The Catalytic Alkylative Desymmetrization of Anhydrides in a Formal Synthesis of Ionomycin

Article abstract of DOI:10.1055/s-0037-1610108

The catalytic desymmetrization of anhydrides with zinc reagents provides access to deoxypolypropionate and polypropionate synthons. A synthesis of ionomycin was pursued in which three of the four fragments were assembled using this methodology. Two of the strategies (enol silane/oxocarbenium coupling and reductive cyclization) were not successful at installing the C23 stereocenter, but this stereochemical issue was overcome through a reduction/S _N 2 approach. In addition to the synthesis of a protected diastereomer of ionomycin, the synthesis of a C17-C32 fragment constitutes a formal total synthesis.

Full text of DOI:10.1055/s-0037-1610108

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
special topic
A
en
K. M. Oberg et al.
Special Topic
Synthesis
The Catalytic Alkylative Desymmetrization of Anhydrides in a
Formal Synthesis of Ionomycin
Kevin M. Oberga
Me
O
O
O
Brian M. Cochrana
Matthew J. Cooka
Tomislav Rovis*a,b
O
O
OH
H
Me H
Me
Me
Me
Me
O
O
O
OH
OBn
0
0
0
0
0-
0
0
1
6-
2
8
7
8-
6
6
9
Me
ionomycin
O
OH
Me
O
Me
Me
a Department of Chemistry, Colorado State University, Fort Col-
lins, CO 80523, USA
b Department of Chemistry, Columbia University, 3000 Broad-
way, New York, NY 10027, USA
OH
HO
O
O
O
Me
Me
tr2504@columbia.edu
Me
Me
Me
Me
Dedicated to Professor Scott Denmark on the occasion of his
65th birthday.
Published as part of the Special Section dedicated to Scott E.
Denmark on the occasion of his 65th birthday.
Received: 07.03.2018
Accepted after revision: 09.04.2018
Published online: 29.05.2018
[Rh(nbd)Cl]2
(R)-t-BuPhox
O
O
O
O
O
O
HO
R
DOI: 10.1055/s-0037-1610108; Art ID: ss-2018-c0160-st
Me
Me
RZnX or ZnR2
Me Me
1
2
Abstract The catalytic desymmetrization of anhydrides with zinc re-
agents provides access to deoxypolypropionate and polypropionate
synthons. A synthesis of ionomycin was pursued in which three of the
four fragments were assembled using this methodology. Two of the
strategies (enol silane/oxocarbenium coupling and reductive cycliza-
tion) were not successful at installing the C23 stereocenter, but this
stereochemical issue was overcome through a reduction/SN2 approach.
In addition to the synthesis of a protected diastereomer of ionomycin,
the synthesis of a C17–C32 fragment constitutes a formal total synthe-
sis.
[Rh(nbd)Cl]2
(R)-t-BuPhox
OP
O
O
O
O
HO
R
Me
Me
RZnX or ZnR2
Me Me
OP
3
4
Scheme 1 Desymmetrization of anhydrides to generate deoxypolypro-
pionate 2 and polypropionate 4 synthons
Key words total synthesis, rhodium, enantioselective synthesis, anhy-
dride desymmetrization, diastereoselectivity
position of the β-diketone (Scheme 2). The C23–C32 frag-
ment, lactone 6, is derived from geraniol acetate 7, follow-
ing precedent from Paterson.9 The C17–C22 polypropionate
fragment 8 is derived from the desymmetrization of anhy-
dride 3a. Both the C10–C16 and C1–C9 deoxypolypropio-
nate fragments, 9 and 10, are derived from desymmetriza-
tion of the same starting material, 2,4-dimethylglutaric an-
hydride (1).
The synthesis of aldehyde 10 began with the desymme-
trization of 2,4-dimethylglutaric anhydride (1) with dial-
kylzinc reagent 11, furnishing keto acid 2a in moderate
yield and good enantioselectivity (Scheme 3). We found
that numerous elements affect the reaction success; diene
ligand on rhodium, counterion on rhodium, and the synthe-
sis of the dialkylzinc reagent. The use of 1,5-cyclooctadiene
(cod) as the diene ligand led to trace amounts of product
formation, whereas norbornadiene (nbd) furnished the
product. The counterion affects efficiency of the desymme-
trization reaction, with [Rh(nbd)OAc]2 as the precatalyst
achieving a higher yield.10,11 The reaction is contaminated
with varying amounts of the ethyl keto acid 2b, which pre-
sumably comes from a mixed zinc reagent following incom-
plete reaction of Et2Zn and the alkyl iodide. An improved
In 2007, we reported the catalytic desymmetrization of
2,4-dimethylglutaric anhydride (1) using zinc reagents gen-
erating enantioenriched keto acids 2 containing a syn-1,3-
dimethyl substitution pattern, a common motif in natural
products (Scheme 1).1 We have recently extended this
methodology to trisubstituted anhydrides 3 constructing
keto acids 4 containing an anti,anti-polypropionate stereo-
triad.2 We hoped to illustrate the power of this method in
enabling polypropionate synthesis, and chose the complex
ionophore ionomycin (5) as a target. Herein, we report our
progress towards this goal.
Ionomycin (5) was isolated from Streptomyces congobla-
tus and its structure established soon after.3 Four total syn-
theses of ionomycin have been reported, by the groups of
Hanessian,4 Evans,5 Lautens,6 and Kocienski.7 In addition to
these completed syntheses, a number of approaches have
also appeared.8 In a similar fashion as previous syntheses,
we retrosynthetically disconnected ionomycin between
C22 and C23, at the C16–C17 double bond, and the C9–C10
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

B
K. M. Oberg et al.
Special Topic
Synthesis
polar toluene solvent. This chelate installs a rigid conforma-
tional bias that hinders alkylation from one face of the eno-
late. When the methyl ester of 2a is subjected to the reac-
tion conditions or when Lewis basic additive such as HMPA
is added, alkylation proceeds with no selectivity, which fur-
ther supports chelate control.
Efforts to deoxygenate the C5 ketone of 12 using Wolff–
Kishner or Clemmensen reduction conditions resulted in
decomposition without isolation of our target material. In-
stead, the ketone was converted into a dithiolane and the
carboxylic acid could be chemoselectively reduced with
borane to generate alcohol 13 (Scheme 4). At this stage, the
dithiolane was desulfurized using Raney nickel and the pri-
mary alcohol oxidized to afford the completed C1–C9 frag-
ment as aldehyde 10.
Me32
23
C22–C23
22
O
O
OH
H
Me H
Me
Me
Me
OH
OH
ionomycin 5
O
17
16
1
OH
O
9
HO
Julia
olefination
10
Me
Me
Me
Me
Me
aldol/oxidation
Me
Me
OH
O
Me
Me
OAc
O
O
Me H
Me
7
6
O
O
O
OBn
O
RO
Me
Me
Me
Me
Me
OBn
O
8
3a
1. 1,2-ethanedithiol
BF3•OEt2
2. BH3•THF
O
OH
O
PTO2S
S
S
Me
O
O
12
OEt
13
Me
Me
9
88%, 73%
Me Me Me
O
O
Me
Me
1
O
O
OEt
1. Raney Ni
2. TPAP, NMO
9
Me
Me
Me
10
OEt
1
54%, 74%
Me Me Me
10
Scheme 2 Retrosynthesis of ionomycin (5). Polypropionate 8 was envi-
sioned to arise from anhydride 3a and deoxypolypropionate fragments
9 and 10 were to be synthesized from anhydride 1.
Scheme 4 Synthesis of aldehyde 10
Anhydride 1 was also used for the synthesis of the C10–
C16 fragment 9. Desymmetrization of anhydride 1 with
methylzinc bromide generates keto acid 2c in good yield
and enantioselectivity. Global reduction of the acid and ke-
tone with LiAlH4, iodination of the primary alcohol, and ox-
idation of the secondary alcohol affords iodo ketone 14. The
ketone was protected as a dioxolane acetal and homologa-
tion of the carbon chain was achieved using lithiated dith-
iane. Removal of the dithiane and reduction of the ensuing
aldehyde generates alcohol 16. Installation of the requisite
sulfone for a Julia–Kocienski olefination was achieved via a
Mitsunobu reaction with the tetrazole thiol,13 and the cor-
responding sulfide was oxidized to the sulfone. The removal
of the acetal was complicated by epimerization at C12 using
typical deprotection conditions (1 M HCl). We circumvent-
ed this issue through the use of cerium(III) chloride hepta-
hydrate and NaI, which deprotects the acetal without epi-
merization delivering sulfone 9 (Scheme 5).14
zinc reagent 11 could be formed using CuI as a catalyst,12
which provides keto acid 2a in higher yields with smaller
amounts of ethyl keto acid 2b contaminant.
[Rh(nbd)OAc]2
(R)-t-BuPhox
O
O
O
OEt
Zn
CO2Et
11
2
8
6
1
HO
58%, 90% ee
Me
Me
2a
O
O
HO
Et
KHMDS (2.0 equiv)
MeI
73%,
5:1 dr
Me
O
Me
Me
2b
O
R
O
O
OEt
O
K
K
Me
8
6
4
O
HO
Me
Me
Me
I
12
With sulfone 9 and aldehyde 10 in hand, we examined
an aldol/oxidation sequence to generate the completed C1–
C16 fragment of ionomycin. Initial boron-aldol conditions
using Bu2BOTf proved to be capricious, however, consistent
yields were achieved with B-I-9-BBN.15 Oxidation of the β-
keto alcohol 17 to the β-diketone 18 was possible with ei-
ther Collins or IBX oxidation conditions;16 however, the lat-
ter protocol was higher yielding and more reproducible
(Scheme 6).
Scheme 3 Desymmetrization of anhydride 1 with dialkylzinc 11 and
diastereoselective alkylation, via chelate I, to synthesize C1-C9 carbon
framework
Installation of the C4 methyl substituent was accom-
plished through a diastereoselective alkylation of keto acid
2a. The carboxylic acid moiety is key to achieving diastereo-
selectivity. We propose the diastereocontrol is due to a che-
late between the potassium carboxylate and potassium
enolate (I, Scheme 3), which would be favored in the non-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

C
K. M. Oberg et al.
Special Topic
Synthesis
[Rh(nbd)Cl]2, (R)-t-BuPhox
[Rh(nbd)Cl]2
(R)-t-BuPhox
MeZnBr
O
O
O
OBn O
MeZnBr
14
12
LiAlH4
96%
1
18
20
HO
Me
2c
HO
4a
Me
89%, 87% ee
3
Me
Me
60%, 91% ee
Me
Me
1. LiAlH4
85%
2. PPh3, im, I2 68%
3. TPAP, NMO 85%
1. TsCl, Et3N, DMAP
or TBDPSCl, im
2. TPAP, NMO
1. TsOH, (HOCH2)2
2.
OR OBn
O
OH OBn OH
Me
S
S
S
Li
I
O
Me
O
O
S
Ts: 67%, 94%
TBDPS: 64%, 84%
Me
Me
Me
Me
Me
Me
15
95%, 74%
8a R = Ts
8b R = TBDPS
19
Me
Me
Me
Me
14
1. MeI, K2CO3 90%
Scheme 7 Synthesis of polypropionate 8 by the desymmetrization of
anhydride 3
2. NaBH4
85%
1. PTSH, DIAD, PPh3
2. mCPBA
3. CeCl3•7H2O, NaI
OH
SO2PT
16
O
O
12
O
lowed by oxidation to provide the completed C17–C22
methyl ketone fragment 8 (Scheme 7).
10
Me
Me
86%, 85%, 95%
Me
Me
16
Me
Me
9
To synthesize the C23–C32 fragment, we employed a
modified synthetic route devised by Paterson and co-work-
ers.9 Geranyl acetate (7) underwent an allylic oxidation and
Sharpless asymmetric epoxidation. In a one-pot procedure,
the epoxyalcohol intermediate was converted into the
iodide and the acetate group cleaved to deliver iodoepoxide
20. A two-carbon homologation could be achieved using
the lithium enolate of tert-butyl acetate, which, following a
second Sharpless epoxidation, delivers diepoxide 21. In a
two-step, one-pot reaction, the primary alcohol is substi-
tuted to a bromide followed by acid-mediated polycycliza-
tion providing lactone 22 (Scheme 8).
The synthesis of the C23–C32 fragment was completed
by hydrogenolysis of the alkyl bromide and the resulting
lactone 6, was reduced with DIBAL-H, which following in
situ trapping with benzoic anhydride affords acetal 23
(Scheme 8).
Scheme 5 Synthesis of ketone 9 from the desymmetrization of anhy-
dride 1; PT: phenyltetrazole
O
SO2PT
9
O
OH
EtO
B-I-9-BBN, Et3N
74%
+
10
Me
Me
Me
Me
Me
17
O
SO2PT
O
16
1
OH
EtO
IBX
65%
Me
Me
Me
Me
Me
18
Scheme 6 Aldol coupling and oxidation completes C1–C16 fragment
18
The synthesis of the polypropionate fragment 8 began
with the desymmetrization of trisubstituted anhydride 3.
Using methylzinc bromide, keto acid 4a was synthesized in
good yield and enantioselectivity, which established the
requisite anti,anti-C18–C20 stereotriad. Global reduction
using lithium aluminum hydride generates diol 19, which
could be protected either as a tosylate or TBDPS ether fol-
Our initial attempts to install the C22–C23 bond, to cou-
ple the northern fragments, utilized a silyl enol ether addi-
tion into an oxocarbenium ion derived from 23 (Scheme 9).
Following conversion of methyl ketone 8 into the silyl enol
ether, the Lewis acid mediated coupling of these two frag-
ments was examined. Treatment of the tosyl variant 8a,
with TMSOTf in the presence of 23, delivered bistetrahydro-
Me
Me
1. SeO2, t-BuOOH
2. Ti(Oi-Pr)4, (–)-DET, t-BuOOH
3. i. PPh3, im, I2
ii. K2CO3, MeOH
1. t-BuOAc, LDA
2. Ti(Oi-Pr)4, (–)-DET,
t-BuOOH
O
I
27
O
O
O
32
32
23
t-BuO
27
32
59%, 61%, 67%
72%, 64%
21
Me
Me
OH
Me
Me
OH
Me
OAc
20
7
i. CBr4, PPh3
ii. TsOH
65%
32
Me32
OBz
i. DIBAL-H
ii. Bz2O
Me
OH
Br
Pd/C, H2, Et3N
82%
23
23
O
O
BzO
O
O
O
O
O
O
OH
Me H
Me
Me H
Me
73%
Me H
Me
6
22
23
Scheme 8 Synthesis of acetal 23 from geraniol acetate (7) utilizing Sharpless epoxidations for stereoinduction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

D
K. M. Oberg et al.
Special Topic
Synthesis
Me
Me
Me
23
23
BzO
O
O
O
O
O
O
OBz
Me H
Me
OBz
OBz
H
Me H
Me
H
Me H
Me
Me
Me
23
O
O
TMSOTf, DTBMP
+
27 R1 = Ts
29 R1 = TBDPS
28 R1 = Ts
30 R1 = TBDPS
Me
Me
OBn OSiR3
Me
OBn
OR1
OBn
OR1
R1O
undesired C23
desired C23
Me
R1
Ts
SiR3
entry
1
yield (%)
dr
24
R3SiOTf,
Et3N
8:1 (27:28)
SiMe3
91
50
0
25
26
2
3
TBDPS
TBDPS
SiMe2t-Bu
3:1 (29:30)
Si(SiMe3)3
-
8
Scheme 9 Enol silane addition to oxocarbenium generates undesired C23 stereocenter as major product
furan 27 in excellent yield and good diastereoselectivity
(Scheme 9, entry 1). The stereochemical outcome of this re-
action was difficult to ascertain at the time; we later inter-
cepted an intermediate previously reported by Kocienski,
which definitively established the stereochemistry at C23
as the undesired 23R-isomer (vide infra).17 Following this
discovery, we attempted to override the selectivity through
the use of more sterically demanding silyl enol ethers. The
TBS enol 25 provided larger amounts of our desired isomer
30, as the addition occurred with more moderate diastereo-
selectivity; however, the major isomer was still the 23R-
diastereomer 29. This gain in selectivity was also accompa-
nied by a large loss in reaction efficiency with moderate
yields of 29 and 30 obtained (entry 2). Increasing the steric
bulk further with a tris(trimethylsilyl)silyl enol ether 26
failed to produce any product (entry 3).
deprotection using photolytic conditions19 and oxidation of
the primary alcohol to generate aldehyde 32.
It was at this time that we confirmed the C-23 stereo-
chemistry to be the undesired 23R-isomer as the spectral
data for both the aldehyde 32 and its alcohol precursor did
not match Kocienski’s reported data. With epi-23 aldehyde
32 in hand, we attempted the Julia–Kocienski olefination
with sulfone ent-18 (generated during route exploration us-
ing the more readily available antipode of ligand). We were
pleased to isolate the protected ionomycin diastereomer 33,
albeit in a low, unoptimized yield (Scheme 10). This
demonstrates that a coupling of a C17 aldehyde with a C16
sulfone, containing an unprotected β-diketone, should be a
viable route to synthesize ionomycin.20
In order to install the desired C23 stereochemistry, we
hypothesized that reversing the C–C bond forming and re-
duction steps would provide the desired S-diastereoisomer
(Figure 1). Indeed, Kishi previously demonstrated the use of
this approach using glycopyranosides.21
As the stereochemistry at C23 was difficult to establish,
we took the major diastereomer 27 forward in the synthe-
sis. The benzyl protecting group was removed via hydroge-
nolysis, which revealed C19 alcohol that was used to direct
the reduction of the C21 ketone.18 The cis-diol was convert-
ed into the acetonide 31, which was followed by tosyl
We settled on a Fukuyama coupling22 of an alkyne 34
and thioester 35 to form the C22–C23 bond (Scheme 11).
The lithium enolate of methyl ketone 8b was O-phosphory-
OMe
Me
Me
OBz
1. Pd/C, H2
2. catecholborane
3. dimethoxypropane
O
O
OBz
H
O
Me H
Me
O
O
21
Me
H
O
Me H
Me
21
Me
19
86%, 65%, 57%
1. hν(254) nm
2. TPAP, NMO
OMe
Me
19
Me
Me
Me
OBn
O
27
31
71%, 93%
OTs
OTs
Me32
OBz
O
Me32
OBz
SO2PT
O
O
16
1
O
OH
EtO
H
O
Me H
Me
Me
O
O
H
O
Me H
Me
Me
Me
Me
Me
O
O
Me
Me
Me
Me
Me
ent-18
Me
Me
Me
17
KHMDS
14%
O
16
O
OH
EtO
Me
1
32
17
O
33
Me
Me
Me
Me
Scheme 10 Completion of ionomycin diastereomer 33 illustrating viability of C1–C16 and C17–C32 Julia–Kocienski coupling
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

E
K. M. Oberg et al.
Special Topic
Synthesis
O
OTMS
R
H-
R
R
Cl2HC
OH, NaBH3CN
68%, 19:1 dr
Me
Me
36
O
O
+
+
O
O
Me
H
H
23
Me
Me
1. Ru(cymene)[(S,S)-Ts-DPEN]
O
O
2. Ms2O, py
OTBS
Me
H
Me H
Me
Figure 1 Approach to invert C23 stereocenter by reversing C–C bond-
49%, 30%
Me
forming and reduction steps
OBn
37
undesired C23
OTBDPS
lated and the resultant vinyl phosphonate eliminated to
generate terminal alkyne 34. Thioester 35 was synthesized
by protection of the primary alcohol of lactone 6 and Lewis
acid mediated ring opening of the lactone with thiophe-
nol.23 With these two coupling partners in hand, the
Fukuyama coupling could be achieved to generate ynone
36.
Me
23
1. Ru(cymene)[(R,R)-Ts-DPEN]
2. Ms2O, py
O
O
OTBS
Me
H
Me H
Me
68%, 59%
Me
OBn
38
desired C23
OTBDPS
O
Scheme 12 Reductive cyclization of ynone 36 generates undesired
C23 diastereomer 37 and synthesis of desired C23 diastereomer 38
TBDPSO
OBn
P
OEt
OEt
1. LiHMDS,
2. t-BuLi
Cl
8b
6
34
Me
O
Me
58%, 63%
ates undesired R-diastereoisomer 37, despite reversing the
C–C bond forming and reduction steps. The use of this two-
step Noyori reduction-cyclization protocol allowed for the
synthesis of bistetrahydrofuran 38 with the correct S-ste-
reochemistry.
1. TBSOTf, Et3N
2. PhSH, AlMe3
O
O
Me
PhS
35
75%, 30%
OTBS
HO
HO
Me H
Me
Me
Pd(dppf)Cl2,
P(Fu)3, CuI,
DIPEA
We elaborated bistetrahydrofuran 38 to known homoal-
lylic alcohol 40, which constitutes a formal synthesis of iono-
mycin (Scheme 13). The benzyl protecting group could be
deprotected under reducing metal conditions, which also
led to a concomitant reduction of the alkyne to the alkene.
These Birch-type conditions also reduce phenyl groups on
the TBDPS protecting group leading to the tert-butyldi-
cyclohexenyl silyl analogue.28 Our formal synthesis is com-
pleted by reconstitution of the TBDPS protecting group to
provide homoallylic alcohol 40. In their synthesis of iono-
mycin, Kocienski and co-workers elaborated this compound
40 to aldehyde 42. Although we had achieved a formal syn-
thesis of aldehyde 42, we sought a shorter route (3 steps vs
6 steps) using the methodology developed by Leighton.29
Upon exposure to chloromercuric acetate in acetone, homo-
allylic alcohol 40 is converted into acetonide 41 in moderate
yield. Although the stereochemistry has not been conclu-
sively established, Leighton’s work suggests that the more
stable cis-acetonide is formed. From here, we envisioned re-
moving the mercury via reduction, removing the silyl ether,
and oxidizing the alcohol to generate aldehyde 42.30
In conclusion, this work demonstrates the utility of al-
kylative anhydride desymmetrization to generate synthons
for deoxypolypropionate and polypropionate synthesis. Af-
ter the synthesis of both the C1–C16 18 and epi-23 C17–
C32 32 fragments of ionomycin, we demonstrated the Julia–
Kocienski olefination in the union of these two fragments
to generate a protected diastereomer of ionomycin. Diffi-
culties were encountered installing the correct C23 stereo-
center, both through an enol silane/oxocarbenium coupling
Me
34
+
Me
O
OTBS
Me H
60%
Me
35
OBn
36
OTBDPS
Scheme 11 Synthesis of ynone 36 via Fukuyama coupling
With ynone 36 in hand, we attempted the reductive cy-
clization to generate the requisite stereoisomer of bistetra-
hydrofuran 38 (Scheme 12). Prototypical conditions using
BF3/Et3SiH result in no reaction and TMSOTf/Et3SiH led to
decomposition of 36.24
The use of dichloroacetic acid and sodium cyanoborohy-
dride25 accomplished the reduction in good yield and excel-
lent diastereoselectivity. Based on Kishi’s work and our pre-
vious experience with the enol silane/oxocarbenium cou-
pling, one would suspect that the S-stereoisomer would be
generated. In order to firmly establish the stereochemistry
of the reductive cyclization, both diastereomers 37 and 38
were synthesized via an alternate route. Noyori transfer hy-
drogenation conditions26 generated a propargyl alcohol
that was activated to an SN2 cyclization with methanesul-
fonic anhydride. As the stereochemical outcome of the
Noyori reduction can be easily predicted, we performed the
reduction with both antipodes of the ligand, which follow-
ing cyclization, provided ready access to both C23 diaste-
reomers selectively.27 This sequence provided compelling
evidence that the reductive cyclization unexpectedly gener-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

F
K. M. Oberg et al.
Special Topic
Synthesis
Me
Me
Me
1. TBAF
2. TBDPSCl
im
23
Li
NH3
O
O
O
O
O
O
OTBS
Me
OTBS
OTBS
H
Me H
Me
H
Me H
Me
H
21
Me H
Me
Me
Me
64%
2:1 E/Z
76%, 20%
19
Me
19
Me
OBn
Me
OH
OH
OTBDPS
40
38
39
OTBDPS
17
O
C6H9 Si C6H9
t-Bu
Scheme 13 Formal synthesis of ionomycin via suitably functionalized fragment 40
and a reductive cyclization approach; however, these were
overcome through a stereoselective reduction/SN2 strategy.
The synthesis of homoallylic alcohol 40 constitutes a formal
synthesis of ionomycin.30
tography to yield 0.631 g (73%, 5:1 dr) of 12 as a colorless liquid; Rf =
0.18 (78:20:2 hexane/EtOAc/AcOH; CAM); [α]D20 +2.3 (c 0.0222 g/mL
benzene);
IR (ATR): 2974, 2937, 2878, 1732, 1705, 1462, 1377, 1179, 1032 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.82 (br s, 1 H), 4.11 (q, J = 7.1 Hz, 2 H),
2.73 (m, 2 H), 2.50 (m, 1 H), 2.26 (m, 2 H), 2.06–1.92 (m, 2 H), 1.61 (m,
1 H), 1.30 (m, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.20 (d, J = 7.0 Hz, 3 H), 1.08
(d, J = 6.7 Hz, 3 H), 1.07 (d, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 216.5, 181.9, 173.2, 60.4, 43.8, 42.7,
37.0, 36.0, 31.8, 27.6, 17.8, 16.5, 16.1, 14.2.
Unless otherwise noted, all reactions were carried out under inert at-
mosphere (N2 or argon). Reactions were performed using oven- or
flame-dried glassware that was evacuated and degassed prior to us-
age. Air- and moisture-sensitive liquids and solutions were trans-
ferred via syringe or stainless steel cannula. All reagents were ob-
tained commercially and used without further purification, unless
otherwise noted. Temperatures for the reactions refer to bath tem-
peratures.
HRMS (APCI): m/z calcd for [C14H25O5]+ (M + H): 273.1697; found:
273.1703.
{[(2R,3S,4S)-3-(Benzyloxy)-6-((2S,2′R,5R,5′S)-5′-{(R)-1-[(tert-bu-
tyldimethylsilyl)oxy]ethyl}-2,5′-dimethyloctahydro-[2,2′-bifu-
ran]-5-yl)-2,4-dimethylhex-5-yn-1-yl]oxy}(tert-
butyl)diphenylsilane (37)
CH2Cl2, Et2O, THF, and toluene were degassed with argon and passed
through a column of neutral alumina using a solvent purification sys-
tem. All other anhydrous solvents were freshly distilled prior to use.
Flash column chromatography was performed on Silicycle® Silica-
Flash® P60 (230–400 mesh) and eluted with the solvents described.
Reactions were monitored by TLC using Silicycle® 250 μm silica gel
60A plates. Visualization was accomplished with UV light (254 nm),
ceric ammonium molybdate (CAM), KMnO4, or anisaldehyde for visu-
alization.
1H, 13C, and 19F NMR spectra were recorded, respectively, at ambient
temperature, and calibrated against the residual solvent peak. Data
are recorded as follows: chemical shift (δ, ppm), multiplicity (stan-
dard abbreviations), coupling constant (Hz), and integration.
One-Step Preparation from 36: (2S,8S,9S,10R)-9-(Benzyloxy)-2-
((2R,5S)-5-{(R)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-5-methyltetra-
hydrofuran-2-yl)-11-[(tert-butyldiphenylsilyl)oxy]-2-hydroxy-8,10-
dimethylundec-6-yn-5-one [36 (see SI for details of preparation);
47.0 mg, 0.058 mmol] was dissolved in trifluoroethanol (3 mL). NaCN-
BH3 (10.9 mg, 0.174 mmol, 3.0 equiv) was added to the reaction fol-
lowed by dichloroacetic acid (22.4 mg, 0.174 mmol, 3.0 equiv) in tri-
fluoroethanol (3 mL). The mixture was stirred for 10 min and
quenched with sat. aq NaHCO3. H2O and CH2Cl2 were added to the re-
action and the mixture was extracted with CH2Cl2 (3 ×). The com-
bined organic layers were dried (MgSO4), concentrated in vacuo, and
purified by preparative TLC to yield 31.2 mg (68%) of 37 as a colorless
oil; Rf = 0.38 (9:1 hexane/EtOAc; UV, CAM); Rf = 0.38 (9:1 hexane/EtOAc;
UV, CAM); [α]D20 +11.6 (c 0.0104 g/mL CHCl3).
Full experimental details of the synthesis of C1–C9, C10–C16, C17–
C22, C23–C32 fragments, fragment couplings, and derivatizations are
provided in the Supporting Information (SI).
IR (ATR): 2958, 2930, 2857, 1461, 1256, 1105, 833, 739 cm–1
.
(2S,4R,6R)-9-Ethoxy-2,4,6-trimethyl-5,9-dioxononanoic Acid (12)
1H NMR (400 MHz, CDCl3): δ = 7.65 (m, 4 H), 7.42–7.31 (m, 6 H), 7.29–
7.22 (m, 5 H), 4.64 (d, J = 11.3 Hz, 1 H), 4.64 (m, 1 H), 4.54 (d, J = 11.3
Hz, 1 H), 3.98 (m, 1 H), 3.78 (dd, J = 9.9, 5.3 Hz, 1 H), 3.72 (dd, J = 9.9,
4.0 Hz, 1 H), 3.60 (q, J = 6.2 Hz, 1 H), 3.38 (dd, J = 7.6, 4.3 Hz, 1 H), 2.84
(m, 1 H), 2.14 (m, 1 H), 2.08–2.01 (m, 2 H), 1.97–1.80 (m, 3 H), 1.65–
1.55 (m, 3 H), 1.22 (d, J = 7.0 Hz, 3 H), 1.12 (d, J = 6.0 Hz, 3 H), 1.12 (s, 3
H), 1.07 (s, 9 H), 1.07 (s, 3 H), 1.06 (d, J = 6.9 Hz, 3 H), 0.87 (s, 9 H), 0.05
(s, 3 H), 0.04 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 138.8, 135.7, 135.6, 133.8, 133.7,
129.5, 129.5, 128.2, 127.6, 127.6, 127.5, 127.2, 86.4, 85.5, 85.1, 83.6,
83.2, 82.0, 73.9, 73.2, 68.5, 65.5, 38.7, 36.2, 35.2, 33.6, 29.0, 27.0, 26.4,
25.8, 22.0, 19.3, 19.1, 18.4, 17.9, 17.6, 14.7, –3.9, –4.9.
Potassium bis(trimethylsilyl)amide (1.328 g, 6.657 mmol, 2.1 equiv)
was added to a flame-dried 100 mL round-bottom flask under an in-
ert atmosphere in a glove box. After removing from the glovebox,
freshly dried toluene (35 mL) was added and the mixture stirred until
a colorless solution was obtained. The flask was cooled to –78 °C and a
solution of (2S,4R)-9-ethoxy-2,4-dimethyl-5,9-dioxononanoic acid
(2a; 0.820 g, 3.17 mmol) was added in THF (20 mL). The solution
turned yellow and was stirred for 1 h. MeI (0.79 mL, 12.68 mmol, 4
equiv) was added neat and the reaction mixture was stirred for 16 h
at –78 °C. The reaction was quenched at –78 °C by the slow addition
of aq 1 M HCl (23 mL) and the reaction mixture was allowed to warm
to 23 °C for 1 h. The biphasic mixture was extracted with EtOAc (3 ×)
and the combined organic layers were washed with sat. aq Na2S2O3 (2
×), dried (MgSO4), filtered, and concentrated in vacuo. The resulting
oil was absorbed onto Celite and purified via flash column chroma-
HRMS (APCI): m/z calcd for [C49H76NO5Si2]+ (M + NH4): 814.5257;
found: 814.5258.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

G
K. M. Oberg et al.
Special Topic
Synthesis
Two-Step Preparation from 36 via S30: (2S,5S,8S,9S,10R)-9-(Benzyl-
oxy)-2-((2R,5S)-5-{(R)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-5-methyl-
tetrahydrofuran-2-yl)-11-[(tert-butyldiphenylsilyl)oxy]-8,10-dimethyl-
undec-6-yne-2,5-diol [S30 (see SI for details of preparation from 36);
16.9 mg, 0.021 mmol] was dissolved in CH2Cl2 (2 mL) and cooled to
0 °C. A solution of methanesulfonic anhydride (36.5 mg, 0.210 mmol,
10.0 equiv) and pyridine (33.2 mg, 0.210 mmol, 20.0 equiv) in CH2Cl2
(8 mL) was added and the reaction mixture was stirred for 2 h. At this
time, the starting material had disappeared [Rf = 0.14 (4:1 hex-
ane/EtOAc; CAM)] and a new spot [Rf = 0.23 (4:1 hexane/EtOAc;
CAM)] had appeared by TLC. The reaction was quenched with sat. aq
NaHCO3. The mixture was extracted with CH2Cl2 (3 ×), the combined
organic layers were dried (MgSO4), and concentrated onto silica gel.
The product was purified to yield 6.2 mg (30%) of 37 as a clear oil.
(MgSO4), concentrated in vacuo, and the residue was purified via pre-
parative TLC to yield 5.5 mg (20%) of 40; Rf = 0.45 (4:1 hexane/EtOAc;
UV, CAM).
1H NMR (300 MHz, CDCl3): δ = 7.73–7.67 (m, 4 H), 7.44–7.36 (m, 6 H),
5.78 (dd, J = 15.5, 7.9 Hz, 0.6 H), 5.54–5.45 (m, 1.4 H), 4.41 (m, 0.6 H),
3.99 (m, 0.6 H), 3.84–3.58 (m, 3 H), 3.40 (m, 1 H), 2.36–1.56 (m, 14 H),
1.15–1.12 (m, 9 H), 1.07 (s, 9 H), 0.87 (s, 9 H), 0.78 (d, J = 6.8 Hz, 3 H),
0.06 (m, 6 H).
LRMS (APCI): m/z calcd for [C42H72NO5Si2]+ (M + NH4): 726.5; found:
726.5.
Acknowledgment
We acknowledge the National Science Foundation for partial support.
M.J.C. acknowledges the American Heart Association for a postdoctor-
al fellowship. We thank Evonik Industries for a gift of (R)-tert-leucine
and Johnson-Matthey for a loan of rhodium salts. We thank Ian Pater-
son (Cambridge) for detailed procedures and helpful discussions. We
thank Paul Blakemore (OSU) and John Wood (Baylor) for helpful dis-
cussions. We thank Dan Henderson (CSU) for synthesizing anhydride
3 used in this work and Chris Rithner (CSU) for assistance with NMR.
{[(2R,3S,4S)-3-(Benzyloxy)-6-((2S,2′R,5S,5′S)-5′-{(R)-1-[(tert-bu-
tyldimethylsilyl)oxy]ethyl}-2,5′-dimethyloctahydro-[2,2′-bifu-
ran]-5-yl)-2,4-dimethylhex-5-yn-1-yl]oxy}(tert-
butyl)diphenylsilane (38)
(2S,5R,8S,9S,10R)-9-(Benzyloxy)-2-((2R,5S)-5-{(R)-1-[(tert-butyldi-
methylsilyl)oxy]ethyl}-5-methyltetrahydrofuran-2-yl)-11-[(tert-bu-
tyldiphenylsilyl)oxy]-8,10-dimethylundec-6-yne-2,5-diol [S29 (see SI
for details of preparation from 36); (20.3 mg, 0.025 mmol] was dis-
solved in CH2Cl2 (2 mL) and cooled to 0 °C. A solution of methanesul-
fonic anhydride (43.6 mg, 0.250 mmol, 10.0 equiv) and pyridine (19.8
mg, 0.250 mmol, 10.0 equiv) in CH2Cl2 (8 mL) was added and the reac-
tion mixture was stirred for 2 h. At this time, the starting material had
disappeared [Rf = 0.14 (4:1 hexane/EtOAc; CAM)] and a new spot [Rf =
0.23 (4:1 hexane/EtOAc; CAM)] had appeared in TLC. The reaction
was quenched by two drops of MeOH and then with sat. aq NaHCO3.
The mixture was extracted with CH2Cl2 (3 ×), the combined organic
layers were dried (MgSO4), and concentrated onto silica gel. The prod-
uct was purified to yield 11.8 mg (59%) of 38 as a clear oil; Rf = 0.68
(4:1 hexane/EtOAc; CAM); [α]D20 –19.3 (c 0.0066 g/mL CHCl3).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609733.
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References
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H), 4.64 (d, J = 11.2 Hz, 1 H), 4.64 (m, 1 H), 4.54 (d, J = 11.3 Hz, 1 H),
3.88 (dd, J = 8.2, 6.4 Hz, 1 H), 3.77 (dd, J = 9.9, 5.4 Hz, 1 H), 3.72 (dd, J =
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H), 1.05 (d, J = 7.0 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 138.9, 135.7, 135.7, 134.8, 133.9,
133.8, 129.6, 129.5, 129.5, 128.1, 127.7, 127.6, 127.6, 127.5, 127.2,
86.4, 85.5, 85.1, 84.0, 83.4, 82.3, 73.9, 73.2, 68.9, 65.5, 38.7, 35.9, 34.2,
33.0, 29.1, 27.4, 27.0, 26.6, 25.8, 24.1, 19.5, 19.3, 18.3, 17.9, 17.7, 14.8,
–3.9, –4.9.
HRMS (ESI): m/z calcd for [C49H76NO5Si2]+ (M + NH4): 814.5257;
found: 814.5254.
(2R,3S,4S)-6-((2S,2′R,5S,5′S)-5′-{(R)-1-[(tert-butyldimethylsi-
lyl)oxy]ethyl}-2,5′-dimethyloctahydro-[2,2′-bifuran]-5-yl)-1-
[(tert-butyldiphenylsilyl)oxy]-2,4-dimethylhex-5-en-3-ol (40)
(2R,3S,4S)-6-((2S,2′R,5S,5′S)-5′-{(R)-1-[(tert-butyldimethylsi-
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methylhex-5-ene-1,3-diol [S31 (see SI for details of preparation from
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(6.0 mg, 0.0873 mmol, 2.0 equiv) and tert-butyldiphenylsilyl chloride
(0.01 mL, 0.0405 mmol, 1.02 equiv) were added. The reaction mixture
was stirred for 12 h. EtOAc and H2O were added and the mixture was
extracted with EtOAc (3 ×). The combined organic layers were dried
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

H
K. M. Oberg et al.
Special Topic
Synthesis
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(a) Filloux, C. M.; Rovis, T. J. Am. Chem. Soc. 2015, 137, 508. For a
review on halide influence on metal catalysis, see: (b) Fagnou,
K.; Lautens, M. Angew. Chem. Int. Ed. 2002, 41, 26.
(11) Under the same conditions using the same zinc reagent 11, the
use of [Rh(nbd)Cl]2 led to 60% conversion and the use of
[Rh(nbd)OAc]2 led to 80% conversion by 1H NMR analysis of the
unpurified reactions (trimethoxybenzene as the internal stan-
dard). Additionally, the [Rh(nbd)OAc]2 produces a cleaner reac-
tion mixture.
(12) The use of catalytic CuI and longer equilibrium times leads to
purer dialkylzinc reagent 11. For synthesis of dialkylzinc
reagents, see: (a) Rozema, M. J.; Sidduri, A.; Knochel, P. J. Org.
Chem. 1992, 57, 1956. (b) Knochel, P.; Singer, R. D. Chem. Rev.
1993, 93, 2117.
(30) Preliminary results show the promise of an oxymercuration
route to targeted aldehyde 42 (Scheme 14).
Me
Me
ClHg
ClHgOAc
cat. Yb(OTf)3
O
O
O
O
OTBS
OTBS
H
Me H
Me
H
O
Me H
Me
Me
Me
acetone
54%
40
41
Me
Me
Me
Me
Me
OTBDPS
OH
OTBDPS
O
1. H–
17
2. NaOH
3. TPAP,
NMO
ref. 7
O
O
OTBS
H
O
Me H
Me
Me
Me
Me
O
O
42
Me
Scheme 14 Oxymercuration route to targeted aldehyde 42
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H