Asymmetric Total Synthesis of Inthomycins A, B, and C

Article abstract of DOI:10.1021/acs.joc.0c00017

Herein, we report the asymmetric total syntheses of inthomycin antibiotics containing a methylene-interrupted oxazolyl-triene motif. Utilizing the α,β-unsaturated aldehyde as a common intermediate, all three inthomycins A-C were divergently synthesized. The asymmetric ynone reduction provided an R-configured secondary alcohol as in the natural products with high enantioselectivity. The geometrically different triene units for each inthomycin were stereoselectively established via methyl cuprate conjugate addition, isomerization of the α,β-unsaturated aldehyde intermediate, and stereoretentive cross-coupling reactions.

Full text of DOI:10.1021/acs.joc.0c00017

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Article
Asymmetric Total Synthesis of Inthomycins A, B and C
Jae Hyun Kim, Yeonghun Song, Min Jung Kim, and Sanghee Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00017 • Publication Date (Web): 12 Mar 2020
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Asymmetric Total Synthesis of Inthomycins A, B and C
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Jae Hyun Kim,† Yeonghun Song,† Min Jung Kim and Sanghee Kim*
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College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea
pennkim@snu.ac.kr
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Table of Contents
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stereo-selective
cuprate addition
O
N
Pd-cat.
cross coupling
Me
O
8
O
7–8 steps
(
)
R
H
Me
OH
OTBS
HO
O
4
BzO
6
Me Me
Me Me
asymmetric
reduction
isomerization
NH2
HO
common
intermediate
Me Me
inthomycin A: 4Z, 6Z, 8E
inthomycin B: 4Z, 6E, 8E
inthomycin C: 4E, 6E, 8E
Abstract
Herein, we report the asymmetric total syntheses of inthomycin antibiotics containing a
methylene-interrupted oxazolyl-triene motif. Utilizing the α,β-unsaturated aldehyde as a common
intermediate, all three inthomycins A–C were divergently synthesized. The asymmetric ynone
reduction provided an R-configured secondary alcohol as in the natural products with high
enantioselectivity. The geometrically different triene units for each inthomycin were
stereoselectively established via methyl cuprate conjugate addition, isomerization of the α,β-
unsaturated aldehyde intermediate, and stereocontrolled cross-coupling reactions.
Introduction
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Inthomycin A (1) and its geometrical isomers B (2) and C (3) are polyene natural products
containing an oxazole ring (Figure 1). These compounds display a wide range of interesting
biological activities including the specific inhibition of cellulose biosynthesis1 as well as
antifungal,2 herbicidal2,3 and anticancer activities.4 This small family of natural products was
isolated from Streptomyces sp. in the early 1990s.1,5 However, prior to this isolation, the entire
structure of 1 was found within other natural products, such as neooxazolomycin (4)6 and
oxazolomycin A (5).7 Later, the structures of 2 and 3 were also found to be embedded in several
natural products in the oxazolomycin family including oxazolomycins B (6) and C (7),8 16-
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methyloxazolomycin,9 curro mycins10 and KSM 2690.11
N
Me
O
O
O
N
HO
NH2
O
Me Me
N
2
(+)-inthomycin B ( )
Me
O
NH2
HO
Me
Me
1
(+)-inthomycin A ( )
Me
O
HO
NH2
O
N
Me Me
3
(–)-inthomycin C ( )
O
Me
O
Me
O
OH
NMe
HO
N
N
H
HO
Me
Me
Me
OH
4
O
neooxazolomycin ( )
O
8'
4'
Me
O
O
Me MeO
HO
O
6'
HO
N
NMe
O
H
Me
Me
OH
Me
5
oxazolomycin A ( ): 4'Z,6'Z,8'E
6
oxazolomycin B ( ): 4'E,6'E,8'E
7
oxazolomycin C ( ): 4'Z,6'E,8'E
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Figure 1. Inthomycins A–C (1–3) and related natural products 4–7.
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The synthesis of inthomycins has attracted much attention due to their interesting biological
activities as well as the total synthesis of oxazolomycin family members.12–15 Although
inthomycins may appear to be simple synthetic targets, the synthesis is challenging due to the
unusually interposed functional groups, such as the allylic alcohol with a α-quaternary carbon
center and the methylene-interrupted oxazoyl-triene motif. An additional synthetic challenge
involves controlling the configuration of the double bonds in the conjugated triene system, which
is susceptible to cis-trans isomerization. Most synthetic efforts focused on this family of natural
products have been directed toward the thermodynamically more favored inthomycin C, which
has a 4E,6E,8E-triene system.12 Less attention has been directed at the synthesis of other
members.13 Only three synthetic strategies that lead to the total synthesis of all three members
are available (Scheme 1).14 To construct the conjugated triene system, Taylor et al. utilized Stille
coupling of an oxazole vinyl iodide unit with a stannyl diene that was derived from stannyl
acrylaldehyde (Scheme 1a).14a Hatakeyama et al. also utilized Stille coupling to introduce the
vinyl oxazole moiety to iododienes which was synthesized from β-lactone compounds (Scheme
1b).14b In Burton’s synthesis, Suzuki or Sonogashira cross-couplings were employed to connect
vinyl iodides with oxazole-containing dienyl boronic acid or enyne (Scheme 1c).14c These three
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syntheses utilized stereoretentive cross-coupling reactions of (E)- or (Z)-vinyl coupling partners
to install the configuration of the double bonds in the triene system.
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Scheme 1. Previous Synthesis of Inthomycins A (1), B (2) and C (3)
SnBu3
SnBu3
Me
CHO
(a)
(b)
CHO
O
N
Me
I
Me
TMS
Me
Me
O
Me
O
O
OMe
O
TBSO
O
O
NH2
Me
HO
Me
N
Me
inthomycins A–C
1 3
Me
( – )
N
+
Me
O
I
or
(c)
OMe
TESO
OR
Me
Me
B
OR
As part of our ongoing research program that is focused on the total synthesis of the
oxazolomycin family of natural products,15d we have investigated the efficient synthesis of all
three inthomycins. Herein, we report results from our synthetic studies of these polyene natural
products. Our synthesis features the highly stereocontrolled installation of triene unit with
alternating E/Z geometry from a common intermediate.
Results and Discussion
While seeking a unified strategy to access all inthomycins A–C, we envisioned that alkynoic
ester 9 could serve as a common intermediate from which both 4E- and 4Z-configurations of
,-unsaturated carbonyl compound 8 could be established by a stereoselective methyl cuprate
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conjugate addition (Scheme 2). The C-6 carbonyl group could be a functional handle for the
installation of the triene unit. Alkynoic ester 9 was envisioned from 3-hydroxy pivalic acid (10)
through alkynylation with propiolate and asymmetric reduction.
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Scheme 2. Retrosynthesis of Inthomycins A (1), B (2) and C (3)
O
O
stereo-selective
N
N
cuprate addition
6
Me
4
O
Me
R
O
H
PO
OP
NH2
Pd-cat.
HO
Me
Me
cross coupling
Me
Me
8
inthomycins A–C
1 3
( – )
MeO
PO
O
asymmetric
reduction
O
OH
OP
HO
Me
10
Me
Me
Me
9
Our total synthesis began with the known TBS-protected hydroxy pivalic acid 1116 (Scheme 3),
which was synthesized in one step from the commercially available 3-hydroxy pivalic acid (10).
Activation of acid 11 to its acid chloride followed by CuI-catalyzed nucleophilic addition of methyl
propiolate afforded ynone 12.15d,17
Several asymmetric ynone reduction protocols, such as Noyori18 and Corey–Bakshi–Shibata19
(CBS) reductions, were examined for the installation of the stereocenter at the sterically
hindered neopentyl position. The best enantioselectivity was obtained using DIPCl.20 The
treatment of 12 with (+)-DIPCl at room temperature, followed by the usual diethanolamine
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workup afforded product 13 in 93% ee and 72% yield. The absolute configuration was assigned
as R based on the well-established stereochemistry of DIP-chloride reduction and confirmed by
NMR studies and X-ray crystallographic analysis of Mosher's esters of 13 (see the Supporting
Information for details).21 The CBS reduction of 12 with (S)-CBS catalyst at –30 °C afforded 13
with a slightly lower enantioselectivity (90% ee) but a higher yield (82%).
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Scheme 3. Synthesis of Common Intermediate (Z)-18a
MeO
a) (COCl)2, DMF, pyridine
O
O
CH2Cl2, 0 ºC to rt
HO
OTBS
b) methylpropiolate
CuI, i-Pr2NEt
Me Me
O
OTBS
CH2Cl2, rt
86% for 2 steps
Me Me
11
12
c) (+)-DIPCl
72%
(93% ee)
hexane, rt
then
diethanolamine
MeO
O
MeO
Me
e) MeLi, CuI
O
BzO
THF, –78 ºC
89%
OTBS
RO
OTBS
Me Me
15
Me Me
(Z)-
13
14
(R = H)
(R = Bz)
d) Et3N, DMAP, BzCl
CH2Cl2, rt, 98%
f) DIBAL-H
THF, –20 ºC
83%
O
Me
g) TPAP, NMO
CH2Cl2, rt
93%
H
BzO
OTBS
Me Me
18
(Z)-
common intermediate
N
O
R = PPh3, PO(OEt)2
R
O
N
N
N
or
S
N
O
N
Ph
Me
O
6
BzO
OTBS
Me Me
19a
19b
(6Z)
(6E)
aReagents and conditions: (a) (COCl)2 (1.5 equiv), pyridine (4 equiv), DMF (3 mol%), CH2Cl2, 0 ºC to rt, 2h; (b)
methylpropiolate (1 equiv), CuI (10 mol%), i-Pr2NEt (1 equiv), CH2Cl2, rt, 16 h, 86% for 2 steps; (c) (+)-DIPCl (1.5
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equiv), hexane, rt, 16 h; then diethanolamine (4 equiv), 0 ºC to rt, 2 h, 72%, 93% ee; (d) Et3N (3 equiv), DMAP (3
mol%), BzCl (2 equiv), CH2Cl2, 0 ºC to rt, 30 min, 98%; (e) MeLi (6 equiv), CuI (3 equiv), THF, –78 ºC, 30 min, 89%;
(f) DIBAL-H (2.5 equiv), THF, –78 ºC to –20 ºC, 2 h, 83%; (g) TPAP (10 mol%), NMO (1.5 equiv), CH2Cl2, rt, 30 min,
93%. DIPCl = B-chlorodiisopinocampheylborane, BzCl = benzoyl chloride, TPAP = tetrapropylammonium
perruthenate, NMO = N-methylmorpholine-N-oxide.
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With ynoate 13 in hand, the addition of methyl copper reagents was investigated to selectively
form the trisubstituted olefin moiety in inthomycins. These type of reactions tend to proceed cis-
selectively via syn addition at low temperatures.22 However, stereoselectivity is sensitive to
numerous factors, such as temperature, solvent, additives, coordinating groups, lithium salts
and the nature of substituents.23 For example, at a higher temperature, cis/trans mixtures are
obtained. In some cases, trans products were observed with good to excellent
stereoselectivities.24 The loss of cis stereoselectivity was attributed to isomerization of the initial
cis-organocopper intermediate to a trans-isomer through the corresponding allenolate.25
Prior to the conjugate addition of the methyl group, the hydroxyl group of ynoate substrate 13
was protected as a benzoate. Treatment of benzoate-protected ynoate 14 with MeLi in the
presence of CuI at –78 °C led to the exclusive formation of the 4Z-configured α,-unsaturated
ester (Z)-15 (Table 1, entry 1), which has suitable olefin geometry for inthomycins A and B. To
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achieve the 4E-geometry of inthomycin C, we varied several factors in the reactions including
temperature, additive, copper salt, and methyl anion source. Most trials yielded complex
mixtures of unidentified products and produced 15 in poor yield (see, for example, entries 2–3).
The highest E selectivity and modest yield were obtained when MeMgBr and CuBr·DMS were
employed at room temperature (entry 4). These conditions afforded the product in 61% yield
with a 1:3 ratio in favor of the E-isomer. However, substrate 16 with a TMS-protecting group
exclusively afforded (E)-17 in the reaction with MeMgBr in the presence of CuI (entry 5).26 It is
important to note that the reaction of 16 with MeLi instead of MeMgBr provided only (Z)-17 at
low temperature in good yield (entry 6). These results are consistent with previous studies in
that the subtle changes in properties of nearby protecting groups, alkyl anion sources and
reaction temperatures substantially affected the stereochemical outcome of the cuprate addition
reaction to ynoates.23–26
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Table 1. Stereo-selective Cuprate Addition to Ynonesa
O
OMe
O
OMe
Me
MeO
Me
conditions
O
THF
RO
OTBS
OTBS RO
OTBS
RO
Me Me
Me Me
Me Me
14
16
15
15
(R = Bz)
(R = TMS)
(Z)- (R = Bz)
(E)- (R = Bz)
17
(E)- (R = TMS)
17
(Z)- (R = TMS)
starting
material
14
entry
1
reagents (equiv.)
MeLi (6), CuI (3)
temp
time
yieldb
89
Z:E
–78 ºC
30 min
1:0
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MeLi (10), CuI (5),
–78 ºC to 0 ºC
TMSCl (5)
2
3
4
14
14
14
12 h
1.5 h
1.5 h
29
29
61
3:1
1:3
1:3
MeMgBr (2.6),
–78 ºC to rt
CuI (2)
MeMgBr (7.5),
0 ºC to rt
CuBr∙DMS (7.5)
5
6
16
16
MeMgBr (6), CuI (3)
MeLi (6), CuI (3)
–78 ºC to rt
–78 ºC
4 h
3 h
61
81
0:1
1:0
aReactions were run with 0.2 mmol of 14 or 16. bCombined yield of Z/E isomers.
Having established selective access to the Z- and E-isomers of 15 and 17, we explored the
incorporation of a triene unit. To synthesize inthomycins A and B, which possess a 4Z-
trisubstituted olefin, the Z-configured α,β-unsaturated ester (Z)-15 was first converted to
aldehyde (Z)-18 by employing a reduction-oxidation sequence using DIBAL-H followed by TPAP
oxidation (Scheme 3). For the rapid assembly of a triene system in inthomycins A (1) or B (2)
from (Z)-18, several olefination methods, such as Wittig reaction, Horner–Wadsworth–Emmons
reaction and Julia–Kocienski olefination, were attempted under various conditions. However,
these trials met with failure. Most reactions afforded 19 in very poor yields and
stereoselectivities. Therefore, we resorted to the stepwise installation of the triene system.
Vinyl boronates or vinyl halides, which are synthetically useful in metal-catalyzed coupling
reactions, are typically derived from alkyne or alkene intermediates. However, to reduce the
number of steps in our synthesis, the direct conversion of aldehyde (Z)-18 into vinyl boronates
or vinyl halides was studied (Scheme 4). Applying the recently developed boron-Wittig reaction
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with bis[(pinacolato)boryl]methane (20) by Morken,27 E-vinyl boronate 21 was obtained in perfect
stereoselectivity.28 Vinyl boronate 21 was coupled with the known E-vinyl iodide 2213c under
Suzuki–Miyaura reaction conditions successfully to afford geometrically pure 4Z,6E,8E-triene
19b. To synthesize inthomycin A (1) in a unified manner with inthomycin B (2), we sought to
stereoselectively install a Z-vinyl boronate functional group from aldehyde (Z)-18. Due to the
lack of appropriate reaction protocols that allow for this transformation in one or two steps, we
decided to install Z-vinyl bromide (Scheme 4). The Z,Z-1-bromodiene 23 was obtained as a
single isomer using Uenishi's two-step protocol,29 consisting of Corey–Fuchs dibromoolefination
and Pd-catalyzed hydrogenolysis. The vinyl bromide 23 was coupled with the known E-vinyl
stannane 2413c under PEPPSI-iPr-catalyzed Stille coupling conditions12b to afford 4Z,6Z,8E-
triene 19a without significant isomerization.
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Scheme 4. Synthesis of Inthomycins B and A Precursorsa
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O
Me
4
5
6
7
H
BzO
OTBS
a)
Bpin
Me Me
d) Pd(PPh3)4
Bu3SnH
toluene, rt
98% for 2 steps
THF
–100 ºC
79%
c) CBr4, PPh3
Et3N, CH2Cl2
0 ºC to rt
Bpin
20
LiTMP
18
(Z)-
8
9
Br
Me
Me
O
B
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11
12
13
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16
17
18
19
20
21
22
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O
BzO
OTBS
BzO
OTBS
Me Me
Me Me
23
e)
O
21
N
b)
N
O
22
24
PEPPSI-iPr
SnBu3
DMF, 55 ºC
70%
THF/H2O (9:1)
rt, 85%
I
Ag2O, Pd(PPh)4
O
N
O
N
Me
BzO
OTBS
Me
Me Me
19b
BzO
OTBS
iPr
iPr
Me Me
19a15d
N
N
iPr iPr
Pd
Cl
Cl
PEPPSI-iPr =
N
Cl
aReagents and conditions: (a) 20 (3 equiv), LiTMP (3 equiv), THF, –100 ºC, 1 h, 79%; (b) 22 (2 equiv), Ag2O (3.7
equiv), Pd(PPh)4 (13 mol%), THF/H2O (9:1), rt, 5 min, 85%; (c) CBr4 (3 equiv), PPh3 (6 equiv), Et3N (10 equiv),
CH2Cl2, 0 ºC to rt, 16 h; (d) Pd(PPh3)4 (10 mol%), Bu3SnH (1.05 equiv), toluene, rt, 16 h, 98% for 2 steps; (e) 24 (2
equiv), PEPPSI-iPr (6 mol%), DMF, 55 ºC, 36 h, 70%. LiTMP = lithium tetramethylpiperidide, PEPPSI-iPr = [1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride.
To complete the total synthesis of inthomycin A (1) and B (2), the final task involves the
conversion of the protected primary alcohol to a primary amide (Scheme 5). First, cleavage of
the silyl ether of 19 with HF∙pyridine in a THF/pyridine co-solvent system delivered alcohol 25
without noticeable isomerization of the triene system. Other desilylating reagents, such as TBAF,
TBAF-AcOH and TAS-F, caused olefin isomerization to some degree. Then the resulting alcohol
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25 was oxidized to the acid 26 via Swern oxidation and the following Pinnick oxidation. Acid 26
was unstable and prone to decomposition, especially under acidic conditions and light exposure.
Finally, EDCI-mediated amidation followed by treatment with K2CO3 in methanol for
debenzoylation afforded (+)-inthomycin A (1) and (+)-inthomcyin B (2), which were purified by
preparative TLC.
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Scheme 5. Completion of Total Synthesis of Inthomycins A (1) and B (2)a
O
O
N
N
a) HF·pyridine
Me
Me
THF/pyridine(7:4)
0 ºC to rt
6
6
BzO
OTBS
BzO
OH
Me Me
Me Me
19a
19b
25a
(6Z, 90%)
25b
(6E, 76%)
(6Z)
(6E)
c) NaClO2, NaH2PO4
2-methyl-2-butene
t-BuOH/water (1:1)
0 ºC to rt
b) (COCl)2, DMSO, Et3N
CH2Cl2, –78 ºC to rt
O
O
N
N
d) EDCI·HCl, NH4Cl
HOBt, Et3N,
MeCN, rt
Me
Me
O
O
e) K2CO3, MeOH, rt
6
6
HO
NH2
BzO
OH
Me Me
(6Z, 43% for 2 steps)
(6E, 72% for 2 stpes)
Me Me
(6Z, 81% for 2 steps)
(6E, 80% for 2 steps)
15d
1
2
26a
26b
aReagents and conditions: (a) HF·pyridine (excess), THF/pyridine (7:4), 0 ºC to rt, 20 h, 90% for 25a, 76% for
25b; (b) (COCl)2 (3 equiv), DMSO (6 equiv), Et3N (13 equiv), CH2Cl2, –78 ºC to rt, 40 min; (c) NaClO2 (3 equiv),
NaH2PO4 (3 equiv), 2-methyl-2-butene (37 equiv), t-BuOH/water (1:1), 0 ºC, 30 min, 81% for 26a for 2 steps, 80%
for 26b for 2 steps; (d) EDCI·HCl (1.2 equiv), NH4Cl (4 equiv), HOBt (1.2 equiv), Et3N (3 equiv), MeCN, rt, 3 h; (e)
K2CO3 (5 equiv), MeOH, rt, 15 h, 43% for 1 for 2 steps, 72% for 2 for 2 steps. EDCI = 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide, HOBt = hydroxybenzotriazole.
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Having succeeded with the synthesis of 1 and 2, we explored the synthesis of inthomycin C
(3), which contains a 4E,6E,8E-triene system. Unfortunately, the selective removal of one silyl
protecting group proved to be a major obstacle when the E-configured ester (E)-17 was
employed as the substrate. To avoid laborious protecting group manipulations, we decided to
use the Z-configured unsaturated aldehyde (Z)-18, which was the common intermediate for 1
and 2. Z-configured unsaturated aldehydes have been isomerized to the more
thermodynamically stable E-isomer.30 With this in mind, a wide range of conditions were
investigated for isomerization. Among the tested conditions, successful isomerization was
delivered with tertiary amine bases. Treatment of (Z)-18 with sterically hindered DBU in THF at
0 °C led to complete isomerization to the E-isomer (Scheme 6). When (Z)-18 was treated with
less basic DABCO in MeCN at 60 °C, isomerization was also achieved. The enantiomeric purity
of the obtained (E)-18 remained unchanged in both cases (93% ee). The isomerization might be
promoted by enolization by abstraction of the γ-methyl proton rather than the sterically hindered
γ-methine proton. Alternatively, a nucleophilic 1,4-addition–elimination of the tertiary amine
might be involved in this isomerization reaction.
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Scheme 6. Isomerization of (Z)-18 to (E)-18 and Total Synthesis of Inthomycin C (3)a
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O
H
4
5
6
7
a) DBU, THF
0 oC, 76%
or
O
Me
Me
H
BzO
OTBS DABCO, MeCN BzO
60 oC, 87%
OTBS
Me Me
Me Me
18
18
(Z)-
(93% ee)
(E)-
(93% ee)
8
9
22
c) , Ag2O, Pd(PPh)4
THF/H2O (9:1), rt
79% for 2 steps
20
b) , LiTMP
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THF, –100 ºC
O
O
N
N
d) HF.pyridine
THF/pyridine (7:4)
e) (COCl)2, DMSO
Et3N, CH2Cl2
Me
Me
f) NaClO2, NaHPO4
2-methyl-2-butene
t-BuOH/water (1:1)
O
BzO
OH
BzO
OTBS
Me Me
28
Me Me
27
O
N
g) EDCI.HCl
NH4Cl, HOBt
Et3N, MeCN
h) K2CO3, MeOH
34% for 5 steps
Me
O
HO
NH2
Me Me
3
aReagents and conditions: (a) DBU (1.5 equiv), THF, 0 ºC, 18 h, 76%, or DABCO (5 equiv), MeCN, 60 ºC, 20 h,
87%; (b) 20 (3 equiv), LiTMP (3 equiv), THF, –100 ºC, 1 h; (c) 22 (2 equiv), Ag2O (3.7 equiv), Pd(PPh)4 (13 mol%),
THF/H2O (9:1), rt, 5 min, 79% for 2 steps; (d) HF·pyridine (excess), THF/pyridine (7:4), 0 ºC to rt, 20 h; (e) (COCl)2
(3 equiv), DMSO (6 equiv), Et3N (13 equiv), CH2Cl2, –78 ºC to rt, 40 min; (f) NaClO2 (3 equiv), NaH2PO4 (3 equiv),
2-methyl-2-butene (37 equiv), t-BuOH/water (1:1), 0 ºC, 30 min; (g) EDCI·HCl (1.2 equiv), NH4Cl (4 equiv), HOBt
(1.2 equiv), Et3N (3 equiv), MeCN, rt, 3 h; (h) K2CO3 (5 equiv), MeOH, rt, 15 h, 34% (8:1 mixture) for 5 steps. DBU =
1,8-diazabicyclo[5.4.0]undec-7-ene, DABCO = 1,4-diazabicyclo[2.2.2]octane.
The total synthesis of inthomycin C (3) was achieved in good overall yield from (E)-18 utilizing
the same sequence of reactions as applied to the synthesis of inthomycin B (2) from (Z)-18
(Scheme 6). Although 3 has all trans-configured double bonds and is expected to be
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thermodynamically more favored than 1 and 2,31 some triene intermediates for 3 were prone to
isomerization more readily than the corresponding triene intermediates for 1 and 2. For example,
partial isomerization was encountered in Swern and Pinnick oxidation steps. Therefore, an 8:1
mixture of the isomer of (–)-inthomycin C (3) was obtained after the final step. The minor isomer
was neither 1 nor 2. Pure 3 was obtained by careful flash column chromatography with some
degree of material sacrifice. The spectroscopic data and specific rotation of the three
inthomycins (1–3) were consistent with those reported for inthomycins A–C.12d,e,14c The absolute
configuration of inthomycin C remained unclear until Hale and Hatakeyama established the
absolute configuration to be R.12d In this study, we reconfirmed the absolute configurations of
inthomycins A–C by the unambiguous assignment of common intermediate 13 as R, which
supports Hale and Hatakeyama’s work.12d
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Conclusion
In conclusion, we have developed efficient asymmetric total syntheses of all three inthomycins
in 15–16 steps from a commercially available material in 8–12% overall yields. In this report, we
introduced the R-configured secondary hydroxy group in the inthomycins by the asymmetric
reduction of ynone 12. The methyl cuprate conjugate addition to alkynoic ester can be achieved
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either with E or Z selectivity based on the use of different protecting groups and reaction
conditions. The C-6 carbonyl group was converted to (E)-vinyl boronate or (Z)-vinyl bromide to
further establish the methylene-interrupted oxazolyl-triene motif using stereoretentive palladium-
catalyzed cross-coupling reactions. This synthesis also features the use of an isomerizable
common intermediate (Z)-18 to access all three inthomycins. In particular, this report provides a
synthetic approach involving stereocontrolled construction of geometrically distinctive polyene
systems. This synthetic study will be further utilized in the total synthesis of inthomycin-
embedded natural products which is currently underway.
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Experimental Section
General Information. All chemicals were reagent grade and used as received. All reactions were
performed under an inert atmosphere that consisted of dry nitrogen using distilled dry solvents. The
reactions were monitored by thin layer chromatography (TLC) analysis using silica gel 60 F-254 TLC
plates. The compound spots were visualized using UV light (254 nm) and staining with either potassium
permanganate or anisaldehyde solutions. Flash column chromatography was performed on silica gel (230-
400 mesh). The melting points were measured using a Buchi B-540 melting point apparatus without
correction. The optical rotations were measured using sodium light (D line 589.3 nm), and the values are
reported as the specific optical rotation with exact temperature, concentration (c/(10 mg/mL)) and solvent.
13
1H NMR (400, 600 or 800 MHz) and C NMR (100, 150, 175 or 200 MHz) spectra were recorded in 
units relative to the non-deuterated solvent as the internal reference. The IR spectra were recorded on a
Fourier transform infrared spectrometer. High-resolution mass spectra (HRMS) were obtained using a
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magnetic sector type mass spectrometer (JEOL JMS-700) and recorded using fast atom bombardment
(FAB). HPLC was performed on an Agilent 1200 series instrument with a diode array detector (DAD) and
CHIRALCEL OD-H column (0.46 × 25 cm, 5 μm).
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Methyl 6-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-4-oxohex-2-ynoate (12). To an ice-cold
solution of acid 11 (9.30 g, 40.0 mmol) in CH2Cl2 (200 mL) was added DMF (0.1 mL), pyridine (12.4
mL, 160 mmol) and oxalyl chloride (5.2 mL, 60.0 mmol) under dry N2 atmosphere. The reaction mixture
was slowly warmed to room temperature and stirred for 2 h. The resulting mixture was concentrated under
reduced pressure and azeotroped with toluene. The residue was concentrated in vacuo to yield crude
mixture of acyl chloride of 11 as a dark red oil, which was used in the next step without further
purification. To a suspension of CuI (762 mg, 4.0 mmol) in CH2Cl2 (100 mL) was added DIPEA (7.0 mL,
40.0 mmol) and methyl propiolate (3.56 mL, 40.0 mmol) at room temperature under a N2 atmosphere. The
solution of the acyl chloride of 11 in CH2Cl2 (30 mL) was slowly added into the above solution at room
temperature and stirred for 16 h at the same temperature. The reaction mixture was diluted with hexane,
filtered through a pad of silica gel and rinsed with hexane/EtOAc (4:1, v/v). The combined organic layer
was concentrated under reduced pressure and the residue was purified by flash chromatography on silica
gel (hexane/EtOAc, 10:1, v/v) to yield 12 (10.3 g, 86% for 2 steps) as a light yellow oil. Rf = 0.45
1
(hexane/EtOAc, 10:1); H NMR (800 MHz, CDCl3) δ = 3.82 (s, 3H), 3.66 (s, 2H), 1.15 (s, 6H), 0.84 (s,
13
9H), 0.02 (s, 6H); C{1H} NMR (200 MHz, CDCl3) δ = 190.9, 152.7, 80.0, 78.9, 69.2, 53.2, 50.8, 25.7
(3C), 20.3 (2C), 18.1, –5.7 (2C); IR (neat, cm–1) υmax 2955, 2930, 2857, 1724, 1687, 1435, 1241, 970, 834,
775; HRMS (FAB) m/z: [M+H]+ Calcd for C15H27O4Si 299.1679; Found 299.1691.
Methyl (R)-6-((tert-butyldimethylsilyl)oxy)-4-hydroxy-5,5-dimethylhex-2-ynoate (13). To 12 (6.72
g, 22.5 mmol) was added (+)-DIPCl (1.6 M in hexane; 21.1 mL, 33.8 mmol) at room temperature under
dry N2 atmosphere and stirred for 16 h at the same temperature. The reaction mixture was cooled to 0 ºC
and diethanolamine (8.7 mL, 90.1 mmol) was added. The mixture was diluted with Et2O and warmed to
room temperature. After 2 h stirring, the mixture was filtered through a pad of silica gel and rinsed with
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hexane/EtOAc (4:1, v/v). The combined organic layer was concentrated under reduced pressure and
purified by flash chromatography on silica gel (hexane/EtOAc, 10:1, v/v) to yield 13 (4.87 g, 72%, 93%
ee) as a light yellow oil. Rf = 0.18 (hexane/EtOAc, 10:1); [α]25D –5.4 (c 1.3, CHCl3); 1H NMR (800 MHz,
CDCl3) δ = 4.30 (d, J = 6.9 Hz, 1H), 3.89 (d, J = 7.0 Hz, 1H), 3.77 (d, J = 9.8 Hz, 1H), 3.75 (s, 3H), 3.39
(d, J = 9.8 Hz, 1H), 1.06 (s, 3H), 0.94 (s, 3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C{1H} NMR (200
MHz, CDCl3) δ = 153.8, 87.2, 71.1, 70.6, 52.6, 39.3, 25.7 (3C), 21.7 (2C), 20.5, 18.1, –5.8 (2C); IR (neat,
cm–1) υmax 3439, 2930, 2857, 1717, 1470, 1246, 1077, 834, 775; HRMS (FAB) m/z: [M+H]+ Calcd for
C15H29O4Si 301.1835; Found 301.1841.
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(R)-MTPA ester of 13. To a solution of 13 (15 mg, 0.05 mmol) in CH2Cl2 (0.3 mL), DMAP (6.1 mg,
0.05 mmol), Et3N (14 µL, 0.10 mmol) and (+)-(S)-MTPA-Cl (11 µL, 0.06 mmol) were added successively
at room temperature. After 20 min at the same temperature, the reaction was quenched with a saturated
aqueous NH4Cl solution, poured into water and extracted twice with CH2Cl2. The combined organic
layers were dried over MgSO4 and concentrated. The residue was purified by flash chromatography on
silica gel (hexane/EtOAc, 20:1) to yield the (R)-MTPA ester of 13 (17.5 mg, 68%) as a white crystalline
1
solid. Rf = 0.47 (hexane/EtOAc, 10:1); mp 49–52 °C; [α]25 +8.5 (c 0.70, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 7.55–7.50 (m, 2H), 7.44–7.38 (m, 3H), 5.62 (s, 1H), 3.78 (s, 3H), 3.54 (s, 3H), 3.39 (dd, J =
26.1, 9.6 Hz, 2H), 1.03 (s, 3H), 0.97 (s, 3H), 0.89 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H); 13C{1H} NMR (200
MHz, CDCl3) δ 165.5, 153.2, 131.7, 129.7, 128.4 (2C), 127.6 (2C), 123.1 (q, J = 286.4 Hz), 84.9 (q, J =
27.9 Hz), 82.1, 78.4, 69.5, 67.9, 55.4, 52.8, 40.1, 25.7 (3C), 21.0, 19.6, 18.1, –5.6, –5.7; IR (neat, cm–1)
υmax 2955, 2935, 2987, 2239, 1756, 1723, 1470, 1436, 1257, 1172, 1102, 1004, 838; HRMS (FAB) m/z:
[M+H]+ Calcd for C25H36F3O6Si 517.2233; Found 517.2246.
(S)-MTPA ester of 13. Following the same experimental procedure as described for the preparation of
the (R)-MTPA ester of 13, compound 13 (15 mg, 0.05 mmol) was treated with (–)-(R)-MTPA-Cl (11 µL,
0.06 mmol) to afford the (S)-MTPA ester of 13 (18.5 mg, 72%) as a white crystalline solid. Rf = 0.44
1
(hexane/EtOAc, 10:1); mp 71–73 °C; [α]25 –11.5 (c 0.78, CHCl3); H NMR (400 MHz, CDCl3) 7.63–
D
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7.50 (m, 2H), 7.43–7.39 (m, 3H), 5.69 (s, 1H), 3.80 (s, 3H), 3.57 (s, 3H), 3.31 (s, 2H), 1.01 (s, 3H), 0.94
(s, 3H), 0.89 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H); 13C{1H} NMR (200 MHz, CDCl3) δ 165.4, 153.2, 132.2,
129.7, 128.5 (2C), 127.4 (2C), 123.3 (q, J = 286.4 Hz), 84.4 (q, J = 28.0 Hz), 82.3, 78.7, 69.2, 67.7, 55.4,
52.8 40.4, 25.7 (3C), 20.9, 19.4, 18.1, –5.6, –5.8; IR (neat, cm–1) υmax 2958, 2932, 2859, 2242, 1759,
1722, 1470, 1433, 1260, 1229, 1173, 1105, 1018, 839; HRMS (FAB) m/z: [M+H]+ Calcd for
C25H36F3O6Si 517.2233; Found 517.2236.
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(R)-1-((tert-Butyldimethylsilyl)oxy)-6-methoxy-2,2-dimethyl-6-oxohex-4-yn-3-yl benzoate (14). To
an ice-cold solution of 13 (4.87 g, 16.2 mmol) in CH2Cl2 (150 mL) was added Et3N (6.8 mL, 48.6 mmol),
DMAP (59.4 mg, 0.49 mmol) and BzCl (3.7 mL, 32.4 mmol). The reaction mixture was warmed to room
temperature and stirred for 30 min. The reaction was quenched by the addition of a saturated NH4Cl
aqueous solution at 0 ºC, and the mixture was extracted with EtOAc three times. The combined organic
fraction was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (hexane/EtOAc, 40:1, v/v) to yield 14 (6.43 g, 98%) as a colorless oil.
Rf = 0.35 (hexane/EtOAc, 10:1); [α]25D –10.9 (c 0.56, CHCl3); 1H NMR (800 MHz, CDCl3) δ = 8.02–8.01,
(m, 2H), 7.57–7.55 (m, 1H), 7.44–7.24 (m, 2H), 5.69 (s, 1H), 3.73 (s, 3H), 3.47 (d, J = 9.7 Hz, 1H), 3.43
13
(d, J = 9.8 Hz, 1H), 1.10 (s, 3H), 1.09 (s, 3H), 0.84 (s, 9H), –0.01 (s, 3H), –0.08 (s, 3H); C{1H} NMR
(200 MHz, CDCl3) δ = 164.9, 153.4, 133.3, 129.7 (2C), 129.6, 128.4 (2C), 83.8, 77.5, 68.2, 67.7, 52.7,
40.6, 25.7 (3C), 21.0, 20.0, 18.1, –5.75, –5.76; IR (neat, cm–1) υmax 2955, 2932, 1734, 1720, 1774, 1674,
1248, 1524, 837, 711; HRMS (FAB) m/z: [M+H]+ Calcd for C22H33O5Si 405.2097; Found 405.2088.
(R,Z)-1-((tert-Butyldimethylsilyl)oxy)-6-methoxy-2,2,4-trimethyl-6-oxohex-4-en-3-yl benzoate ((Z)-
15). To a solution of CuI (9.08 g, 47.7 mmol) in dry THF (130 mL) was slowly MeLi (1.6 M in Et2O;
59.6 mL, 95.4 mmol) at –78 ºC under dry N2 atmosphere and stirred for 1 h. 14 (6.43 g, 15.9 mmol) in
THF (15 mL) was added slowly to the above mixture at –78 ºC and stirred for 30 min at the same
temperature. The reaction was quenched by the addition of a saturated NH4Cl aqueous solution and
cooling bath was removed. After vigorous stirring for 2 h at room temperature, the mixture was diluted
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with water and EtOAc and extracted with EtOAc twice. The combined organic fraction was dried over
MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on
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silica gel (hexane/EtOAc, 40:1, v/v) to yield (Z)-15 (5.95 g, 89%) as a light yellow oil. Rf = 0.62
1
(hexane/EtOAc, 4:1); [α]25 +71.5 (c 3.2, CHCl3); H NMR (600 MHz, CDCl3) δ = 8.05–8.03 (m, 2H),
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7.55–7.53 (m, 1H), 7.44–7.41 (m, 2H), 6.80 (s, 1H), 5.86 (s, 1H), 3.70 (s, 3H), 3.56 (d, J = 9.6 Hz, 1H),
3.41 (d, J = 9.6 Hz, 1H), 1.89 (d, J = 1.4 Hz, 3H), 1.06 (s, 3H), 1.03 (s, 3H), 0.85 (s, 9H), –0.02 (s, 3H), –
0.05 (s, 3H); C{1H} NMR (150 MHz, CDCl3) δ = 165.8, 165.2, 153.8, 132.9, 130.4, 129.5 (2C), 128.4
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(2C), 120.4, 75.5, 69.2, 51.1, 41.0, 25.8 (3C), 21.3, 21.2, 21.1, 18.2, –5.7 (2C); IR (neat, cm–1) υmax 2952,
2856, 1720, 1643, 1267, 1082, 834, 773, 709; HRMS (FAB) m/z: [M+H]+ Calcd for C23H37O5Si
421.2410; Found 421.2417. The configuration was determined by NOESY experiments (see the
Supporting Inforamtion for details).
(R,E)-1-((tert-Butyldimethylsilyl)oxy)-6-methoxy-2,2,4-trimethyl-6-oxohex-4-en-3-yl
benzoate
((E)-15). To a solution of CuBr∙DMS (308 mg, 1.5 mmol) in distilled THF (2.0 mL), MeMgBr (3.0 M in
diethyl ether, 0.5 mL, 1.5 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After
1 h, 14 (81 mg, 0.20 mmol) in THF (0.5 mL) was added at 0 °C. Then, the mixture was warmed to room
temperature and stirred for 90 min. After 90 min, the reaction was quenched by addition of a saturated
aqueous NH4Cl solution. Then, the mixture was extracted twice with ethyl acetate. The combined organic
layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (hexane/EtOAc, 40:1) to yield (Z)-15 (13.0 mg, 15%) and (E)-15 (39.0
mg, 46%). (E)-15: light yellow oil. Rf = 0.43 (hexane/EtOAc, 8:1); [α]25D +65.0 (c 1.04, CHCl3); 1H NMR
(800 MHz, CDCl3) δ 8.04–8.02 (m, 2H), 7.57–7.55 (m, 1H), 7.45–7.43 (m, 2H), 5.89 (s, 1H), 5.32 (s,
1H), 3.65 (s, 3H), 3.44 (d, J = 9.7 Hz, 1H), 3.30 (d, J = 9.7 Hz, 1H), 2.24 (d, J = 1.2 Hz, 3H), 1.03 (s, 3H),
0.97 (s, 3H), 0.86 (s, 9H), –0.02 (s, 3H), –0.06 (s, 3H); 13C{1H} NMR (200 MHz, CDCl3) δ 166.6, 165.3,
156.2, 133.1, 130.2, 129.5 (2C), 128.5 (2C), 117.8, 80.8, 69.2, 50.9, 40.3, 25.8 (3C), 21.1, 20.9, 18.20,
18.17, –5.6, –5.7; IR (neat, cm–1) υmax 2953, 2931, 2858, 1722, 1651, 1268, 1216, 1153, 1097, 838, 776,
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712; HRMS (FAB) m/z: [M+H]+ Calcd for C23H37O5Si 421.2410; Found 421.2412. The configuration was
determined by NOESY experiments (see the Supporting Inforamtion for details).
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Methyl (R)-6-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-4-((trimethylsilyl)oxy)hex-2-ynoate (16).
To a solution of 13 (350 mg, 1.5 mmol) in CH2Cl2 (15 mL), Et3N (418 µL, 3.0 mmol), DMAP (183 mg,
1.5 mmol) and TMSCl (381 µL, 3.0 mmol) were added at 0 °C. The reaction mixture was warmed to
room temperature. After 1 h, a saturated aqueous NH4Cl solution was added to the mixture and extracted
twice with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (hexane/EtOAc, 20:1) to yield 16 (475 mg,
85%) as a colorless oil. Rf = 0.41 (hexane/EtOAc, 8:1); [α]25D –20.7 (c 1.18, CHCl3); 1H NMR (400 MHz,
CDCl3) δ = 4.45 (s, 1H), 3.77 (s, 3H), 3.46 (d, J = 9.6 Hz, 1H), 3.26 (d, J = 9.6 Hz, 1H), 0.93 (s, 3H), 0.90
(s, 3H), 0.89 (s, 9H), 0.16 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ = 154.2,
88.7, 77.2, 68.1, 66.6, 52.8, 41.4, 26.1 (3C), 20.9, 19.4, 18.5, 0.2 (3C), –5.3, –5.4; IR (neat, cm–1) υmax
2956, 2931, 2858, 2234, 1720, 1249, 1091, 1063, 871, 838, 775, 750; HRMS (FAB) m/z: [M+H]+ Calcd
for C18H37O4Si2 373.2230; Found 373.2226.
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Methyl (R,Z)-6-((tert-butyldimethylsilyl)oxy)-3,5,5-trimethyl-4-((trimethylsilyl)oxy)hex-2-enoate
((Z)-17). To a solution of CuI (114 mg, 0.60 mmol) in distilled THF (2.0 mL), MeLi (1.6 M in diethyl
ether, 0.75 mL, 1.2 mmol) was added at 0 °C. The reaction mixture was stirred at the same temperature
for 1 h. Then, 16 (65 mg, 0.20 mmol) in THF (0.5 mL) was added to the reaction mixture at –78 °C. After
3 h of stirring at –78 °C, the reaction was quenched by addition of a saturated aqueous NH4Cl solution.
The mixture was warmed to 0 °C and stirred for an additional 1 h. The mixture was extracted twice with
ethyl acetate, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (hexane/EtOAc, 40:1) to yield (Z)-17 (64 mg,
81%) as a yellow oil. Rf = 0.59 (hexane/EtOAc, 10:1); [α]25D +29.3 (c 1.10, CHCl3); 1H NMR (400 MHz,
CDCl3) δ = 5.69 (s, 1H), 5.53 (s, 1H), 3.64 (s, 3H), 3.39 (d, J = 9.6 Hz, 1H), 3.25 (d, J = 9.2 Hz, 1H), 1.87
(s, 3H), 0.87 (s, 9H), 0.82 (s, 3H), 0.80 (s, 3H), 0.05 (s, 9H), –0.00 (s, 3H), –0.01 (s, 3H); 13C{1H} NMR
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(100 MHz, CDCl3) δ = 166.6, 160.6, 118.1, 72.3, 69.3, 51.1, 41.5, 26.2 (3C), 21.3, 21.1, 20.5, 18.6, 0.1
(3C), –5.2, –5.3; IR (neat, cm–1) υmax 2955, 2931, 2858, 1722, 1252, 1148, 1093, 1073, 1051, 891, 839,
774; HRMS (FAB) m/z: [M+H]+ Calcd for C19H41O4Si2 389.2543; Found 389.2540. The configuration
was determined by NOESY experiments (see the Supporting Inforamtion for details).
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Methyl (R,E)-6-((tert-butyldimethylsilyl)oxy)-3,5,5-trimethyl-4-((trimethylsilyl)oxy)hex-2-enoate
((E)-17). To a solution of CuI (114 mg, 0.60 mmol) in distilled THF (2.0 mL), MeMgBr (3.0 M in diethyl
ether, 0.40 mL, 1.2 mmol) was added at –40 °C. The reaction mixture was stirred at the same temperature
for 30 min. Then, 16 (65 mg, 0.20 mmol) in THF (0.5 mL) was added to the reaction mixture at –78 °C.
After 2 h of stirring at –78 °C, the reaction mixture was warmed to room temperature and stirred for 2 h.
Then, the reaction was quenched by addition of acetic acid at 0 °C. After 20 min, the mixture was warmed
to room temperature and stirred for 20 min. Then, the mixture was extracted twice with ethyl acetate. The
combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (hexane/Et2O, 40:1) to yield (E)-17 (48 mg, 61%) as a colorless oil. Rf
= 0.41 (hexane/EtOAc, 8:1); [α]25D +13.1 (c 1.11, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 5.80 (s, 1H),
4.10 (s, 1H), 3.68 (s, 3H), 3.36 (d, J = 9.2 Hz, 1H), 3.13 (d, J = 9.6 Hz, 1H), 2.10 (s, 3H), 0.88 (s, 9H),
0.81 (s, 3H), 0.73 (s, 3H), 0.03 (s, 9H), 0.01 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ = 167.3, 161.2,
117.3, 79.7, 69.4, 51.1, 41.2, 26.2 (3C), 21.2, 20.6, 18.5, 17.4, 0.1 (3C), –5.2, –5.4; IR (neat, cm–1) υmax
2954, 2931, 2858, 1722, 1251, 1212, 1152, 1086, 880, 838, 775; HRMS (FAB) m/z: [M+H]+ Calcd for
C19H41O4Si2 389.2543; Found 389.2540. The configuration was determined by NOESY experiments (see
the Supporting Inforamtion for details).
(R,Z)-1-((tert-Butyldimethylsilyl)oxy)-2,2,4-trimethyl-6-oxohex-4-en-3-yl benzoate ((Z)-18). To a
solution of (Z)-15 (5.94 g, 14.1 mmol) in dry THF (30 mL) was added a solution of DIBAL–H (1.0 M in
THF; 35.3 mL, 35.3 mmol) at –78 ºC under a N2 atmosphere. The resulting mixture was allowed to warm
to –20 ºC and was stirred for 2 h. The reaction was quenched by the addition of aqueous Rochelle salt at –
20 ºC and the mixture was allowed to stir for an additional 2 h at room temperature. The mixture was
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diluted with water and EtOAc and extracted with EtOAc three times. The combined organic fraction was
dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash
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as a colorless oil. Rf = 0.37 (hexane/EtOAc, 3:1); [α]25 +31.1 (c 1.4, CHCl3); H NMR (600 MHz,
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D
CDCl3) δ = 8.02–8.01 (m, 2H), 7.55–7.53 (m, 1H), 7.43–7.41 (m, 2H), 5.89 (s, 1H), 5.78–5.75 (m, 1H),
4.56 (dd, J = 12.8, 9.2 Hz, 1H), 3.92–3.91 (m, 1H), 3.46 (d, J = 9.2, 1H), 3.22 (d, J = 9.6 Hz, 1H), 2.82–
2.81 (m, 1H), 1.76 (s, 3H), 1.06 (s, 3H), 0.95 (s, 3H), 0.86 (s, 9H), –0.03 (s, 3H), –0.07 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ = 165.9, 134.4, 133.0, 131.0, 130.4, 129.4 (2C), 128.4 (2C), 74.9, 69.2, 58.1,
39.9, 25.8 (3C), 21.6, 21.2, 20.2, 18.1, –5.7 (2C); IR (neat, cm–1) υmax 3502, 2954, 2930, 2857, 1720,
1706, 1471, 1270, 1093, 834, 709; HRMS (FAB) m/z: [M+H]+ Calcd for C22H37O4Si 393.2461; Found
393.2446.
To a solution of the previously obtained alcohol (4.60 g, 11.7 mmol) in CH2Cl2 (115 mL) was added
TPAP (412 mg, 1.17 mmol) and NMO (2.06 g, 17.6 mmol) at room temperature. The reaction mixture
was stirred for 30 min and filtered through a pad of silica gel and rinsed with hexane/EtOAc (4:1, v/v).
The residue was concentrated in vacuo to yield (Z)-18 (4.26 g, 93%) as a colorless oil. Rf = 0.48
(hexane/EtOAc, 5:1); [α]25D +85.4 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ = 10.18 (d, J = 7.8 Hz,
1H), 8.02 (d, J = 7.8 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 6.33 (br, 1H), 6.01 (d, J =
7.3 Hz, 1H), 3.52 (d, J = 10.1 Hz, 1H), 3.30 (d, J = 9.7 Hz, 1H), 1.99 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H),
0.84 (s, 9H), –0.03 (s, 3H), –0.08 (s, 3H); C{1H} NMR (150 MHz, CDCl3) δ = 190.5, 165.3, 156.6,
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133.2, 131.8, 129.8, 129.4 (2C), 128.5 (2C), 74.9, 68.9, 40.3, 25.8 (3C), 21.9, 21.3 (2C), 18.1, –5.73, –
5.77; IR (neat, cm–1) υmax 2956, 2931, 2858, 1723, 1678, 1267, 1093, 837, 777, 712; HRMS (FAB) m/z:
[M+H]+ Calcd for C22H35O4Si 391.2305; Found 391.2304.
(R,4Z,6E)-1-((tert-Butyldimethylsilyl)oxy)-2,2,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)hepta-4,6-dien-3-yl benzoate (21). To a solution of 2,2,6,6-tetramethylpiperidine
(510 µL, 3.0 mmol) in distilled THF (10 mL), n-BuLi (1.6 M in hexane, 1.9 mL, 3.0 mmol) was slowly
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added at 0 °C. After 30 min, 20 (804 mg, 3.0 mmol) in THF (2 mL) was slowly added to the mixture at 0
°C. After stirring at the same temperature for 5 min, the reaction mixture was cooled to –100 °C. Then, a
solution of (Z)-18 (390 mg, 1.0 mmol) in THF (2 mL) was added to the reaction mixture. The reaction
mixture was stirred at the same temperature for 1 h. Then, the reaction was quenched by addition of a
saturated aqueous NH4Cl solution and warmed to room temperature. The mixture was extracted twice
with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane/EtOAc,
20:1) to yield 21 (406 mg, 79%) as a colorless oil. Rf = 0.59 (hexane/EtOAc, 5:1); [α]25D +159.4 (c 1.23,
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CHCl3); H NMR (400 MHz, CDCl3) δ 8.05–8.03 (m, 2H), 7.56–7.52 (m, 1H), 7.46–7.41 (m, 3H), 6.13
(d, J = 11.6 Hz, 1H), 6.01 (brs, 1H), 5.43 (d, J = 17.2 Hz, 1H), 3.52 (d, J = 9.6 Hz, 1H), 3.25 (d, J = 9.6
Hz, 1H), 1.83 (s, 3H), 1.20–1.24 (m, 12H), 1.04 (s, 3H), 0.97 (s, 3H), 0.88 (s, 9H), –0.01 (s, 3H), –0.06 (s,
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3H); C{1H} NMR (100 MHz, CDCl3) δ 165.4, 145.2, 137.9, 133.3, 133.0, 130.8, 129.74 (2C), 129.70,
128.6 (2C), 83.2 (2C), 77.4, 69.4, 41.2, 26.2 (3C), 26.1, 25.04 (2C), 25.02 (2C), 22.3, 21.4, 18.5, –5.38, –
5.42; IR (neat, cm–1) υmax 2972, 2932, 2854, 1723, 1591, 1332, 1464, 1265, 1091; HRMS (FAB) m/z:
[M+H]+ Calcd for C29H48BO5Si 515.3364; Found 515.3370.
(R,4Z,6E,8E)-1-((tert-Butyldimethylsilyl)oxy)-2,2,4-trimethyl-10-(oxazol-5-yl)deca-4,6,8-trien-3-yl
benzoate (19b). The reaction flask was wrapped with aluminum foil to perform the reaction in the dark.
To a solution of 21 (240 mg, 0.47 mmol) in THF/H2O (9:1, 8.0 mL), Ag2O (400 mg, 1.73 mmol) and
Pd(PPh3)4 (69 mg, 0.06 mmol) were added at 0 °C. After 5 min, 22 (226 mg, 0.96 mmol) in THF/H2O
(9:1, 2.0 mL) was added to the mixture. The reaction mixture was warmed to room temperature. After 5
min, the reaction mixture was quenched by addition of a saturated aqueous Na2S2O3 solution. The mixture
was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel
(hexane/EtOAc, 10:1) to yield 19b (198 mg, 85%) as a yellow oil. Rf = 0.31 (hexane/EtOAc, 3:1); [α]25
D
1
+148.2 (c 2.37, CHCl3); H NMR (400 MHz, CDCl3) δ 8.04–8.02 (m, 2H), 7.77 (s, 1H), 7.56–7.52 (m,
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1H), 7.44–7.41 (m, 2H), 6.78 (s, 1H), 6.66 (dd, J = 14.0, 11.7 Hz, 1H), 6.23–6.00 (m, 4H), 5.73–5.66 (m,
1H), 3.48–3.45 (m, 3H), 3.23 (d, J = 9.6 Hz, 1H), 1.82 (s, 3H), 1.05 (s, 3H), 0.94 (s, 3H), 0.88 (s, 9H), –
0.03 (s, 3H), –0.06 (s, 3H); 13C{1H} NMR (200 MHz, CDCl3) δ 165.3, 150.9, 150.4, 134.3 133.7, 132.8,
131.7, 130.9, 130.6, 129.5 (2C), 128.5, 128.4 (2C), 126.8, 122.5, 75.3, 69.2, 40.8, 29.7, 25.9 (3C), 22.0
(2C), 21.2, 18.2, –5.6 (2C); IR (neat, cm–1) υmax 2955, 2921, 2854, 1720, 1509, 1453, 1270, 1088; HRMS
(FAB) m/z: [M+H]+ Calcd for C29H42NO4Si 496.2883; Found 496.2894.
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(R,4Z,6Z)-7-Bromo-1-((tert-butyldimethylsilyl)oxy)-2,2,4-trimethylhepta-4,6-dien-3-yl
benzoate
(23). To an ice-cooled mixture solution of CBr4 (10.8 g, 32.7 mmol) in CH2Cl2 (70 mL) was added PPh3
(17.2 g, 65.4 mmol) and stirred for 10 min. To the mixture was added Et3N (15.2 mL, 109 mmol) and (Z)-
18 (4.26 g, 10.9 mmol) in CH2Cl2 (15 mL) at 0 ºC. The resulting mixture was allowed to warm to room
temperature and stirred for 16 h. The solution was diluted with hexane and filtered through a pad of silica
gel and rinsed with hexane/EtOAc (4:1, v/v). The combined organic solution was concentrated under
reduced pressure and purified by flash chromatography on silica gel (hexane/EtOAc, 40:1, v/v) to yield
1,1-dibromoolefin compound (5.90 g, 99%) as a colorless oil. Rf = 0.26 (hexane/EtOAc, 40:1); [α]25
D
+175 (c 0.33, CHCl3); 1H NMR (800 MHz, CDCl3) δ = 8.05–8.04 (m, 2H), 7.57–7.55 (m, 1H), 7.47–7.43
(m, 3H), 6.09 (d, J = 10.8 Hz, 1H), 5.85 (br, 1H), 3.48 (d, J = 9.6 Hz, 1H), 3.24 (d, J = 9.6 Hz, 1H), 1.84
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(s, 3H), 1.06 (s, 3H), 0.96 (s, 3H), 0.90 (s, 9H), 0.01 (s, 3H), –0.04 (s, 3H); C{1H} NMR (200 MHz,
CDCl3) δ = 165.2, 138.7, 132.9, 132.8, 130.2, 129.4 (2C), 128.4 (2C), 127.0, 91.7, 75.8, 69.0, 40.5, 25.9
(3C), 21.9, 21.1 (2C), 18.2, –5.62, –5.65; IR (neat, cm–1) υmax 2954, 2928, 2856, 1722, 1268, 1096, 838,
776, 710; HRMS (FAB) m/z: [M+H]+ Calcd for C23H35Br2O3Si 545.0722; Found 545.0715.
To a solution of previously obtained 1,1-dibromoolefin compound (5.72 g, 10.5 mmol) and Pd(PPh3)4
(1.21 g, 1.05 mmol) in toluene (100 mL), Bu3SnH (2.95 mL, 11.0 mmol) was added slowly over 2 h at
room temperature under a N2 atmosphere. The resulting suspension was stirred for 16 h and then diluted
with hexane. The mixture was filtered through a pad of silica gel/Celite and rinsed with hexane/EtOAc
(4:1, v/v). The residue was concentrated in vacuo and purified by flash chromatography on silica gel
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(hexane/EtOAc, 10:1, v/v) to yield 23 (4.85 g, 99%) as a colorless oil. Rf = 0.26 (hexane/EtOAc, 40:1);
[α]25D +131 (c 0.9, CHCl3); 1H NMR (800 MHz, CDCl3) δ = 8.03–8.02 (m, 2H), 7.55 (t, J = 7.4 Hz, 1H),
7.43 (t, J = 7.8 Hz, 2H), 7.13 (dd, J = 10.7, 7.2 Hz, 1H), 6.38 (d, J = 10.8 Hz, 1H), 6.15 (d, J = 7.1 Hz,
1H), 5.91 (br, 1H), 3.43 (d, J = 9.6 Hz, 1H), 3.25 (d, J = 9.7 Hz, 1H), 1.86 (s, 3H), 1.05 (s, 3H), 0.95 (s,
3H), 0.86 (s, 9H), –0.03 (s, 3H), –0.06 (s, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ = 165.5, 138.7, 133.1,
130.5, 129.6 (2C), 128.6 (2C), 128.4, 126.3, 108.8, 75.5, 69.2, 40.9, 26.0 (3C), 21.9, 21.6 (2C), 18.4, –
5.45, –5.50; IR (neat, cm–1) υmax 2954, 2930, 2856, 1721, 1269, 1097, 838, 776, 710; HRMS (FAB) m/z:
[M+H]+ Calcd for C23H36BrO3Si 467.1617; Found 467.1632.
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(R,4Z,6Z,8E)-1-((tert-Butyldimethylsilyl)oxy)-2,2,4-trimethyl-10-(oxazol-5-yl)deca-4,6,8-trien-3-yl
benzoate (19a). To a stirred solution of 23 (480 mg, 1.03 mmol) in degassed DMF was added 24 (818
mg, 2.05 mmol) and PEPPSI-iPr (41.9 mg, 0.06 mmol) at room temperature under protection from light.
The resulting suspension was allowed to warm to 55 ºC and stirred for 36 h under a N2 atmosphere. After
the completion of the reaction, the reaction mixture was diluted with EtOAc, filtered through a pad of
Celite and washed with EtOAc. The combined organic phase was concentrated under reduced pressure
and the residue was purified by flash chromatography on silica gel (hexane/EtOAc, 20:1 to 3:1, v/v) to
yield 19a (356 mg, 70%) as a light yellow oil. The Z/E selectivity of 19a was determined by 1H NMR in
>30:1 ratio. Rf = 0.42 (hexane/EtOAc, 3:1); [α]25D +162 (c 0.73, CH2Cl2); 1H NMR (800 MHz, CDCl3) δ
= 8.04–8.02 (m, 2H), 7.76 (s, 1H), 7.54–7.52 (m, 1H), 7.43–7.41 (m, 2H), 6.78 (s, 1H), 6.64 (dd, J = 14.4,
11.7 Hz, 1H), 6.49–6.44 (m, 2H), 6.00 (br, 1H), 5.96 (t, J = 10.6 Hz, 1H), 5.74 (dt, J = 14.6, 7.2 Hz, 1H),
3.49 (d, J = 7.0 Hz, 2H), 3.45 (d, J = 9.6 Hz, 1H), 3.25 (d, J = 9.5 Hz, 1H), 1.86 (s, 3H), 1.05 (s, 3H), 0.95
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(s, 3H), 0.86 (s, 9H), –0.03 (s, 3H), –0.06 (s, 3H); C{1H} NMR (200 MHz, CDCl3) δ = 165.3, 150.8,
150.4, 135.1, 132.8, 130.6, 129.5 (2C), 128.44, 128.36 (2C), 128.0, 127.9, 125.6, 124.8, 122.5, 75.1, 69.2,
40.9, 29.0, 25.8 (3C), 21.9 (2C), 21.4, 18.2, –5.6, –5.7; IR (neat, cm–1) υmax 2954, 2929, 2856, 1720, 1270,
1097, 954, 837, 776, 712; HRMS (FAB) m/z: [M+H]+ Calcd for C29H42NO4Si 496.2883; Found 496.2877.
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(R,4Z,6Z,8E)-1-hydroxy-2,2,4-trimethyl-10-(oxazol-5-yl)deca-4,6,8-trien-3-yl benzoate (25a). The
reaction flask was wrapped with aluminum foil to perform the reaction in the dark. To a solution of 19a
(219 mg, 0.44 mmol) in THF (2.8 mL) and pyridine (1.6 mL) was added HF∙pyridine 70 wt% solution
(1.4 mL) at 0 ºC. The resulting mixture was stirred for 15 h at the same temperature and then warmed to
room temperature. The mixture was stirred for an additional 5 h, and re-cooled to 0 ºC. To the reaction
mixture was added a saturated NaHCO3 aqueous solution and extracted with EtOAc twice. The combined
organic fraction was washed with brine and water. The organic layer was dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane/EtOAc,
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2:1, v/v) to yield 25a (152 mg, 90%) as a light yellow oil. Rf = 0.24 (hexane/EtOAc, 1:1) [α]25 +192 (c
D
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0.7, CH2Cl2); H NMR (800 MHz, CDCl3) δ = 8.04–8.03 (m, 2H), 7.77 (s, 1H), 7.57–7.55 (m, 1H), 7.44
(t, J = 7.8 Hz, 2H), 6.78(s, 1H), 6.64–6.61 (m, 1H), 6.50 (d, J = 12.3 Hz, 1H), 6.40 (t, J = 11.5 Hz, 1H),
6.10 (s, 1H), 6.00 (t, J = 11.1 Hz, 1H), 5.77 (dt, J = 14.6, 7.2 Hz, 1H), 3.49 (d, J = 7.0 Hz, 2H), 3.46 (d, J
= 11.7 Hz, 1H), 3.25–3.23 (m, 1H), 2.35 (br, 1H), 1.95 (s, 3H), 1.02 (s, 3H), 1.01 (s, 3H); 13C{1H} NMR
(200 MHz, CDCl3) δ = 166.2, 150.7, 150.4, 134.6, 133.2, 130.0, 129.8 (2C), 128.8, 128.6, 128.5 (2C),
128.2, 125.8, 124.1, 122.5, 75.1, 69.3, 41.1, 29.0, 21.8, 21.4, 21.1; IR (neat, cm–1) υmax 3302, 2963, 2922,
2873, 1713, 1509, 1268, 1107, 949, 824, 711; HRMS (FAB) m/z: [M]+ Calcd for C23H27NO4 381.1940;
Found 381.1932.
(R,4Z,6E,8E)-1-Hydroxy-2,2,4-trimethyl-10-(oxazol-5-yl)deca-4,6,8-trien-3-yl benzoate (25b).
Following the same experimental procedure as described for the preparation of 25a, compound 19b (150
mg, 0.30 mmol) was converted to 25b (86.9 mg, 76%), which was obtained as a yellow oil. Rf = 0.30
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(hexane/EtOAc, 2:1); [α]25 +168.9 (c 1.25, CHCl3); H NMR (400 MHz, CDCl3) δ 8.06–8.04 (m, 2H),
D
7.78 (s, 1H), 7.58–7.55 (m, 1H), 7.45–7.43 (m, 2H), 6.78 (s, 1H), 6.61 (dd, J = 14.4, 11.7 Hz, 1H), 6.25
(dd, J = 15.0, 10.7 Hz, 1H), 6.15 (dd, J = 14.6, 10.7 Hz, 1H), 6.10–6.08 (m, 2H), 5.72 (td, J = 5.6, 10.9
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Hz, 1H), 3.45–3.50 (m, 3H), 3.25–3.23 (m, 1H), 1.92 (s, 3H), 1.02 (s, 6H); C{1H} NMR (200 MHz,
CDCl3) δ 166.3, 150.8, 150.4, 133.8, 133.5, 133.2, 132.4, 131.1, 130.0, 129.7 (2C), 128.5 (2C), 127.8,
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127.5, 122.5, 75.4, 69.3, 41.1, 28.9, 21.9, 21.2, 21.1; IR (neat, cm–1) υmax 3471, 2980, 2935, 2904, 1734,
1445, 1374, 1231; HRMS (FAB) m/z: [M]+ Calcd for C23H27NO4 381.1934; Found 381.1940.
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(R,4Z,6Z,8E)-3-(Benzoyloxy)-2,2,4-trimethyl-10-(oxazol-5-yl)deca-4,6,8-trienoic acid (26a). The
reaction flask was wrapped with aluminum foil to perform the reaction in the dark. To a solution of oxalyl
chloride (2.0 M in CH2Cl2; 0.3 mL, 0.67 mmol) in CH2Cl2 (3.0 mL) was added DMSO (95 μL, 1.34
mmol) at –78 ºC. After the 30 min stirring, 25a (85.0 mg, 0.22 mmol) in CH2Cl2 (1.0 mL) was added
dropwise to the above mixture at –78 ºC. The resulting mixture was stirred for an additional 30 min, and
Et3N (0.4 mL, 2.90 mmol) was added at the same temperatrue. After 10 min, the reaction was allowed to
warm to room temperature and stirred for an additional 30 min. The reaction mixture was diluted with
water and extracted with CH2Cl2 three times. The combined organic phase was dried over MgSO4,
concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel
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(hexane/EtOAc, 3:1, v/v) to yield the corresponding aldehyde (81.2 mg, 96%) as a light yellow oil. Rf =
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0.62 (hexane/EtOAc, 1:1); [α]25 +249 (c 0.5, CH2Cl2); H NMR (800 MHz, CDCl3) δ = 9.78 (s, 1H),
D
8.00–7.99 (m, 2H), 7.77 (s, 1H), 7.57–7.55 (m, 1H), 7.44–7.42 (m, 2H), 6.79 (s, 1H), 6.62 (dd, J = 14.8,
11.5 Hz, 1H), 6.53 (d, J = 12.1 Hz, 1H), 6.38 (t, J = 11.5 Hz, 1H), 6.13 (s, 1H), 6.05 (t, J = 11.1 Hz, 1H),
5.80 (dt, J = 15.6, 7.2 Hz, 1H), 3.50 (d, J = 6.9 Hz, 2H), 1.82 (s, 3H), 1.20 (s, 3H), 1.16 (s, 3H); 13C{1H}
NMR (200 MHz, CDCl3) δ = 203.7, 165.2, 150.6, 150.4, 133.3, 132.6, 129.6 (2C), 129.5, 129.3, 128.5
(2C), 128.5, 128.1, 126.7, 123.5, 122.6, 75.9, 50.5, 29.0, 20.7, 20.4, 18.3; IR (neat, cm–1) υmax 2972, 2924,
1720, 1509, 1268, 1103, 957, 713; HRMS (FAB) m/z: [M+H]+ Calcd for C23H26NO4 380.1862; Found
380.1855.
To an ice-cold solution of obtained aldehyde (57.4 mg, 0.15 mmol) in t-BuOH/water (3 mL, 1:1, v/v)
was added NaClO2 (80%, 50.8 mg, 0.45 mmol), NaH2PO4∙H2O (62.0 mg, 0.45 mmol), and 2-methyl-2-
butene (0.6 mL) under protection from light. The reaction mixture was stirred for 30 min and quenched by
addition of a saturated Na2S2O3 aqueous solution at 0 ºC. The mixture was extracted with EtOAc three
times. The combined organic phase was dried over MgSO4, concentrated under reduced pressure and
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purified by flash chromatography on silica gel (CH2Cl2/MeOH, 20:1, v/v) to yield 26a (50.3 mg, 84%) as
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a pale yellow oil. Rf = 0.37 (hexane/EtOAc, 1:1); [α]25 +206 (c 0.4, CH2Cl2); H NMR (400 MHz,
D
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CDCl3) δ = 8.02–8.00 (m, 2H), 7.79 (s, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 6.79 (s,
1H), 6.66–6.53 (m, 2H), 6.41 (t, J = 11.5 Hz, 1H), 6.18 (s, 1H), 6.00 (t, J = 11.2 Hz, 1H), 5.75 (dt, J =
14.6, 7.2 Hz, 1H), 3.50–3.45 (m, 2H), 1.82 (s, 3H), 1.35 (s, 3H), 1.27 (s, 3H); 13C{1H} NMR (200 MHz,
CDCl3) δ = 180.0, 165.1, 150.8, 150.6, 133.1, 133.0, 129.9, 129.6 (2C), 128.9, 128.8, 128.4 (2C), 128.3,
126.7, 124.1, 122.4, 76.5, 29.67, 29.0, 23.2, 21.1, 20.8; IR (neat, cm–1) υmax 3249, 2984, 2924, 1719, 1638,
1471, 1270, 1107, 981, 712; HRMS (FAB) m/z: [M]+ Calcd for C23H25NO5 395.1733; Found 395.1729.
(R,4Z,6E,8E)-3-(Benzoyloxy)-2,2,4-trimethyl-10-(oxazol-5-yl)deca-4,6,8-trienoic acid (26b).
Following the same experimental procedure as described for the preparation of the corresponding
aldehyde from 25a, compound 25b (44 mg, 0.11 mmol) was converted to the corresponding aldehyde (41
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mg, 96%), which was obtained as a yellow oil. Rf = 0.51 (hexane/EtOAc, 1:1); [α]25 +205.3 (c 0.88,
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CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 8.00–7.98 (m, 2H), 7.78 (s, 1H), 7.58–7.54 (m, 1H),
7.43 (t, J = 7.4 Hz, 2H), 6.80 (s, 1H), 6.62–6.56 (m, 1H), 6.28–6.10 (m, 4H), 5.75 (td, J = 5.6, 10.5 Hz,
1H), 3.48 (d, J = 6.9 Hz, 2H), 1.78 (s, 3H), 1.20 (s, 3H), 1.16 (s, 3H); 13C{1H} NMR (200 MHz, CDCl3) δ
203.8, 165.2, 150.7, 150.4, 133.32, 133.28, 133.27, 132.0, 131.7, 129.7, 129.6 (2C), 128.5 (2C), 128.2,
127.1, 122.6, 76.3, 50.5, 28.9, 20.51, 20.46, 18.4; IR (neat, cm–1) υmax 2972, 2921, 2851, 2722, 1776,
1723, 1599, 1442, 1259, 1105; HRMS (FAB) m/z: [M+H]+ Calcd for C23H26NO4 380.1862; Found
380.1858.
Following the same experimental procedure as described for the preparation of 26a, previously obtained
aldehyde (35.0 mg, 0.092 mmol) was converted to the corresponding 26b (30 mg, 83%), which was
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obtained as a white gum. Rf = 0.31 (hexane/EtOAc, 1:1); [α]20 +186.0 (c 0.94, CHCl3); H NMR (800
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MHz, CDCl3) δ 8.02–8.00 (m, 2H), 7.80 (s, 1H), 7.54–7.52 (m, 1H), 7.42–7.39 (m, 2H), 6.78 (s, 1H), 6.62
(dd, J = 14.0, 11.6 Hz, 1H), 6.23 (dd, J = 15.0, 10.8 Hz, 1H), 6.18–6.11 (m, 3H), 5.71 (td, J =10.8, 5.6 Hz,
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