Cryptocaryols A and B: Total syntheses, stereochemical revision, structure elucidation, and structure-activity relationship

Article abstract of DOI:10.1021/ja404401f

The first total syntheses and structural elucidation of cryptocaryol A and cryptocaryol B were achieved in 23 and 25 linear steps, respectively. The synthesis relied on the use of a key pseudo-C_s symmetric pentaol intermediate, which in a stere

Full text of DOI:10.1021/ja404401f

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Communication
Cryptocaryol A and B: Total Syntheses, Stereochemical Revi-
sion, Structure Elucidation and Structure-Activity Relationship
Yanping Wang, and George A. O'Doherty
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja404401f • Publication Date (Web): 11 Jun 2013
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Cryptocaryol A and B: Total Syntheses, Stereochemical Revi-
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Yanping Wang and George A. O'Doherty*
Ph
Ph
Ph
Ph
C2
O
6
O
O
O
O
OPMB
16
PMBO
O
O
O
O
O
EtO
O
OEt
6
16
O
O
OH OH OH OH OR
O
6
OH OH OH OH OR
C15H31
*
6
C
15H31
16
16
ent-cryptocaryol A: C-6 (S) R = H
ent-cryptocaryol B: C-6 (S) R = Ac
purported cryptocaryol B : C-6 (R) R = Ac
(i.e., 6-epi-ent-cryptocaryol B)
cryptocaryol A: R = H
cryptocaryol B: R = Ac
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Cryptocaryol A and B: Total Syntheses, Stereochemical Revi-
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Yanping Wang and George A. O'Doherty*
Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115
Supporting Information Placeholder
tetradecanoylphorbol-13-acetate (TPA) challenged cells with EC50
ranging from 1.3 to 4.9 mM. The structures of these compounds
ABSTRACT: The first total syntheses and structural elucidation
of cryptocaryol A and cryptocaryol B were achieved in 23 and 25
linear steps, respectively. The synthesis relied on the use of a key
pseudo-Cs symmetric pentaol intermediate, which in a stereo-
chemically divergent manner was converted into either enantio-
mer as well as diastereomers. This synthetic effort enabled the
were elucidated by a combination of NMR, HRMS and CD anal-
yses. The all syn-tetraol relative configuration was assigned using
Kishi's 13C NMR database,8 and the absolute configuration of
pyranone at C-6 was assigned as R from its Cotton effect.9 Unfor-
tunately, knowledge gained from the structure-activity relation-
first structure-activity relationships of this class of PDCD4 stabi-
ship (SAR) study was limited by the ambiguities associated with
the absolute and relative stereochemistry of these structures.10
lizing natural products.
Scheme 1. Retrosynthetic analysis of cryptocaryol A and B
O
O
The early success and subsequent limitation found with the de-
velopment of PKC as a target for cancer and other diseases, have
led to the search for alternative downstream kinase targets for
development (e.g., mTOR, Akt).1 It is believed that the regulation
of these new targets will selectively produce all the desired out-
comes (e.g., tumor suppression) without side effects (e.g., non-
cancer cell toxicity).2 Programmed cell death 4 (PDCD4), a
downstream target of Akt, is a novel tumor suppressor protein.
PDCD4 interaction with eukaryotic initiation factor 4A (eIF4A)
inhibits protein synthesis.3 In addition, PDCD4 suppresses the
activation of activator protein-1 (AP-1) through c-Jun.4 Not sur-
prisingly, the stabilization of PDCD4 is linked to the induction of
apoptosis.5 Conversely, its low expression levels are linked with
the progression of several cancers (e.g., lung, liver, ovary and
brain).6
O
6
OH OH OH OH OR
16 C15H31
O
6
OH OH OH OH OR
16 C15H31
1/2
11
purported cryptocaryol A/B
diastereomeric alternatives
!
Ph
Ph
Ph
Ph
O
O
O
O
O
OPMB
X
O
O
O
O
Y
EtO
O
6
(16)
16
(6)
13
14
pseudo-Cs Symmetry
C2 rotation
H
O
H
O
O
6
OH OH OH OH OR
O
H
H
C15H31
16
EtO
OPMB
12
2
(ent)-purported cryptocaryol A/B
15
O
O
O
OH OH
O
OH OH OH OH OR
Thus, we devised a plan for the synthesis of cryptocaryol A and
B with the aims of establishing the 3D structure and providing
material for SAR studies (Scheme 1). In particular, we envisioned
an approach that would take advantage of the pseudo-Cs sym-
metry of a tetraol fragment in 13,11 which would be amenable for
the synthesis of the purported structures of these natural products
(1 and 2), along with their enantiomer (12) and C6/16-
diastereomers (e.g., 9, 10 and 11). Recently, we developed an
iterative hydration of polyene strategy to build 1,3-polyols,12
which has proved to be extremely successful for the syntheses of
related 1,3-polyol-natural products13 as well as more complicated
variants.14
6
8
16
n
n
14
m
OH
cryptocaryol A (1) R = H; EC50 = 4.9
cryptocaryol B (2) R = Ac; EC50 = 3.0
cryptocaryol F (6) m = 4, ntotal = 12; EC50 = 3.5
cryptocaryol G (7) m = 3, ntotal = 12; EC50 = 1.3
cryptocaryol H (8) m = 2, ntotal = 12; EC50 = 1.8
O
O
O
OH OR
m
O
OH OH OH OH OR
14
OH
14
cryptocaryol C (3) R = H, m = 4; EC50 = 1.6
cryptocaryol D (4) R = Ac, m = 4; EC50 = 1.5
cryptocaryol E (5) R = H, m = 3; EC50 = 1.8
cryptocaryol A (9) R = H (revised)
cryptocaryol B (10) R = Ac (revised)
Figure 1. Purported structures of cryptocaryols A–H and re-
vised structures of cryptocaryol A (9) and B (10). EC50 = mM
conc. for recovery of 50% PDCD4 concentration from TPA-
induced degradation.7
Towards this end, we began with the synthesis of orthogonally
protected pentaol 13 from commercially available 5-hexyn-1-ol
(16) (Scheme 2). The primary alcohol was protected as a PMB
ether and the terminal alkyne was homologated (n-BuLi/methyl
chloroformate, 16 to 17) and then subsequently isomerized
(PPh3/PhOH)15 to give dienoate 18 in excellent overall yield for 3
steps (88%). The distal double bond of dienoate 18 was asymmet-
rically oxidized under the Sharpless conditions ((DHQ)2PHAL) to
give a 2-enoate-4,5-diol,16 which upon treatment with triphosgene
and pyridine gave carbonate 19. A Pd-catalyzed regioselective
In an effort to find natural products that stabilize levels of
PDCD4, Gustafson et al. developed a high-throughput in vivo
cell-based assay that identified cryptocaryols A–H (1–8) (Figure
1).7 This class of natural products isolated from cryptocarya sp.
shares a 5,6-dihydro-α-pyranone and a 1,3-polyol segment. In
addition, the eight cryptocaryols stablized PDCD4 in 12-O-
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reduction of 19 with (Et3N/HCO2H, catalytic Pd/PPh3) produced
7b, and H-8) and the 13C NMR (C-6, C-7 and C-8), with the vari-
ances (0.6 to 0.9 ppm) in the 13C NMR values being the hardest to
reconcile. In order to gain a locus for further comparison, we at-
tempted to convert 2 into the structure reported for cryptocaryol A
(1). Unfortunately, we were unable to find conditions to selective-
ly hydrolyze the C-16 acetate without concomitant hydrolysis of
the pyranone ring. Next, we targeted the C-6 diastereomers of 1
and 2 (30a and 30b, respectively), as the stereochemical relation-
ship between the C-6 and C-8 positions was ambiguously as-
signed by Gustafson.7 Moreover, we found the greatest variance
1
2
3
4
5
6
7
8
δ-hydroxy enoate 20. Acetal formation using the Evans’ condi-
tions (benzaldehyde/KOt-Bu) diastereoselectively transformed 20
into benzylidene protected syn-1,3-diol 21.17 Thus in 4 steps, the
initial protected diol fragment of 13 was installed in 21 from 18.
Scheme 2. Synthesis of pseudo-Cs symmetric intermediate
13
O
a) PMBCl
c) PPh3 PhOH
OPMB
OPMB
MeO
OH
b) ClCO2Me
1
in the C-5 to C-9 positions in our comparison of the H and 13C
16
17
9
O
NMR.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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O
O
d) AD-mix-!*
f) HCO2H/Et3N,
MeO
MeO
MeO
Scheme 3. Synthesis of 6-epi-ent-cryptocaryol B (2)
e) (Cl3CO)2CO
PdPPh3
O
O
PMBO
OH
18
19
Ph
Ph
c) 1-pentadecyne,
n-BuLi
O
Ph
a) DDQ
b) DMP
O
O
O
O
OPMB
O
O
O
O
g) PhCHO
h) DIBALH
d) DMP
e) (S,S)-Noyori
O
O
O
OPMB
Ph
i) (S,S)-Leighton
EtO
EtO
EtO
H
2
2
2
13
Ph
23
PMBO
Ph
MeO
20
21
Ph
Ph
j) ethyl acrylate,
Grubbs II
f) diimide
g) DIBALH
O
O
OH
O
O
O
OH
C15H31
O
O
O
O
O
OPMB
OH
22
O
O
OPMB
h) Ac2O, Et3N
k) PhCHO
EtO
C13H27
2
24
25
EtO
13
p-BrC6H4
Ph
O
Ph
Mes
N
N
Mes
i) (S,S)-Leighton
N
N
O
O
O
OAc
O
O
O
OAc
C15H31
Cl
j) acrylic acid,
DCC
Si
Cl
Ru
H
C15H31
Ph
Cl
2
2
26
27
(S,S)-Leighton
PPh3
Grubbs II
p-BrC6H4
O
O
k) Grubbs I
l) AcOH/H2O
OH OH OH OH OAc
C15H31
Reagents and conditions: a) PMBCl, NaH, DMF, TBAB, 0 °C, 99%; b) ClCO2Me,
n-BuLi, THF, –78 to 0 °C, 99%; c) PPh3, PhOH, benzene, 50 °C, 90%; d) AD-mix-
!* = K3Fe(CN)6 (3 equiv), K2CO3 (3 equiv), MeSO2NH2 (1 equiv), (DHQ)2PHAL
(2 mol %), OsO4 (1 mol %), t-BuOH/H2O, 0 °C, 85%; e) triphosgene, pyridine,
DMAP, CH2Cl2, –78 °C, 89%; f) PdPPh3 = Pd2(dba)3•CHCl3/PPh3 (0.3 mol %),
Et3N, HCO2H, THF, reflux, 95%; g) PhCHO, KOt-Bu, THF, 0 °C, 67%; h) DIBALH,
CH2Cl2, –78 °C, 95%; i) (S,S)-Leighton, Sc(OTf)3 (2.5 mol %), CH2Cl2, –10 °C,
72%, dr = 8.7:1.0; j) ethyl acrylate, Grubbs II (1.5 mol %), CH2Cl2, 99%;
k) PhCHO, KOt-Bu, THF, 0 °C, 77%.
2
O
PPh3
Cl
Ts
Ph
N
O
OH OH OH OH OH
Ru
Ru
Cl
Ph
N
C15H31 Ph
Cl
(S,S)-Noyori
1
H2
PPh3
Grubbs I
Reagents and conditions: a) DDQ, CH2Cl2, H2O, 0 °C, 92%; b) Dess-Martin
periodinane, CH2Cl2, 0 °C, 81%; c) 1-pentadecyne, n-BuLi, THF, –78 °C; d) Dess-
Martin periodinane, CH2Cl2, 0 °C, 67 % (two steps); e) (S,S)-Noyori (5 mol %),
Et3N, HCO2H, 94%; f) NBSH, Et3N, CH2Cl2, 90%; g) DIBALH, CH2Cl2, –78 °C,
87%; h) Ac2O, Et3N, DMAP, CH2Cl2, 0 °C, 72%; i) (S,S)-Leighton, Sc(OTf)3
(5 mol %), CH2Cl2, –10 °C, 75%; j) acrylic acid, DCC, DMAP, CH2Cl2, 61%; k)
Grubbs I (5 mol %), CH2Cl2, reflux, 75%; l) AcOH/H2O (4:1), 80 °C, 75%.
The installation of the second protected diol fragment of 13 be-
gan with an ester to aldehyde reduction of 21 (DIBALH) followed
by Leighton allylation to give homoallylic alcohol 22.18 The
homoallylic alcohol stereochemistry of 22 was used to stereospe-
cifically install the final benzylidene protected diol fragment. This
was accomplished with a 2-step cross metathesis (ethyl acry-
late/Grubbs II) and Evans' acetal formation sequence to furnish
the pentaol 13.19
These revised efforts returned to alcohol 25 and involved the
use of the enantiomeric (R,R)-Leighton reagent (Scheme 4). In
practice, we protected the secondary alcohol in 25 as a TBS ether
and reduced the ester to aldehyde 28. Application of the diaster-
omeric Leighton allylation, acylation (acrylic acid/DCC) gave
diene 29a, which in 2 steps (Grubbs I; AcOH/H2O) was converted
With the key pentaol 13 in hand, our efforts were turned to the
synthesis of the purported cryptocaryol A (1) and B (2). The PMB
group in 13 was deprotected with DDQ to release the primary
alcohol, which then was oxidized with DMP to afford aldehyde 23
(Scheme 3). Nucleophilic alkyne addition (1-pentadecyne/n-BuLi,
–78 °C) to aldehyde 23 gave a propargyl alcohol, which upon
oxidation (Dess-Martin) and reduction (Noyori) diastereoselec-
tively gave propargyl alcohol 24.20 The alkyne in 24 was reduced
to alkane 25 with excess diimide (NBSH/Et3N). A 2-step
DIBALH reduction and alcohol acylation procedure on ester 25
produced aldehyde 26. The final stereocenter in 2 was installed
with the use of a second Leighton allylation, which after acylation
(acrylic acid/DCC) was then converted into diene 27. A ring clos-
ing metathesis (Grubbs I) installed the desired pyranone, which
after benzylidene deprotection (AcOH/H2O) furnished the struc-
ture purported to be cryptocaryol B (2).10,21
1
into 30a. The H NMR and 13C NMR spectral data for synthetic
30a were found to be identical to the data reported for crypto-
caryol A. While the optical rotation data was consistent in magni-
tude, it was opposite in sign (reported: [α]D = +12 (c = 0.1,
21
MeOH); synthetic: [α]D = –13.4 (c = 0.1, MeOH)). Replacing
the TBS group in 29a with an acetate group (TBAF; Ac2O/EtN3)
gave 29b, the precursor for ent-cryptocaryol B, which in 2 steps
(Grubbs I; AcOH/H2O) was converted into 30b. Once again, the
spectral data for synthetic 30b were identical to the data reported
for cryptocaryol B.22 Thus the structures for cryptocaryol A and B
should be reassigned to 9 and 10, respectively.21
With the elucidation of the structures for the cryptocaryol A
and B, we set out to undertake their enantioselective synthesis and
biological evaluation as anticancer agents. This effort began with
pseudo-Cs symmetric protected pentaol 13, and requires the rever-
sal in the order of pyranone and side chain installation (Scheme
Although great similarities existed between the 1H and 13C
NMR spectra of 2 and the data reported for cryptocaryol B,7 our
analysis led us to conclude that they did not match.10 This includ-
1
ed discrepancies in the H NMR (e.g., H-5a/H-5b, H-6, H-7a/H-
2
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5). The revised route begins with the conversion of ester 13 into
Scheme 6. Synthesis of cryptocaryol analogues for SAR
1
2
3
4
5
6
7
8
ynone 31 (DIBALH; 1-penadecyne; Dess-Martin). The C-16 ste-
reochemistry was installed in alcohol 32 by a 2-step Noyori
asymmetric and diimide reduction procedure. Adjustments of the
protecting groups involved the protection of the C-16 alcohol of
32 as a TBS group (TBSCl) followed by PMB-deprotection
(DDQ) to give 33a. Oxidation of the primary alcohol in 33a
(Dess-Martin) followed by Leighton allylation and acrylate acyla-
tion (acrylic acid/DCC) provided diene 34a, from which 34b was
prepared with the required C-16 acetate group.
Ph
Ph
O
OH
O
O
O
O
OR
C15H31
O
OH OH
OH
OH OAc
C15H31
33a: R = TBS
33b: R = Ac
10
a) Ac2O
b) DDQ
32
d) Pd/C, H2
OH OH OH OH OAc
C15H31
O
c) AcOH/H2O
OH OH OH OH OH OR
O
C15H31
35a: R = H
35b: R = Ac
36
9
Scheme 4. Synthesis of ent-cryptocaryol A and B (30a/b)
Reagents and conditions: a) Ac2O, pyridine, DMAP, CH2Cl2, 0 °C, 98%;
b) DDQ, CH2Cl2, H2O, 0 °C, 72%; c) AcOH/H2O (4:1), 80 °C, 65% or 69%;
d) Pd/C (10% wt/wt, 10 mol %), H2 (1 atm), 66%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
Ph
c) (R,R)-
Leighton
d) acrylic acid,
C15H31 DCC
a) TBSCl
O
O
O
O
OH
O
O
O
OTBS
b) DIBALH
C15H31
While other PDCD4 stabilizers are known to be cytotoxic,
there is very little data to correlate their activity to PDCD4 stabili-
zation.23 With access to cryptocaryol A and B, two known
PDCD4 stabilizers (4.9 and 3.0 mM, see Gustafson’s assay), this
comparison can be made. We chose to study MCF-7 breast cancer
cells (Table 1 and Figure 2),24 because of their high expression
level of PDCD4.25 We found that both cryptocaryol A and B pos-
sessed growth inhibitory activity against MCF-7 in the mircomo-
lar range and their relative activity was consistent with their
PDCD4 stabilizing activity (i.e., 10 slightly more active than 9).
The two analogues without a pyranone ring 35a/b (>10 fold) and
the one without the double bond 36 (>100 fold) were the least
active. The surprisingly greater loss in activity for 36, could be a
result of its propensity to ring open (e.g., unstable in CD3OD).
The diastereomer 2 (with only the C-6 pyrano-stereocenter re-
tained) had a small loss in activity (~2 fold). The effect of C-16
acylation could be seen in the comparison between cryptocaryol A
and B (9/10), as well as, 35a/35b. Surprisingly, the stereochemis-
try of natural products did not have a significant effect on activity
as ent-cryptocaryol A (30a) had only a ~3 fold loss of activity.
EtO
H
2
2
25
28
e) Grubbs I
f) AcOH/H2O
(4:1)
Ph
O
O
O
O
OR
O
OH OH OH OH OR
C15H31
C15H31
g) TBAF
h) Ac2O, Et3N
2
29a: R = TBS
29b: R = Ac
30a: R = H
30b: R = Ac
Reagents and conditions: a) TBSCl, imidazole, DMF, 96%; b) DIBALH, CH2Cl2,
–78 °C, 90%; c) (R,R)-Leighton, Sc(OTf)3 (5 mol %), CH2Cl2, –10 °C, 95%;
d) acrylic acid, DCC, DMAP, CH2Cl2, 64%; e) Grubbs I (5-10 mol %), CH2Cl2,
reflux, 87% or 78%; f) AcOH/H2O (4:1), 80 °C, 77% or 75%; g) TBAF, THF, 91%;
h) Ac2O, Et3N, DMAP, CH2Cl2, 0 °C, 96%.
Using the same ring closing metathesis/deprotection sequence,
the dienes 34a and 34b were uneventfully converted into crypto-
1
caryol A (9) and B (10). The H and 13C NMR data for the syn-
thetic material were identical to the data reported for the isolated
material.21 In addition to providing ample material for structural
elucidation, the route also provided enough material for the cancer
cell cytotoxicity studies. As part of these SAR studies, additional
analogues (hexaol 35a, hexaol acetate 35b and saturated pyranone
compound 36) were required for evaluation. These analogues
were readily prepared from intermediates 33a/b and cryptocaryol
B (10) by deprotection of benzylidene and hydrogenation of al-
kene, respectively (Scheme 6).
Table 1. Cytotoxicity of cryptocaryol analogues (MCF-7)
IC50 (µM)a
Compounds
Scheme 5. Synthesis of cryptocaryol A and B (9 and 10)
cryptocaryol A (9)
cryptocaryol B (10)
8.5 ± 2.6
6.0 ± 1.6
14.0 ± 4.5
28.0 ± 10.7
242 ± 180
170 ± 104
>500
a) DIBALH
b) 1-pentadecyne,
n-BuLi
Ph
Ph
PMB
O
PMB
O
d) (R,R)-Noyori
O
O
O
O
O
O
O
c) DMP
e) Diimide
6-epi-ent-cryptocaryol B (2)
ent-cryptocaryol A (30a)
hexaol (35a)
OEt
2
2
13
Ph
31
C13H27
Ph
h) DMP
i) (S,S)-Leighton
PMB
O
f) TBSCl
g) DDQ
O
OH
OH
O
O
OTBS
C15H31
j) acrylic acid,
DCC
hexaol acetate (35b)
2H-cryptocaryol B (36)
C15H31
2
2
32
33a
k) Grubbs I
l) AcOH/H2O
(4:1)
OR
etoposide
1.2 ± 0.6
O
Ph
O
a
O
O
O
O
OH OH OH OH OR
C15H31
The IC50 values were measured from 72 h treatment of MCF-7
cells in a MTT assay. All values represent the standard error of
the mean value of three independent experiments with two dupli-
cate determinations.
C15H31
2
34a: R = TBS
34b: R = Ac
9: R = H
10: R = Ac
m) TBAF
n) Ac2O, Et3N
Reagents and conditions: a) DIBALH, CH2Cl2, –78 °C, 90%; b) 1-pentadecyne,
n-BuLi, THF, –78 °C; c) Dess–Martin periodinane, CH2Cl2, 0 °C, 68 % (2 steps);
d) (R,R)-Noyori (5 mol %), Et3N, HCO2H, 98%; e) NBSH, Et3N, CH2Cl2, 98%;
f) TBSCl, imidazole, DMF, 94%; g) DDQ, CH2Cl2, H2O, 0 °C, 92%; h) Dess-Martin
periodinane, CH2Cl2, 0 °C, 62%; i) (S,S)-Leighton, Sc(OTf)3 (5 mol %), CH2Cl2,
–10 °C, 95%; j) acrylic acid, DCC, DMAP, CH2Cl2, 80%; k) Grubbs I (5-10 mol %),
CH2Cl2, reflux, 76% or 70%; l) AcOH/H2O (4:1), 80 °C, 70%; m) TBAF, THF, 92%;
n) Ac2O, Et3N, DMAP, CH2Cl2, 0 °C, 72%.
3
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cryptocaryol A (9)
cryptocaryol B (10)
ent-cryptocaryol A (30a)
epi-ent-cryptocaryol B (2)
hexaol (35a)
hexaol acetate (35b)
9
2H-cryptocaryol B (36)
10
11
12
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14
15
0
1
2
3
4
5
Drug Concentration (log nM)
4
Yang, H. S.; Knies, J. L.; Stark, C.; Colburn, N. H. Oncogene 2003, 22,
3712-3720.
Figure 2. Graph of MCF-7 cell viability for cryptocaryols and
their analogues. The dose-response curve of cell viability from
a 72 h drug treatment (1 nM to 100 µM).
5 Afonja, O.; Juste, D.; Das, S.; Matsuhashi, S.; Samuels, H. H. Oncogene
2004, 23, 8135-8145.
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6 Wang, Q.; Sun, Z.; Yang, H. S. Oncogene 2007, 27, 1527-1535.
Grkovic, T.; Blees, J. S.; Colburn, N. H.; Schmid, T.; Thomas, C. L.;
7
In conclusion, the first total synthesis, structural elucida-
tion/correction and SAR of cryptocaryol A and B have been
achieved. The enantioselective synthesis was accomplished in 23
and 25-step linear sequence, respectively, from commercially
available 5-hexyn-1-ol. The stereochemically divergent synthesis
concisely enabled the exact stereochemical assignment, as well as,
the SAR for cryptocaryol A and B in a cancer cell cytotoxicity
assay. It is worth noting that the difficulties in distinguishing be-
tween the two diastereomers (e.g., 1 and 9) demonstrate the need
for stereochemically divergent approaches for structural determi-
nation, as well as, enabling SAR-studies that probe the effects of
stereochemistry on activity.
Henrich, C. J.; McMahon, J. B.; Gustafson, K. R. J. Nat. Prod. 2011, 74,
1015-1020.
8
(a) Kobayashi, Y.; Tan, C.-H.; Kishi, Y. Helv. Chim. Acta 2000, 83,
2562-2571. (b) Higashibayashi, S.; Czechtizky, W.; Kobayashi, Y.; Kishi,
Y. J. Am. Chem. Soc. 2003, 125, 14379-14393.
9 Snatzke, G. Angew. Chem. Int. Ed. 1968, 7, 14-25.
10
As this manuscript was in preparation, Mohapatra et al. described the
synthesis of purported cryptocaryol A (1) and mistakenly reported it as
Cryptocaryol A (9), see: Reddy, D. S.; Mohapatra, D. K. Eur. J. Org.
Chem. 2013, 2013, 1051-1057.
11 Hunter, T. J. Ph.D. Thesis, the University of Minnesota, 2003.
12
(a) Wang, Y.; Xing, Y.; Zhang, Q.; O'Doherty, G. A. Chem. Commun.
2011, 47, 8493-8505. (b) Ahmed, Md. M.; Mortensen, M. S.; O’Doherty,
G. A. J. Org. Chem. 2006, 71, 7741-7746. (c) Hunter, T. J.; O’Doherty,
G. A. Org. Lett. 2001, 3, 1049-1052.
13
ASSOCIATED CONTENT
Supporting Information
(a) Hunter, T. J.; O'Doherty, G. A. Org. Lett. 2001, 3, 2777-2780. (b)
Smith, C. M.; O'Doherty, G. A. Org. Lett. 2003, 5, 1959-1962. (c) Garaas,
S. D.; Hunter, T. J.; O'Doherty, G. A. J. Org. Chem. 2002, 67, 2682-2685.
For alternative approaches, see, ref. 10 and (d) Melillo, B.; Smith, A. B.
Org. Lett. 2013, 15, 2282-2285.
Detailed experimental procedures, full characterization data, and
copies of spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
14
(a) Guo, H.; Mortensen, M. S.; O’Doherty, G. A. Org. Lett. 2008, 10,
3149-3152. (b) Gao, D.; O’Doherty, G. A. Org. Lett. 2010, 12, 3752-3755.
(c) Li, M.; O'Doherty, G. A. Org. Lett. 2006, 8, 6087-6090. (d) Li, M.;
O'Doherty, G. A. Org. Lett. 2006, 8, 3987-3990.
AUTHOR INFORMATION
15
(a) Rychnovsky, S. D.; Kim, J. J. Org. Chem. 1994, 59, 2659-2660. (b)
Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933-7935.
16
Corresponding Author
g.odoherty@neu.edu
Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114,
7570-7571.
17 Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446-2453.
18 Kubota, K.; Leighton, J. L. Angew. Chem. Int. Ed. 2003, 115, 976-978.
19
Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron
Notes
The authors declare no competing financial interest.
Lett. 1999, 40, 2247-2250.
20
Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 7562-7563.
ACKNOWLEDGMENT
21
The absolute and relative configuration for all stereocenters was
We are grateful to NIH (GM090259) and NSF (CHE-1213596)
for financial support of this research and Michael F. Cuccarese for
assistance with the biological assays.
confirmed by a combination of Mosher and 1H NMR analyses, see SI.
22
Unfortunately, no optical rotation data for cryptocaryol B was reported,
see: ref. 7.
23
(a) Yin, C.-H.; Bach, E. A.; Baeg, G.-H. J. Biomol. Screen. 2011, 16,
443-449. (b) Wee, J. L.; Sundermann, K.; Licari, P.; Galazzo, J. J. Nat.
Prod. 2006, 69, 1456-1459.
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3
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C.; Costes, S.; Lockett, S. J.; Sonenberg, N.; Colburn, N. H. Mol. Cell.
4
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Cryptocaryol A and B: Total Syntheses, Stereochemical Revi-
sion, Structure Elucidation and Structure-Activity Relationship
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Yanping Wang and George A. O'Doherty*
Ph
Ph
Ph
Ph
C2
O
6
O
O
O
O
OPMB
16
PMBO
O
O
O
O
O
EtO
O
OEt
6
16
O
O
OH OH OH OH OR
O
6
OH OH OH OH OR
C15H31
*
6
C
15H31
16
16
ent-cryptocaryol A: C-6 (S) R = H
ent-cryptocaryol B: C-6 (S) R = Ac
purported cryptocaryol B : C-6 (R) R = Ac
(i.e., 6-epi-ent-cryptocaryol B)
cryptocaryol A: R = H
cryptocaryol B: R = Ac
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