasaki,
M. Chem.Eur. J. 2004, 10, 1527. (c) Wang, X.; Wang, W.; Zheng,
H.; Su, Y.; Jiang, T.; He, Y.; She, X. Org. Lett. 2009, 11, 3136.
(5) For syntheses of leiocarpin A, see: (a) Chen, J.; Lin, G.-Q.; Liu,
H.-Q. Tetrahedron Lett. 2004, 45, 8111. (b) Nagaiah, K.; Sreenu, D.;
Purnima, K. V.; Rao, R. S.; Yadav, J. S. Synthesis 2009, 1386. (c) Paioti,
P. H. S.; Coelho, F. Tetrahedron Lett. 2011, 52, 6180. (d) Sabitha, G.;
Rammohan Reddy, T.; Yadav, J. S. Tetrahedron Lett. 2011, 52, 6550.
(6) For syntheses of polyrhacitides A and B, see: (a) Menz, H.;
Kirsch, S. F. Org. Lett. 2009, 11, 5634. (b) Ghosh, S.; Nageswara Rao,
Ch. Tetrahedron Lett. 2010, 51, 2052. (c) Yadav, J. S.; Rajendar, G.;
Ganganna, B.; Srihari, P. Tetrahedron Lett. 2010, 51, 2154.
(d) Mohapatra, D. K.; Bhimireddy, E.; Krishnarao, P. S.; Das, P. P.;
Yadav, J. S. Org. Lett. 2011, 13, 744. (e) Yadav, J. S.; Rajendar, G. Eur.
J. Org. Chem. 2011, 6781. (f) Kumaraswamy, G.; Murthy, A. N.;
Sadaiah, K. Tetrahedron 2012, 68, 3179.
́
(7) For syntheses of tetraketide, see: (a) Solladie, G.; Gressot-
Kempf, L. Tetrahedron: Asymmetry 1996, 7, 2371. (b) Garaas, S. D.;
Hunter, T. J.; O’Doherty, G. A. J. Org. Chem. 2002, 67, 2682. (c) Lee,
H.-Y.; Sampath, V.; Yoon, Y. Synlett 2009, 249.
(8) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J.
Am. Chem. Soc. 2001, 123, 10942.
(9) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(10) (a) For a recent review, see: Vougioukalakis, G. C.; Grubbs, R.
H. Chem. Rev. 2010, 110, 1746. (b) Chatterjee, A. K.; Choi, T. L.;
Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360.
(11) (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.
(12) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.
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