Asymmetric Iterative Hydration of Polyene Strategy to Cryptocaryols A and B

Article abstract of DOI:10.1055/s-0035-1561607

The development of two iterative asymmetric hydration approaches to the synthesis of all syn- and syn/anti/syn-1,3,5,7-tetraol motifs is described. These pseudo-symmetric products are synthetic precursors for 1,3-hexol products. The utility of the route to the all syn-1,3,5,7-tetraol diastereoisomer was demonstrated with its use in the synthesis of cryptocaryols A and B, as well as, stereoisomers.

Full text of DOI:10.1055/s-0035-1561607

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–K
A
special topic
T. J. Hunter et al.
Special Topic
Synthesis
Asymmetric Iterative Hydration of Polyene Strategy to Crypto-
caryols A and B
Thomas J. Hunterb
Yanping Wanga
Jiamin Zhenga
George A. O’Doherty*a
O
12 steps
13%
σ
O
5
OH OH OH OH OH
Ph
Ph
C15H31
7
9
11
13
15
O
O
O
O
O
OPMB
cryptocaryol A
OH OH OH OH OAc
C15H31
O
14 steps
8%
5
(15)
15
EtO
a Department of Chemistry and Chemical Biology, Northeastern
University, Boston, MA 02115, USA
b MilliporeSigma, 645 Science Drive, Madison, WI 53711, USA
G.ODoherty@neu.edu
(5)
O
8 steps
14%
cryptocaryol B
O
OPMB
EtO
Received: 21.02.2016
O
Accepted after revision: 11.03.2016
Published online: 13.04.2016
DOI: 10.1055/s-0035-1561607; Art ID: ss-2016-c0125-st
O
5
OH OH OH OH OH
7
9
11
13
15
C15H31
cryptocaryol A (1)
Abstract The development of two iterative asymmetric hydration ap-
proaches to the synthesis of all syn- and syn/anti/syn-1,3,5,7-tetraol
motifs is described. These pseudo-symmetric products are synthetic
precursors for 1,3-hexol products. The utility of the route to the all syn-
1,3,5,7-tetraol diastereoisomer was demonstrated with its use in the
synthesis of cryptocaryols A and B, as well as, stereoisomers.
O
O
OH OH OH OH OAc
C15H31
O
cryptocaryol B (2)
O
OH OH OH OH OH
C15H31
purported cryptocaryol A (3)
Key words asymmetric synthesis, iterative hydration, cryptocaryol A,
O
O
cryptocaryol B, 1,3-polyols
OH OH OH OH OAc
C15H31
Cryptocaryols A and B (1 and 2) are two members of a
class of 5,6-dihydro-α-pyranone/1,3-polyol natural prod-
ucts that were reported in 2011 by Gustafson (Figure 1).1
Using a high-throughput PDCD4 stabilization assay, eight
cryptocaryols were found in extracts from the plant Crypto-
carya sp. with EC50 ranging from 1.3 to 4.9 μM. Using de-
tailed NMR, HRMS, and CD analyses,2,3 the structures for
cryptocaryols A and B were tentatively assigned as the pur-
ported structures 3 and 4. These initial structures had the
correct connectivity but lacked certainty in terms of their
absolute and relative stereochemistry. This stereochemical
uncertainty was not resolved until the purported and actu-
al structures succumbed to total synthesis by us and oth-
ers.4–6 In addition to elucidating the structure of the crypto-
caryols, our successful synthetic efforts provided material
for the initial SAR studies of this class of natural products as
both stabilizers of PDCD4 and anticancer agents.7 Thus,
both enantiomers of cryptocaryols A (1) and B (2) as well as
their diastereomers were prepared and studied.
purported cryptocaryol B (4)
Figure 1 Cryptocaryol A and B
structed by diastereoselectively appending the C-5/C-15
pyranone and the C-15/C-5 alkyl side chain to a single en-
antiomer of syn-8. This stereodivergent approach takes ad-
vantage of the pseudo-symmetry of syn-8, which allows for
its stereoselective elaboration into any of the eight most
likely stereoisomers of the cryptocaryols. Herein, we dis-
close the development of the synthetic chemistry that un-
derpinned this effort. Specifically, this includes the devel-
opment of a dienoate iterative asymmetric hydration, its
elaboration to the asymmetric synthesis of Cs- and C2-sym-
metric protected tetraol precursors, and finally the use of
one of these stereoisomeric polyols for the synthesis, struc-
ture elucidation, and medicinal chemistry study of the
cryptocaryols (Scheme 1).
Our strategy focused on the synthesis of the all syn-
tetraol relative configuration of the C-5 to C-15 portion of
the cryptocaryols.8 This approach resulted from the recog-
nition that the complete natural product could be con-
Our approach to the 1,3-syn-diol motif builds on the
idea that a 3,5-dihydroxy carboxylic ester 12 would result
from the iterative alkene hydration of a 2,4-dienoate 9
(Scheme 2).9–11 Key to controlling the sequence and regio-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

B
T. J. Hunter et al.
Special Topic
Synthesis
Table 1 Optimization of the Asymmetric Hydration of Dienoatesa
σ
σ
Ph
Ph
Ph
Ph
O
OH
X
O
O
O
O
Y
O
O
O
O
O
OPMB
O
a) AD-mix-α
EtO
CH3
5
15
(5)
EtO
15
(5)
5
(15)
71%
EtO
CH3
(15)
OH
14a
syn-8
syn-7
pseudo-Cs symmetry
13a
O
OR1
CH3
b) BzCl, 57%
H
O
H
O
H
O
H
O
O
OPMB
EtO
or c) ClCO2Et, 81%
or d) (Cl3CO)2CO, 87%
O
OPMB
OR1
H
H
H
H
EtO
15
EtO
5
6
O
OR2
O
e) HCO2H/Et3N
+
PdPPh3
EtO
CH3 EtO
CH3
C2
C2
Ph
Ph
Ph
Ph
16
13a
X
O
O
O
O
Y
O
O
O
O
O
OPMB
Entry
Compound
R1
Bz
R2
Yield (%)
Ratio
5
(15)
15
(5)
EtO
5
(15)
15
(5)
anti-8
anti-7
pseudo-C2 symmetry
1
2
3
16a:13a
16b:13a
16c:13a
Bz
43
47
70
4:1
4:1
1:0
CO2Et
CO2Et
H
Scheme 1 Retrosynthetic analysis of cryptocaryol A and B
-(C=O)-
a Reaction conditions: a) OsO4 (1 mol%), (DHQ)2PHAL (1.1 mol%),
K3FeCN6/MeSO2NH2, 71%; b) BzCl, Et3N, CH2Cl2, 57%; c) ClCO2Et, Et3N,
CH2Cl2, 81%; d) (Cl3CO)2CO, pyridine, CH2Cl2, 87%; e) HCO2H/Et3N,
Pd2(dba)3·CHCl3, PPh3, THF, 66 °C.
control of the first hydration step comes from the recogni-
tion that an asymmetric hydration of the distal double bond
of a 2,4-dienoate 9 to a 5-hydroxy-1-enoate 11 would result
by an asymmetric oxidation and reduction sequence. Final-
ly, the remaining alkene can be diastereoselectively hydrat-
ed by the in situ trapping of a hemiacetal using the Evans
protocol resulting in the benzylidene protected 3,5-dihy-
droxy carboxylic ester 12.12
We next explored the applicability of the protocol on a
variety of δ-substituted dienoates 13a–g (Table 2). When
the variously substituted dienoates 13a–g were exposed to
the Sharpless dihydroxylation and carbonate forming con-
ditions, carbonates 17a–g were obtained in improved yields
and enantiomeric excesses. Similar yields and enantiomeric
purities were obtained from the (DHQ)2PHAL or the
(DHQD)2PHAL ligand system (80–95% ee). Exposing the cy-
clic carbonates 17a–g to our optimized Pd-reduction condi-
tions [2.5 mol% Pd2(dba)3·CHCl3/6.3 mol% PPh3] gave ho-
moallylic alcohols 18a–g (66–93%) with no loss of enantio-
meric excess (80–95% ee). With the demonstrated
generality for the first asymmetric hydration set, we next
pursued the subsequent hydration/protection step.
regio-/stereo-
selective reduction
O
OH
asymmetric
oxidation
O
R1O
R3
R1O
R3
HO R2
10
R2
9
Ph
O
OH
diastereoselective
hydration/protection
O
O
O
R1O
R3
R1O
R3
R2
R2
11
12
As with the first three steps, we found a broad substrate
scope for the Evans acetal forming reaction. Thus, when ex-
posing the δ-hydroxy enoates 18a–g to the Evans procedure
(1.1 equiv of benzaldehyde and 0.11 equiv of KOt-Bu, 0 °C,
repeat 3 times every 15 min), all but one proceeded
smoothly to the desired benzylidene protected 3,5-dihy-
droxy carboxylic esters 19a–c,e–g. Typical yields for these
transformations are in the 60% range. The exception to this
was the substrate with the C-6 tert-butyldimethylsiloxy
group in Table 3, entry 4. Unfortunately, under the basic
conditions, the TBS group migrated to the C-5 alkoxide
leaving behind a C-6 alkoxy group, which was ideally poised
to intramolecularly add across the enoate to give tetrahy-
drofuran 20. This issue with silyl-group migration was easi-
ly solved by simply switching the TBS group to a base-stable
PMB group (19f and 19g).
Scheme 2 Asymmetric hydration route to syn-1,3-diol
Our first attempt to execute the initial hydration step
began with the Sharpless dihydroxylation of ethyl sorbate
(13a) to give 4,5-dihydroxy-1-enoate 14a (71%, 80% ee).13,14
We next explored converting the allylic alcohol into ester
and carbonate type Pd-π-allyl leaving groups 15a–c (see Ta-
ble 1 for R).15 When 15a,b were exposed to our typical π-
allyl Pd-hydride reducing conditions [2.5 mol%
Pd2(dba)3·CHCl3/6.3 mol% PPh3], a significant amount of re-
ductive elimination occurred along with the benzoate 16a
and ethyl carbonate 16b. In contrast, the cyclic carbonate
15c was reduced under the same conditions to give the de-
sired 5-hydroxy-1-enoate 16c without any elimination
(70%).16
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

C
T. J. Hunter et al.
Special Topic
Synthesis
Table 2 Scope of Asymmetric Hydration of Polyenea
O
OR3
R2
O
a) AD-mix-α
R1O
R1O
R2
OR3
13
14 R3 = H
b) (Cl3CO)2CO
17 R3 = -(CO)-
OH
c) HCO2H/Et3N
O
PdPPh3
17
R1O
R2
18
Entry
Compound
R1
Et
R2
Yield (%) of 14, ee (%)
Yield (%) of 17
Yield (%) of 18
1
2
3
a
b
c
Me
Pr
71, 80
81, 95
79, 95
87
94
91
70
80
72
Me
Et
Ph
O
OR3
R2
O
a') AD-mix-β
R1O
R1O
R2
OR3
13
ent-14 R3 = H
b) (Cl3CO)2CO
ent-17 R3 = -(CO)-
c) HCO2H/Et3N
O
OH
R2
PdPPh3
ent-17
R1O
ent-18
Entry
Compound
ent-d
R1
R2
Yield (%) of ent-14, ee (%)
Yield (%) of ent-17
Yield (%) of ent-18
4
5
6
7
Et
CH2OTBS
82, 95
91, 95
79, 95
NA
94
95
95
57
88
87
93
66
ent-e
Et
(CH2)2OTBS
(CH2)2OPMB
CH2OPMB
ent-f
Me
Et
ent-g
a Reaction conditions: a) OsO4 (1 mol%), (DHQ)2PHAL (1.1 mol%), K3FeCN6/MeSO2NH2; a′) OsO4 (1 mol%), (DHQD)2PHAL (1.1 mol%), K3FeCN6/MeSO2NH2; b)
(Cl3CO)2CO, pyridine, CH2Cl2; c) HCO2H/Et3N, Pd2(dba)3·CHCl3, PPh3, THF, 66 °C.
b NA: not attempted.
Building upon this observation, we decided to use the
benzylidene protected 3,5-dihydroxy carboxylic esters with
a C-7 OPMB group to build the next 1,3-syn-diol unit
(Scheme 3). To accomplish this, we first needed to append
another dienoate functional group onto the carbon chain.
This undertaking was most easily accomplished by a
DIBALH reduction of the methyl ester in ent-19f, which
cleanly provided aldehyde 21 (93%). A subsequent vinylo-
gous Horner–Wadsworth–Emmons olefination of aldehyde
21 with phosphonate 25 and base gave the desired dienoate
22 (66%).17 With the E,E-dienoate in place in 22, it can then
be elaborated into a second 1,3-syn-diol unit subunit. Sim-
ply repeating the four-step iterative hydration sequence of
22 would install the second benzylidine acetal as in ent-
syn-8. Thus exposing 22 to the typical Sharpless asymmetric
dihydroxylation conditions [OsO4 (1 mol%), (DHQD)2PHAL
(1.1 mol%), K3FeCN6, MeSO2NH2], diol 23 was produced as a
single diastereomer (71%). Treating diol 23 with triphos-
gene and base readily converted the diol into a cyclic car-
bonate, which when exposed to the Pd-reduction condi-
tions [HCO2H/Et3N, 1 mol% Pd2(dba)3·CHCl3/2.5 mol% PPh3]
cleanly gave the 5-hydroxy-1-enoate syn-24 (90%). Finally,
exposing syn-24 to the Evans acetal formation condition
[PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C)
easily converted it into the bis(benzylidene)-protected es-
ter ent-syn-8 in good yield (63%).
Concerns over the scale-ability and dienoate stability
inspired us to pursue an alternative approach for the ste-
reoselective installation of the second benzylidene unit (i.e.,
22 to syn-8). In this regard, we devised an allylation/cross
metathesis strategy (Scheme 4). This alternative approach
began with a one-pot reduction/allylation sequence, which
involved an in situ addition of the allyl Grignard reagent di-
rectly to the ester 19f/DIBALH reaction mixture.10 When
this reaction was warmed to room temperature and
quenched, a 1.2:1 ratio of homoallylic alcohols syn-26 and
anti-26 were isolated in good overall yield (91%). Unfortu-
nately, all of our efforts to improve upon this modest selec-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

D
T. J. Hunter et al.
Special Topic
Synthesis
Table 3 Evans Acetal Formationa
zation (90%). Then, treating a THF solution of 27 with L-Se-
lectride at –90 °C provided syn-26 in a 4:1 ratio (89%).
In spite of our desire to try to use a substrate controlled
approach to control the stereochemistry in the next ben-
zylidene subunit, a much more practical and simplified
procedure resulted when we turned to a reagent control
approach in the allylation reaction. This involved turning to
the Leighton allylation reagents 29.18 Thus, this revised pro-
cedure to the installation of the second protected diol frag-
ment of 19f began with the same ester to aldehyde reduc-
tion with DIBALH (19f to ent-21, 93%) (Scheme 5). In this
alternative approach, exposure of purified aldehyde ent-21
to the (S,S)-Leighton reagent cleanly afforded homoallylic
alcohol syn-26 as a single diastereoisomer. A Grubbs II type
cross metathesis reaction between syn-26 and ethyl acry-
late gave a single alkene isomer, which we previously have
shown can be converted into bis(benzylidene)-protected
ester syn-8.19 The stereodivergent aspect of the synthesis
can be seen in its ability to just as easily be used for the
conversion of 19f into the diastereomeric bis(benzylidene)-
protected ester anti-8. This involves the switching of the
(S,S)-Leighton reagent to the (R,R)-Leighton reagent in the
allylation of ent-21. Thus when ent-21 is treated with the
(R,R)-Leighton reagent homoallylic alcohol anti-26 is pro-
duced as a single diastereomer. The diastereomeric alcohol
anti-26 reacted similarly under the Grubbs II cross-metath-
esis conditions to give the 5-hydroxy-1-enoate ent-anti-24
(90%). Finally the Evans acetal forming reaction [PhCHO (1.1
equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 77%] is used
to install the final benzylidene unit in the diastereomeric
bis(benzylidene)-protected ester anti-8 (Scheme 5).
Ph
a) PhCHO
KOt-Bu
O
OH
O
O
O
R2O
R1
R2O
R1
18
19
Entry
Compound
R
R′
Et
Yield (%)
1
2
3
19a
19b
19c
Me
Pr
60
60
52
Me
Et
Ph
Ph
a) PhCHO
KOt-Bu
O
R2O
O
OH
or
O
O
O
R2O
R1
O
OTBS
R2O
R1
ent-18
ent-19
20
Entry
Compound
20
R1
R2
Yield (%)
88
4
5
6
7
CH2OTBS
Et
ent-19e
ent-19f
ent-19g
CH2CH2OTBS
CH2CH2OPMB
CH2OPMB
Et
68
Me
Et
62
61
a Reaction conditions: a) PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times,
THF, 0 °C.
tivity in the allylation reaction were unsuccessful. These ef-
forts included the addition of various chelating Lewis acids
(Al, Ti, Zn) in combination with an allyl anion, in an attempt
to take advantage of the β-alkoxy group. While these ho-
moallylic alcohols can be separated by silica gel chromatog-
raphy, the ratio would be improved by an oxidation/reduc-
tion reaction sequence. Thus, treatment of a diastereomeric
mixture of syn-26 and anti-26 with Dess–Martin perio-
dinane (DMP) reagent gave a clean conversion to the β,γ-
unsaturated ketone 27, without any double bond isomeri-
With access to the Cs- and C2-symmetric protected
tetraol precursors syn-8 and anti-8, we next looked to in-
stall the remaining C-5/C-15 stereochemistry of the crypto-
caryols (Scheme 6). Because we wanted to be able to install
both R- and S-stereochemistry at the C-5/C-15, we looked
Ph
Ph
Ph
b) 25, LiOH•H2O
PMBO
O
O
O
c) AD-mix-β
a) DIBALH
93%
PMBO
O
O
O
PMBO
O
O
O
71%
66%
OMe
H
OEt
ent-19f
Ph
21
22
Ph
Ph
Ph
f) PhCHO
KOt-Bu
d) (Cl3CO)2CO, 92%
PMBO
O
O
OH
O
PMBO
O
O
OH
O
PMBO
O
O
O
O
O
e) HCO2H/Et3N
PdPPh3
63%
OEt
OEt
OEt
OH
90%
23
syn-24
ent-syn-8
O
O
(MeO)2P
OEt
25
Scheme 3 Iterative oxidation/reduction approach to syn-1,3-polyols. Reagents and conditions: a) DIBALH, CH2Cl2, –78 °C, 93%; b) LiOH·H2O, phospho-
nate 25, 4 Å molecular sieves, THF, 66%; c) OsO4 (1 mol%), (DHQD)2PHAL (1.1 mol%), K3FeCN6, MeSO2NH2, 71%; d) (Cl3CO)2CO, pyridine, CH2Cl2, 90%; e)
Pd2(dba)3·CHCl3 (1 mol%), PPh3 (2.5 mol%), HCO2H/Et3N, THF, 66 °C, 90%; f) PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 63%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

E
T. J. Hunter et al.
Special Topic
Synthesis
Ph
OH
OH
O
O
O
OPMB
OPMB
Ph
Ph
a) DIBALH,
then allylMgCl
OPMB
91%
c) L-Selectride
syn-26
b) DMP
90%
_90 °C
O
O
O
+
Ph
O
O
O
89%
OPMB
dr = 1.2:1
O
MeO
27
19f
anti-26
Ph
Ph
Ph
Ph
d) ethyl acrylate
Grubbs II
e) PhCHO
77%
OH
O
O
O
OH
O
O
O
O
O
O
O
OPMB
99%
OPMB
EtO
OPMB
EtO
syn-26
dr = 4:1
28
syn-8
Scheme 4 Second-generation approach to protected 1,3-syn-polyol. Reagents and conditions: a) DIBALH, CH2Cl2, –78 °C, 1 h, then allyMgCl (2 M THF
solution), r.t., 91%; b) DMP, CH2Cl2, 90%; c) L-Selectride, –90 °C, 89%, dr = 4:1; d) ethyl acrylate, Grubbs II cat. (2.5 mol%), CH2Cl2, 99%; e) PhCHO (1.1
equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 77%.
Ph
Ph
Ph
Ph
Ph
c), d)
76%
b) (S,S)-29
a) DIBALH
93%
O
O
O
OH
O
O
O
O
O
O
O
OPMB
O
O
O
72%
MeO
OPMB
OPMB
EtO
H
OPMB
19f
ent-21
syn-26
syn-8
Ph
Ph
Ph
Ph
Ph
f) ethyl acrylate
Grubbs II
g) PhCHO
e) (R,R)-29
O
O
O
O
O
OPMB
O
OH
O
O
O
O
O
H
O
O
OH
99%
77%
72%
EtO
EtO
OPMB
OPMB
OPMB
ent-21
anti-26
ent-anti-24
anti-8
p-BrC6H4
p-BrC6H4
(S,S)-29
(R,R)-29
N
N
N
N
Si
Si
Cl
Cl
(S,S)-Leighton
p-BrC6H4
(R,R)-Leighton
p-BrC6H4
Scheme 5 Synthesis of protected syn- and anti-1,3-polyols. Reagents and conditions: a) DIBALH, CH2Cl2, –78 °C, 93%; b) (S,S)-29, Sc(OTf)3 (2.5 mol%),
CH2Cl2, –10 °C, 72%; c) ethyl acrylate, Grubbs II (2.5 mol%), 99%; d) PhCHO (1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 77%; e) (R,R)-29, Sc(OTf)3
(2.5 mol%), CH2Cl2, –10 °C, 72%; f) ethyl acrylate, Grubbs II cat. (2.5 mol%), 99%; g) PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 77%.
into using a reagent-controlled approach. We found that
this was most easily accomplished with the use of the
Leighton reagent for the C-5 position and the Noyori hydro-
gen transfer reaction for the C-15 position.20 For the Noyori
reduction to occur with high stereocontrol, an ynone func-
tionality needed to be introduced, as in 31. This was most
easily accomplished by removing the PMB group (DDQ,
92%) and oxidizing the primary alcohol with the Dess–
Martin reagent (81%) to give 30. An unselective addition of
1-lithiopentadec-1-yne to aldehyde 30 and a subsequent
Dess–Martin oxidation was used to give 31 (62%). Exposure
of 31 to our typical Noyori reduction conditions [(S,S)-
Noyori (5 mol%), Et3N, formic acid, 94%] gave a propargyl al-
cohol as a single diastereomer, which upon exposure to ex-
cess diimide gave secondary alcohol 32 with the desired R-
stereochemistry at C-15. The R-stereochemistry at C-5 was
installed by reducing the ester to an aldehyde with DIBALH
(87%), acylating the C-15 alcohol (Ac2O, 72%) and finally a
diastereoselective addition of an allyl anion with the (S,S)-
Leighton reagent (75%) resulting in homoallylic alcohol 33.
A similar approach was used to convert 32 into 34 with the
S-stereochemistry at C-5 [TBSCl, DIBALH, and (R,R)-Leigh-
ton; 82%]. However, in this alternative approach the C-15
alcohol was protected as a TBS group.
To install the C-5/C-15 with the opposite tetraol stereo-
chemistry (ent-34), all we need to do is apply the same se-
quences to the opposite ends of the tetraol precursors syn-8
(Scheme 6). This began with a DIBALH reduction of syn-8
followed by an unselective 1-lithiopentadec-1-yne to re-
sulting aldehyde and a subsequent Dess–Martin oxidation
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

F
T. J. Hunter et al.
Special Topic
Synthesis
Ph
Ph
Ph
a) DDQ, 92%
b) DMP, 81%
c) 1-pentadecyne, n-BuLi
O
O
O
O
e) (S,S)-Noyori, 94%
O
O
O
O
O
O
O
O
d) DMP
67% over 2 steps
f) diimide, 90%
EtO
2
EtO
H
EtO
OPMB
31
2
2
C13H27
30
syn-8
Ph
Ph
g) DIBALH, 87%
O
O
O
OH
OH
O
OAc
h) Ac2O, Et3N, 72%
EtO
C15H31
C15H31
i) (S,S)-29
75%
2
2
32
33
Ph
Ph
i) TBSCl, 96%
O
O
O
OH
OH
O
O
OTBS
C15H31
j) DIBALH, 90%
k) (R,R)-29
95%
EtO
C15H31
2
2
32
34
Ph
Ph
l) DIBALH, 90%
m) 1-pentadecyne
n-BuLi
Ph
q) TBSCl, 94%
r) DDQ, 92%
PMBO
O
O
O
O
O
O
o) (R,R)-Noyori, 98%
O
O
OH
C15H31
n) DMP
68% over 2 steps
p) diimide, 98%
PMBO
OEt
2
2
PMBO
2
C13H27
syn-8
35
36
Ph
Ph
s) DMP, 62%
t) (S,S)-29
O
O
OTBS
C15H31
OH
O
O
OTBS
C15H31
HO
95%
2
2
37
ent-34
Scheme 6 Synthesis of protected tetraol intermediates
was used to give ynone 35 (62%). Noyori reduction of 35
[(R,R)-Noyori (5 mol%), Et3N, formic acid, 98%] gave a prop-
argyl alcohol as a single diastereomer, which upon expo-
sure to excess diimide gave secondary alcohol 36 with the
desired S-stereochemistry at C-15. TBS protection of the
secondary alcohol (94%) and DDQ-promoted removal of the
O
a) acrylic acid,
DCC
O
OH OH OH OH OH
b) Grubbs I
Ph
c) 80%AcOH/H2O
42% over 3 steps
C15H31
1: Cryptocaryol A
OH
O
O
OTBS
C15H31
e) acrylic acid,
DCC
2
O
O
f) TBAF
g) Ac2O, Et3N
ent-34
O
O
OH OH OH OH OAc
C15H31
h) Grubbs I
i) 80%AcOH/H2O
28% over 5 steps
2: Cryptocaryol B
a, b, c
OH OH OH OH OH
Ph
43% over 3 steps
C15H31
OH
O
O
OTBS
C15H31
ent-1: ent-cryptocaryol A
O
O
2
34
e, f,g,h,i
O
O
OH OH OH OH OAc
C15H31
38% over 5 steps
ent-2: ent-cryptocaryol B
Ph
a, b, c
OH
O
O
OAc
C15H31
OH OH OH OH OAc
35% over 3 steps
C15H31
2
33
4: purported cryptocaryol B
Scheme 7 Synthesis of 1,3-syn-ploly/pyranones
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

G
T. J. Hunter et al.
Special Topic
Synthesis
PMB group (92%) gave 37. Finally the C-5 R-stereochemistry
was installed by oxidation of the primary alcohol and addi-
tion of the (S,S)-Leighton reagent (95%).
2-((2R,4R,6R)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-
dioxan-4-yl)acetaldehyde (21)
DIBALH (11.5 mL of a 1 M solution in CH2Cl2) was added to a –78 °C
solution of the ester ent-19f (3.06 g, 7.64 mmol) in CH2Cl2 (40 mL).
After 30 min, acetone was added to quench the reaction and it was
stirred for 10 min before warming to r.t. A 20% solution of sodium po-
tassium tartrate (30 mL) was added and the biphasic mixture was
stirred until the two layers rapidly separated on cessation of stirring.
The aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The com-
bined organic layers were washed with brine, filtered, and concen-
trated. The crude product was purified by silica gel chromatography
to produce benzylidene-protected diol 21 (2.63 g) in 93% yield as a
clear oil; Rf = 0.58 (3:2 hexanes–EtOAc); [α]D +37.0 (c 1.0, CH2Cl2).
With all the stereochemistry installed in homoallylic al-
cohol ent-34, it was readily converted into cryptocaryol A
(1), by a three-step procedure. This began with an acryla-
tion of the C-5 alcohol, ring-closing metathesis with the
Grubbs I reagent, and aqueous acetic acid deprotection to
give 1 (42% over three steps).21 By replacing the C-15 TBS
group with an acetate (TBAF then Ac2O) after the acrylation
at C-5, homoallylic alcohol ent-34 could also be converted
into cryptocaryol B (2) (28% over five steps). Applying the
identical 3- and 5-step sequences to 34 provided ent-cryp-
tocaryol A (ent-1) and ent-cryptocaryol B (ent-2). Both syn-
thetic cryptocaryols A and B, gave identical spectral data as
was reported for the natural material.1 Finally, the homoal-
lylic alcohol 33 was converted into purported cryptocaryol
B (4), the initially assigned structure for cryptocaryol B, by a
three-step acrylation of the C-5 alcohol, ring-closing me-
tathesis with the Grubbs I reagent and aqueous acetic acid
deprotection (35%, over 3 steps) (Scheme 7).
In conclusion, we have described the full account of our
recently completed synthesis of cryptocaryol A (1) and
cryptocaryol B (2). The route featured three different ap-
proaches to the Cs- and C2-symmetric protected tetraol pre-
cursors syn-8 and anti-8, which are key building blocks for
the synthesis of many polyacetate type natural products.
The utility of this approach was demonstrated in the appli-
cation of various stereoisomeric analogues of the crypto-
caryols, which in turn enabled structure activity relation-
ship studies.
IR (neat): 3035, 3002, 2858, 2729, 2358, 2060, 1732, 1614, 1586,
1515, 1455, 1345, 1302, 1248, 1176, 1101 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 9.86 (dd, J = 2, 2 Hz, 1 H), 7.44 (m, 2 H),
7.34 (m, 3 H), 7.26 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.5 Hz, 2 H), 5.57 (s,
1 H), 4.47 (d, J = 12 Hz, 1 H), 4.43 (d, J = 12 Hz, 1 H), 4.42 (m, 1 H), 4.09
(dddd, J = 11, 8, 4.5, 2.5 Hz, 1 H), 3.79 (s, 3 H), 3.67 (ddd, J = 9.5, 8.5,
5.5 Hz, 1 H), 3.56 (ddd, J = 9.5, 5.5, 5.5 Hz, 1 H), 2.80 (ddd, J = 17, 7.5, 2
Hz, 1 H), 2.61 (ddd, J = 17, 5, 2 Hz, 1 H), 1.92 (dddd, J = 13.5, 8, 5, 5 Hz,
1 H), 1.84 (m, 1 H), 1.69 (ddd, J = 13, 2.5, 2.5 Hz, 1 H), 1.50 (ddd, J =
12.5, 11, 11 Hz, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 200.4, 159.2, 138.3, 130.5, 129.3,
128.7, 128.2, 128.2, 126.0, 113.8, 100.6, 73.7, 72.7, 71.9, 65.5, 55.3,
49.4, 36.7, 36.0.
HRMS (ESI): m/z calcd for [C22H26O5 + Na + MeOH]+: 425.1940; found:
425.1952.
Ethyl (2E,4E)-6-((2S,4S,6R)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-
phenyl-1,3-dioxan-4-yl)hexa-2,4-dienoate (22)
To phosphonate 25 (469 mg, 2.11 mmol) in THF (8 mL) was added
LiOH·H2O (81 mg, 1.94 mmol) and 4 Å (1.5 g) molecular sieves. This
mixture was heated at reflux for 30 min. before aldehyde 21 (625 mg,
1.69 mmol) dissolved in THF (2 mL) THF was added. This mixture was
heated at reflux for 6 h and then filtered through a plug of Celite. The
solvent was removed under reduced pressure and the crude product
was purified by silica gel chromatography to produce dienoate 22
(523 mg) in 66% yield as a clear oil; Rf = 0.71 (3:2 hexanes–EtOAc);
[α]D + 7.8 (c 1.16, CH2Cl2).
1H and 13C NMR spectra were recorded on a Varian 300, 400, or 500
MHz spectrometer. Chemical shifts were reported relative to internal
TMS (δ = 0.00) or CDCl3 (δ = 7.26) or CD3OD (δ = 3.30) for 1H NMR and
CDCl3 (δ = 77.2) or CD3OD (δ = 49.05) for 13C NMR. In the case of 19F
NMR, trifluoroacetic acid (δ = –76.55) was used as an external refer-
ence for Mosher ester analyses. IR spectra were obtained on a FT-IR
spectrometer. Optical rotations were measured with a digital po-
larimeter in the solvent specified. Melting points were determined
with a standard melting point apparatus. Flash column chromatogra-
phy was performed on 60–200 or 230–400 mesh silica gel. Analytical
TLC was performed with precoated glass-backed plates and visualized
by quenching of fluorescence and by charring after treatment with p-
anisaldehyde or KMnO4 stain. Rf values were obtained by elution in
the stated solvent ratios. Et2O, THF, CH2Cl2, and Et3N were dried by
passing through activated Al2O3 column with argon gas pressure.
Commercial reagents were used without purification, unless other-
wise noted. Air- and/or moisture-sensitive reactions were carried out
under an atmosphere of argon/N2 using oven- or flame-dried glass-
ware and standard syringe/septa techniques.
IR (neat): 2948, 1714, 1644, 1614, 1586, 1514, 1454, 1367, 1302,
1250, 1173, 1097 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 7.46 (m, 2 H), 7.35 (m, 3 H), 7.26 (d, J =
9 Hz, 2 H), 7.26 (m, 1 H), 6.87 (d, J = 8.7 Hz, 2 H), 6.28 (dd, J = 15.3, 9.6
Hz, 1 H), 6.20 (ddd, J = 15, 6.3, 6.3 Hz, 1 H), 5.82 (d, J = 15.3 Hz, 1 H),
5.51 (s, 1 H), 4.48 (d, J = 11.7 Hz, 1 H), 4.42 (d, J = 11.7 Hz, 1 H), 4.20 (q,
J = 7.2 Hz, 2 H), 4.02 (dddd, J = 12, 7.5, 4.5, 2.5 Hz, 1 H), 3.91 (m, 1 H),
3.79 (s, 3 H), 3.66 (ddd, J = 9, 9, 5.1 Hz, 1 H), 3.56 (ddd, J = 9.6, 5.4, 5.4
Hz, 1 H), 2.53 (ddd, J = 14.7, 6.3, 6.3 Hz, 1 H), 2.42 (ddd, J = 14.4, 6.6,
6.6 Hz, 1 H), 1.76–1.98 (m, 2 H), 1.60 (ddd, J = 13.2, 2.4, 2.4, Hz, 1 H),
1.44 (ddd, J = 13.2, 11.1, 11.1 Hz, 1 H), 1.30 (t, J = 7.2 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 166.9, 159.0, 144.3, 138.8, 138.5, 130.6,
130.4, 129.1, 128.4, 128.0, 125.9, 120.0, 113.6, 100.3, 75.7, 73.5, 72.5,
65.4, 60.1, 55.1, 39.2, 36.5, 35.9, 14.2.
HRMS (ESI): m/z calcd for [C28H34O6 + Na]+: 489.2253; found:
489.2227.
Complete experimental data for the synthesis of all starting materials,
intermediates, and final targeted products (Scheme 7) are provided in
detail in the Supporting Information.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

H
T. J. Hunter et al.
Special Topic
Synthesis
Ethyl (4R,5R,E)-4,5-Dihydroxy-6-((2R,4S,6R)-6-{2-[(4-methoxy-
HRMS (ESI): m/z calcd for [C29H34O9 + Na]+: 549.2101; found:
benzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)hex-2-enoate (23)
549.2082.
Into a 25 mL round bottom flask containing dienoate 22 (131 mg, 0.28
mmol) were added t-BuOH (2 mL), H2O (2 mL), K3Fe(CN)6 (277 mg,
0.84 mmol), K2CO3 (116 mg, 0.84 mmol), MeSO2NH2 (27 mg, 0.28
mmol), and (DHQD)2-PHAL (13 mg, 16.8 μmol). The mixture was
stirred at r.t. for 15 min and then cooled to 0 °C. To this solution was
added OsO4 (3.6 mg, 14 μmol) and the reaction mixture was stirred
vigorously at 0 °C overnight. The reaction was quenched with sat. aq
Na2SO3 (4 mL) at r.t. EtOAc (5 mL) was added to the reaction mixture,
and after separation of the layers, the aqueous phase was further ex-
tracted with EtOAc (2 × 10 mL). The combined organic layers were
washed with aq 2 N KOH (10 mL) to remove the methanesulfonamide
and brine, and then dried (anhyd Na2SO4). After removal of the sol-
vents in vacuo, flash chromatography on silica gel afforded 99 mg
(71%) of 23 as a clear oil; Rf = 0.16 (3:2 hexanes–EtOAc); [α]D +18.6 (c
1.2, CH2Cl2).
Ethyl (S,E)-5-Hydroxy-6-((2R,4S,6R)-6-{2-[(4-methoxyben-
zyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)hex-2-enoate (syn-24)
Into a 10 mL round bottom flask fitted with a condenser and main-
tained under N2 were placed 23a (80 mg, 0.152 mmol),
Pd2(dba)3·CHCl3 (1.6 mg, 1.5 μmol), PPh3 (1 mg, 3.8 μmol), and THF
(1.5 mL). Et3N (63 μL, 0.46 mmol) and formic acid (17 μL, 0.46 mmol)
were added and the mixture was allowed to reflux for 3 h. The reac-
tion was cooled to r.t. and quenched with sat. aq NaHCO3 (2 mL). The
aqueous layer was extracted with Et2O (3 × 5 mL). The organic layer
was washed with brine (5 mL) and dried (anhyd Na2SO4). After re-
moval of the solvents in vacuo, flash chromatography on silica gel af-
forded syn-24 as a yellow oil (66 mg, 90%); Rf = 0.22 (3:2, hexanes–
EtOAc); [α]D +7.7 (c 1.0, CH2Cl2).
IR (neat): 3518, 3035, 2938, 2863, 1886, 1722, 1714, 1658, 1652,
1614, 1586, 1514, 1463, 1454, 1368, 1302, 1248, 1174 cm–1
.
IR (neat): 3478, 2914, 1713, 1660, 1613, 1586, 1547, 1514, 1463,
1454, 1304, 1100 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.41 (m, 2 H), 7.34 (m, 3 H), 7.26 (d, J =
9 Hz, 2 H), 6.98 (ddd, J = 15.5, 7.5, 7.5 Hz, 1 H), 6.86 (d, J = 8.5 Hz, 2 H),
5.90 (ddd, J = 15.5, 1.5, 1.5 Hz, 1 H), 5.56 (s, 1 H), 4.46 (d, J = 12 Hz, 1
H), 4.42 (d, J = 12 Hz, 1 H), 4.18 (q, J = 7 Hz, 2 H), 4.03–4.15 (m, 3 H),
3.79 (s, 3 H), 3.65 (ddd, J = 9.5, 8.5, 5 Hz, 1 H), 3.55 (ddd, J = 9.5, 5.5, 5.5
Hz, 1 H), 2.39 (m, 2 H), 1.92 (dddd, J = 14, 8.5, 5.5, 5.5 Hz, 1 H), 1.76–
1.86 (m, 2 H), 1.68 (ddd, J = 14.5, 2.5, 2.5 Hz, 1 H), 1.60 (ddd, J = 13,
2.5, 2.5 Hz, 1 H), 1.50 (ddd, J = 13, 11, 11 Hz, 1 H), 1.29 (q, J = 7 Hz, 3
H).
1H NMR (CDCl3, 300 MHz): δ = 7.41 (m, 2 H), 7.35 (m, 3 H), 7.26 (d, J =
9 Hz, 2 H), 6.96 (dd, J = 15.5, 5 Hz, 1 H), 6.87 (d, J = 9 Hz, 2 H), 6.14 (dd,
J = 15.5, 2 Hz, 1 H), 5.56 (s, 1 H), 4.45 (d, J = 11.5 Hz, 1 H), 4.45 (d, J =
11.5 Hz, 1 H), 4.20 (q, J = 7 Hz, 2 H), 4.19 (m, 2 H), 4.07 (dddd, J = 10.5,
7.5, 4, 2 Hz, 1 H), 3.93 (dddd, J = 9.5, 4.5, 2.5, 2.5 Hz, 1 H), 3.79 (s, 3 H),
3.65 (ddd, J = 9, 8, 5 Hz, 1 H), 3.56 (ddd, J = 9.5, 5.5, 5.5 Hz, 1 H), 1.92
(m, 2 H), 1.84 (m, 1 H), 1.77 (ddd, J = 15, 3, 3 Hz, 1 H), 1.62 (m, 1 H),
1.52 (ddd, J = 13, 11, 11 Hz, 1 H), 1.29 (t, J = 7 Hz, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 166.3, 159.2, 146.8, 138.1, 130.5,
129.4, 129.0, 128.4, 126.0, 122.4, 113.8, 100.7, 80.7, 77.1, 73.8, 73.1,
72.7, 65.4, 60.5, 55.3, 38.6, 37.0, 36.0, 14.3.
HRMS (ESI): m/z calcd for [C28H36O8 + Na]+: 523.2308; found:
523.2329.
13C NMR (CDCl3, 75 MHz): δ = 166.3, 159.2, 145.0, 138.2, 130.5, 129.3,
128.9, 128.3, 126.0, 123.8, 113.8, 100.6, 77.4, 73.8, 72.7, 70.0, 65.5,
60.3, 55.3, 42.1, 40.2, 37.1, 36.0, 14.3.
HRMS (ESI): m/z calcd for [C28H36O7 + Na]+: 507.2359; found:
507.2348.
Ethyl (E)-3-{(4R,5R)-5-[((2R,4R,6R)-6-{2-[(4-Methoxyben-
zyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)methyl]-2-oxo-1,3-diox-
olan-4-yl}acrylate (23a)
Ethyl 2-{(2R,4R,6R)-6-[((2R,4R,6R)-6-{2-[(4-Methoxyben-
zyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)methyl]-2-phenyl-1,3-di-
oxan-4-yl}acetate (ent-syn-8)
Into a 10 mL volumetric flask containing diol 23 (90 mg, 0.18 mmol)
and pyridine (57 μL) was placed CH2Cl2 (2 mL). This mixture was
cooled to 0 °C and triphosgene (27 mg, 0.09 mmol) dissolved in
CH2Cl2 (1 mL) was added slowly using an addition funnel. The reac-
tion mixture was stirred for 1.5 h and quenched with sat. aq NH4Cl (4
mL). The layers were separated and the aqueous layer was extracted
with CH2Cl2 (3 × 5 mL). The combined organic layers were washed
with sat. aq NaHCO3 (10 mL), brine (10 mL), and dried (anhyd Na2SO4).
After removal of the solvents in vacuo, flash chromatography on silica
gel afforded 23a as a clear colorless oil (87 g, 92%); Rf = 0.11 (4:1 hex-
anes–EtOAc); [α]D +39.3 (c 1.7, CH2Cl2).
To a solution of alcohol syn-24 (75 mg, 0.155 mmol) in THF (1.5 mL) at
0 °C was added benzaldehyde (15 μL, 0.16 mmol), followed by KOt-Bu
(1.7 mg, 0.016 mmol). The solution was stirred for 15 min. The addi-
tion of benzaldehyde/KOt-Bu was repeated 3 more times and the re-
action was quenched with pH 7 phosphate buffer (1 mL) and diluted
with Et2O (3 mL). The layers were separated, and the aqueous layer
was extracted with Et2O (3 × 5 mL). The combined organic layers were
washed with brine, dried (anhyd Na2SO4), filtered, and concentrated
in vacuo. The crude product was purified by silica gel chromatogra-
phy to produce (syn,syn,syn)-dibenzylidene ent-syn-8 (58 mg) in 63%
yield as a clear oil; Rf = 0.26 (4:1 hexanes–EtOAc); [α]D +18.9 (c 0.9,
CH2Cl2).
IR (neat): 2920, 1810, 1716, 1668, 1615, 1586, 1560, 1516, 1456, 1248
cm–1
.
IR (neat): 2920, 2864, 1732, 1614, 1586, 1514, 1455, 1346, 1303,
1248, 1216, 1112, 1028 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 7.42 (m, 2 H), 7.36 (m, 3 H), 7.27 (d, J =
8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 6.83 (dd, J = 15.6, 5.7 Hz, 1 H),
6.14 (dd, J = 15.6, 1.5 Hz, 1 H), 5.51 (s, 1 H), 5.14 (ddd, J = 7.2, 5.7, 1.5
Hz, 1 H), 4.63 (ddd, J = 6.6, 5.1, 5.1 Hz, 1 H), 4.48 (d, J = 11.7 Hz, 1 H),
4.43 (d, J = 11.7 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.02–4.18 (m, 2 H),
3.80 (s, 3 H), 3.66 (ddd, J = 9.3, 8.1, 5.1 Hz, 1 H), 3.57 (ddd, J = 11.1, 5.4,
5.4 Hz, 1 H), 2.08–2.18 (m, 2 H), 1.80–1.98 (m, 2 H), 1.58 (m, 2 H), 1.29
(t, J = 7.2 Hz, 3 H).
1H NMR (CDCl3, 300 MHz): δ = 7.49 (m, 4 H), 7.36 (m, 6 H), 7.27 (d, J =
8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.59 (s, 1 H), 5.54 (s, 1 H), 4.50 (d,
J = 11.7 Hz, 1 H), 4.44 (d, J = 11.7 Hz, 1 H), 4.35 (dddd, J = 11.1, 6.6, 6.6,
2.1 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 4.02–4.18 (m, 3 H), 3.79 (s, 3 H),
3.69 (ddd, J = 9, 8.1, 5.1 Hz, 1 H), 3.60 (ddd, J = 9.6, 5.7, 5.7 Hz, 1 H),
2.76 (dd, J = 15.6, 7.2 Hz, 1 H), 2.54 (dd, J = 15.6, 6 Hz, 1 H), 2.16 (ddd,
J = 15.6, 7.2 Hz, 1 H), 1.64–2.00 (m, 5 H), 1.45–1.62 (m, 2 H), 1.28 (t, J =
7.2 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 164.7, 159.0, 153.5, 139.1, 137.9, 130.3,
129.2, 128.7, 128.1, 125.8, 124.8, 113.6, 100.5, 79.4, 78.0, 73.6, 72.5,
71.9, 65.2, 60.9, 55.1, 37.7, 36.2, 35.8, 14.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

I
T. J. Hunter et al.
Special Topic
Synthesis
13C NMR (CDCl3, 75 MHz): δ = 170.6, 160.0, 138.6, 138.2, 130.4, 129.2,
128.5, 128.4, 128.0, 128.0, 125.9, 125.9, 113.6, 100.4, 100.3, 73.6, 73.1,
72.9, 72.9, 72.5, 65.5, 60.5, 55.1, 41.6, 40.9, 36.7, 36.2, 36.0, 14.1.
HRMS (ESI): m/z calcd for [C35H42O8 + Na]+: 613.2777; found:
613.2785.
1-((2S,4S,6S)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-di-
oxan-4-yl)pent-4-en-2-one (27)
In a 10 mL round bottom flask was placed the alcohol 26 (90 mg) in
CH2Cl2 (2 mL). To this solution was added of Dess–Martin periodinane
(140 mg, 0.33 mmol). The reaction was stirred for 1.5 h. Et2O was
added to the reaction and the solution was filtered through a pad of
silica gel, followed by removal of the solvents under reduced pressure.
The crude product was purified by silica gel chromatography to pro-
duce 80 mg (89% yield) of ketone 27 as a clear oil; [α]D +22.3 (c 1.0,
CH2Cl2).
(R)-1-((2S,4R,6S)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-
1,3-dioxan-4-yl)pent-4-en-2-ol (syn-26) and (S)-1-((2S,4R,6S)-6-
{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)pent-
4-en-2-ol (anti-26)
IR (neat): 2922, 1714, 1644, 1614, 1586, 1515, 1455, 1360, 1347,
To a solution of ester 19f in CH2Cl2 (10 mL) at –78 °C was added
DIBALH (3.75 mL, 1.0 M solution in CH2Cl2). This solution was allowed
to stir for 1 h when allylmagnesium chloride (2.5 mL, 2 M solution in
THF) was added to the flask. The reaction was allowed to warm to r.t.
and stirred for 3 h, after which MeOH (1 mL) and a 20% sodium potas-
sium tartrate solution (10 mL) were added. This solution was stirred
vigorously until the layers separated rapidly upon cessation of stir-
ring. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The
organic layers were combined and washed with brine and dried (an-
hyd Na2SO4). Removal of the solvents in vacuo followed by passage
through a short pad of silica gel yielded the alcohol (876 mg, 85%) as a
clear oil and a mixture of diastereomers.
1245, 1174, 1098, 1028 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.42 (m, 2 H), 7.33 (m, 3 H), 7.26 (d, J =
8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.93 (dddd, J = 17.1, 10.2, 7.2, 7.2
Hz, 1 H), 5.54 (s, 1 H), 5.18 (m, 2 H), 4.47 (d, J = 11.7 Hz, 1 H), 4.43 (d,
J = 11.7 Hz, 1 H), 4.34 (m, 1 H), 4.06 (dddd, J = 10.5, 7.5, 4.5, 2.7 Hz, 1
H), 3.79 (s, 3 H), 3.66 (ddd, J = 9, 7.8, 5.4 Hz, 1 H), 3.56 (ddd, J = 9.3, 5.7,
5.7 Hz, 1 H), 3.25 (m, 2 H), 2.90 (dd, J = 16.2, 7.2 Hz, 1 H), 2.57 (dd, J =
16.2, 5.7 Hz, 1 H), 1.84 (m, 2 H), 1.70 (ddd, J = 12.9, 2.4, 2.4 Hz, 1 H),
1.40 (ddd, J = 12.9, 11.1, 11.1 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 206.2, 159.0, 138.3, 130.3, 130.0, 129.1,
128.4, 128.0, 125.8, 119.0, 113.6, 100.3, 73.5, 72.9, 72.5, 65.4, 55.1,
48.7, 48.0, 36.7, 35.9.
HRMS (ESI): m/z calcd for [C25H30O5 + Na]+: 433.1991; found:
433.1997.
syn-26
Rf = 0.19 (4:1 hexanes–EtOAc); [α]D21 –19.2 (c 0.92, CH2Cl2).
IR (neat): 3532, 3071, 2918, 1727, 1641, 1614, 1586, 1515, 1455,
1303, 1247, 1174, 1102 cm–1
.
(R)-1-((2S,4R,6S)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-
1,3-dioxan-4-yl)pent-4-en-2-ol (syn-26)
1H NMR (CDCl3, 500 MHz): δ = 7.43 (m, 2 H), 7.33 (m, 3 H), 7.26 (d, J =
8.5 Hz, 2 H), 6.87 (d, J = 8.5 Hz, 2 H), 5.85 (dddd, J = 17.5, 10.5, 7, 7 Hz,
1 H), 5.56 (s, 1 H), 5.13 (m, 2 H), 4.47 (d, J = 11.5 Hz, 1 H), 4.43 (d, J =
11.5 Hz, 1 H), 4.12 (dddd, J = 11.5, 8.5, 3.5, 2.5 Hz, 1 H), 4.06 (dddd, J =
11, 8, 4.5, 2.5 Hz, 1 H), 3.98 (dddd, J = 9, 6, 6, 2.5 Hz, 1 H), 3.79 (s, 3 H),
3.66 (ddd, J = 9.5, 8.5, 5 Hz, 1 H), 3.56 (ddd, J = 9.5, 5.5, 5.5 Hz, 1 H),
2.26 (m, 2 H), 1.92 (dddd, J = 14, 8.5, 5.5, 5.5 Hz, 1 H), 1.84 (m, 1 H),
1.79 (ddd, J = 14.5, 9.5, 9.5 Hz, 1 H), 1.70 (ddd, J = 14.5, 3.5, 2.5 Hz, 1
H), 1.62 (ddd, J = 13, 2.5, 2.5 Hz, 1 H), 1.50 (ddd, J = 13.5, 11.5, 11.5 Hz,
1 H).
From27: To a solution of ketone 27 (55 mg, 0.13 mmol) in THF (1.5
mL) at –90 °C was added a 1.0 M solution of L-selectride in THF (0.26
mL, 0.26 mmol). After stirring for 3 h, a solution of 30% H2O2 and aq 1
M NaOH were added and the reaction was allowed to warm to r.t. and
diluted with Et2O. The organic layer was separated, washed with sat.
aq Na2S2O3 and brine, dried (anhyd Na2SO4), filtered, and concentrat-
ed. The crude material was purified by flash chromatography to pro-
vide 48 mg (89%) of alcohol 26 as a mixture (4:1) of diastereomers.
From ent-21: To a stirred solution of ent-21 (2.23 g, 6.02 mmol) in
CH2Cl2 (20 mL) at –10 °C was added a solution of (S,S)-Leighton re-
agent (5.01 g, 9.03 mmol) in CH2Cl2 (10 mL) slowly via syringe, fol-
lowed by Sc(OTf)3 (74.1 mg, 0.151 mmol) under N2. Then the result-
ing mixture was transferred to a freezer at –10 °C. After 12 h, the re-
action was quenched by adding aq 1 N HCl (20 mL). The formed solid
was filtered through a fritted funnel, and the filtrate was extracted
with EtOAc (3 × 50 mL). The combined organic layers were washed
with brine, dried (anhyd Na2SO4), filtered, and concentrated under re-
duced pressure. The crude residue was purified by flash chromatog-
raphy (10 to 30% EtOAc in hexanes) on silica gel (50 mL) to afford syn-
26 (1.79 g, 72%, dr = 8.7:1.0) as a colorless oil.
13C NMR (CDCl3, 125 MHz): δ = 159.2, 138.3, 134.8, 130.5, 129.3,
128.8, 128.2, 126.0, 117.6, 113.8, 100.6, 77.3, 73.9, 72.7, 70.4, 65.5,
55.3, 42.0, 42.0, 37.2, 36.0.
HRMS (ESI): m/z calcd for [C25H32O5 + Na]+: 435.2147; found:
435.2132.
anti-26
Rf = 0.19 (4:1 hexanes–EtOAc); [α]D –25.6 (c 1.0, CH2Cl2).
IR (neat): 3446, 3069, 2917, 2861, 1718, 1700, 1684, 1654, 1637,
1613, 1586, 1514, 1456, 1405, 1100, 1028 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 7.44 (m, 2 H), 7.34 (m, 3 H), 7.26 (d, J =
9 Hz, 2 H), 6.87 (d, J = 9 Hz, 2 H), 5.84 (dddd, J = 17.5, 11, 7.5, 7.5 Hz, 1
H), 5.54 (s, 1 H), 5.15 (m, 2 H), 4.47 (d, J = 11.5 Hz, 1 H), 4.43 (d, J =
11.5 Hz, 1 H), 4.17 (m, 1 H), 4.04 (m, 2 H), 3.79 (s, 3 H), 3.67 (ddd, J = 9,
8.5, 5 Hz, 1 H), 3.57 (ddd, J = 9.5, 5.5, 5.5 Hz, 1 H), 2.30 (m, 2 H), 1.93
(dddd, J = 14, 8.5, 5.5, 5.5 Hz, 1 H), 1.84 (m, 1 H), 1.78 (ddd, J = 15, 8.5,
3 Hz, 1 H), 1.69 (ddd, J = 14.5, 9, 3 Hz, 1 H), 1.55 (m, 2 H).
13C NMR (CDCl3, 125 MHz): δ = 159.2, 138.7, 134.8, 130.6, 129.3,
128.6, 128.2, 126.0, 118.0, 113.8, 100.6, 74.2, 73.9, 72.7, 67.0, 65.6,
55.3, 42.3, 42.1, 36.9, 36.1.
(S)-1-((2S,4R,6S)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-
1,3-dioxan-4-yl)pent-4-en-2-ol (anti-26)
To a stirred solution of ent-21 (1.10 g, 3.0 mmol) in CH2Cl2 (10 mL) at
–10 °C was added a solution of (R,R)-Leighton reagent (2.50 g, 4.51
mmol) in CH2Cl2 (5 mL) slowly via syringe, followed by Sc(OTf)3 (37
mg, 0.075 mmol) under N2. Then the resulting mixture was trans-
ferred to freezer at –10 °C. After 12 h, the reaction was quenched by
adding aq 1 N HCl (10 mL). The formed solid was filtered through a
fritted funnel, and the filtrate was extracted with EtOAc (3 × 25 mL).
The combined organic layers were washed with brine, dried (anhyd
Na2SO4), filtered, and concentrated under reduced pressure. The
HRMS (ESI): m/z calcd for [C25H32O5 + Na]+: 435.2147; found:
435.2132.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

J
T. J. Hunter et al.
Special Topic
Synthesis
crude residue was purified by flash chromatography (10 to 30% EtOAc
in hexanes) on silica gel (50 mL) to afford anti-26 (1.79 g, 72%, dr =
8:1) as a colorless oil.
HRMS (ESI): m/z [M + Na]+ calcd for C35H42O8Na: 613.2777; found:
613.2785.
Ethyl (S,E)-5-Hydroxy-6-((2S,4R,6S)-6-{2-[(4-methoxyben-
zyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)hex-2-enoate (ent-anti-
Acknowledgment
We are grateful to NIH (GM090259) and NSF (CHE-1213596) for fi-
nancial support of this research.
24)
To a stirred solution of anti-26 (2.95 g, 7.15 mmol) in CH2Cl2 (10 mL)
at r.t. was added ethyl acrylate (30.4 mL, 0.286 mol), followed by the
Grubbs second-generation catalyst (146 mg, 0.179 mmol) under N2.
The resulting mixture was degassed by two freeze-pump-thaw cy-
cles, then warmed to r.t. and stirred at the same temperature. After 3
h, the mixture was diluted with hexanes (100 mL), and purified by
flash chromatography (20 to 50% EtOAc in hexanes) on silica gel (100
mL) to afford anti-29 (3.43 g, 99%) as a colorless oil; Rf = 0.34 (50%
EtOAc in hexanes); [α]D21 –15.6 (c 1.79, CH2Cl2).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561607.
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References
IR (neat): 3501, 3037, 2917, 1888, 1715, 1698, 1652, 1614, 1586,
1515, 1456, 1246 cm–1
.
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1H NMR (CDCl3, 300 MHz): δ = 7.42 (m, 2 H), 7.34 (m, 3 H), 7.26 (d, J =
8.7 Hz, 2 H), 6.98 (ddd, J = 15.6, 7.2, 7.2 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 2
H), 5.91 (ddd, J = 15.6, 1.5, 1.5 Hz, 1 H), 5.52 (s, 1 H), 4.47 (d, J = 11.7
Hz, 1 H), 4.42 (d, J = 11.7 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 4.17 (m, 2
H), 4.05 (m, 1 H), 3.78 (s, 3 H), 3.65 (ddd, J = 9.3, 8.1, 5.4 Hz, 1 H), 3.56
(ddd, J = 9.6, 5.4, 5.4 Hz, 1 H), 2.40 (m, 2 H), 1.80–1.98 (m, 2 H), 1.72–
1.78 (m, 2 H), 1.55 (m, 2 H), 1.28 (t, J = 7.2 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 166.1, 159.0, 144.9, 138.4, 130.3, 129.1,
128.5, 128.0, 125.8, 123.7, 113.6, 100.4, 73.9, 73.7, 72.5, 66.7, 65.4,
60.2, 55.1, 41.9, 40.3, 36.5, 35.9, 14.2.
HRMS (ESI): m/z calcd for [C28H36O7 + Na]+: 507.2359; found:
507.2329.
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To a stirred solution of ent-anti-24 (0.75 g, 1.6 mmol) in THF (30 mL)
at 0 °C was added benzaldehyde (0.18 mL, 1.75 mmol), followed by
KOt-Bu (0.02g, 0.175 mmol) under N2. The resulting mixture was
stirred for 15 min. Then the addition of benzaldehyde/KOt-Bu was re-
peated 3 more times. The mixture was passed through a pad of silica
gel, and the silica gel was washed with EtOAc (100 mL). The filtrate
was concentrated, and the crude residue was purified by flash chro-
matography (5 to 40% EtOAc in hexanes) on silica gel to afford anti-8
21
(0.72 g, 77%) as a colorless oil; Rf = 0.41 (30% EtOAc in hexanes); [α]D
–18.0 (c = 1.72, CH2Cl2).
IR (neat): 2918, 2859, 1732, 1512, 1247, 1107, 1010 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.57–7.41 (m, 4 H), 7.43–7.28 (m, 6 H),
7.26 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 9.0 Hz, 2 H), 5.58 (s, 1 H), 5.53 (s, 1
H), 4.45 (d, J = 11.6 Hz, 1 H), 4.43 (d, J = 11.5 Hz, 2 H), 4.34 (dddd, J =
11.5, 7.0, 7.0, 2.5 Hz, 1 H), 4.17 (q, J = 7.0 Hz, 2 H), 4.13 (m, 3 H), 3.78
(s, 3 H), 3.68 (ddd, J = 8.5, 8.5, 5.0 Hz, 1 H), 3.58 (ddd, J = 9.5, 5.5, 5.5
Hz, 1 H), 2.74 (dd, J = 15.5, 7.0 Hz, 1 H), 2.53 (dd, J = 15.5, 6.0 Hz, 1 H),
2.15 (ddd, J = 14.0, 7.0, 7.0 Hz, 1 H), 1.93 (dddd, J = 14.0, 8.0, 5.0, 5.0
Hz, 1 H), 1.86 (dddd, J = 14.0, 8.0, 5.5, 4.5 Hz, 1 H), 1.81 (ddd, J = 13.0,
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129.6, 129.0, 128.9, 128.41, 128.38, 126.29, 126.26, 114.0, 100.8,
100.7, 74.0, 73.5, 73.27, 72.20, 72.9, 65.9, 60.9, 55.5, 41.9, 41.2, 37.1,
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K