Total Synthesis of Meayamycin B

Article abstract of DOI:10.1021/acs.joc.9b03370

Meayamycin B is currently the most potent modulator of the splicing factor 3b subunit 1 and used by dozens of research groups. However, current supply for this natural product analogue is limited because of the lengthy synthetic scheme. Here, we report a more concise, more cost-effective, and greener synthesis of this compound by developing and employing a novel asymmetric reduction of a prochiral enone to afford an allylic alcohol with high enantioselectivity. In addition to this reaction, this synthesis highlights a scalable Mukaiyama aldol reaction, Nicolaou-type epoxide opening reaction, stereoselective Corey-Chaykovsky-type reaction, and a modified Horner-Wadsworth-Emmons Z-selective olefination. We also discuss a Z-E isomerization during the α,β-unsaturated amide formation. The new synthesis of meayamycin B consists of 11 steps in the longest linear sequence and 24 total steps.

Full text of DOI:10.1021/acs.joc.9b03370

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Article
Total synthesis of meayamycin B
Robert K. Bressin, Sami Osman, Ivanna Pohorilets, Upamanyu Basu, and Kazunori Koide
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03370 • Publication Date (Web): 12 Mar 2020
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The Journal of Organic Chemistry
Total synthesis of meayamycin B
Robert K. Bressin, Sami Osman, Ivanna Pohorilets, Upamanyu Basu, and Kazunori Koide*
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Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States
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koide@pitt.edu
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KEYWORDS enantioselectivity, total synthesis, aldol, reduction, natural products, isomerization
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Table of Content figure
New enantioselective reduction:
O
OH
OH OH
NaBH4
96% ee
(<9% ee with known methods)
OH
OH
New synthetic route:
•More economical
•Shorter
(cat.)
•Greener
O
N
O
O
O
O
Meayamycin B
•splicing modulator
•pM potency
O
N
HO
H
Carbamate-promoted Z-E isomerization
O
ABSTRACT: Meayamycin B is currently the most potent modulator of the splicing factor 3b subunit 1 and used
by dozens of research groups. However, current supply for this natural product analog is limited due to the lengthy
synthetic scheme. Here, we report a more concise, more cost effective, and greener synthesis of this compound by
developing and employing a novel asymmetric reduction of a prochiral enone to afford an allylic alcohol with high
enantioselectivity. In addition to this reaction, this synthesis highlights a scalable Mukaiyama aldol reaction, Nico-
laou-type epoxide opening reaction, stereoselective Corey-Chaykovsky type reaction, and a modified Horner-
Wadsworth-Emmons Z-selective olefination. We also discuss a Z-E isomerization during the a,b-unsaturated amide
formation. The new synthesis of meayamycin B consists of 11 steps in the longest linear sequence and 24 total
steps.
Introduction
FR901464 is a natural product first reported in 1996.1-3 Its structure and biological activity attracted synthetic
chemists, culminating in four total syntheses to date.4-10 A closely related natural product, thailanstatin A, was also
syntheized.11 These synthetic studies afforded spliceostatin A,12 1-desoxy FR901464,5 and meayamycins9 (Figure
1). Structurally simplified FR901464 analogs, sudemycins, exhibited promising antitumor activity in xenograft
models.13 The efficacy of meayamycins was also examined in mice.14 FR901464 was found to bind the spliceo-
some and modulate pre-mRNA splicing.15 FR901464 and these analogs also perturbed pre-mRNA splicing in live
cells.16, 17 Spliceostatin A and meayamycins have been widely used in the studies on splicing.18-30 Subsequently,
biosynthetic studies of FR901464 and its analogs have become an active area of research.31-33 Meayamycin B is
the most potent splicing modulator to date34 and is the target in this synthetic study. Our previous synthesis is
summarized in Scheme S1 in the Supporting Information.
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R2
O
O
O
O
R1
O
N
H
HO
O
R1
R2
6
7
8
9
CH3
CH3
FR901464
meayamycin
OH
CH3
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CH3
meayamycin B
spliceostatin A
N
O
OCH3
CH3
Figure 1. Structures of FR901464 analogs.
In our previous synthesis of the meayamycin B left-hand fragment 14 (Scheme 1), the unsaturated lactone
4 was prepared in 5 steps from the commercially available L-threonine derivative 1 in 45% overall yield (Scheme
S1B in the Supporting Information).8, 9 This synthesis was undesirable in several aspects; first, the olefination of
1 with Ph3P=CH2 is not atom economical because the carbon installed in this step is lost after the ring-closing
metathesis (RCM) step (S16 to S17). Second, although only 1 mol% of a ruthenium precatalyst is required in the
RCM step, this is expensive when the synthesis is performed in a multiple-gram scale. Third, the allylic oxidation
of S17 with 6 equivalents of a chromium reagent is not green. To produce meayamycin B for basic and transla-
tional studies,35 a more scalable synthesis was needed.
Results and Discussion
We hypothesized that Ando's variant of the Horner-Wadsworth-Emmons (HWE) reaction36 could be used
to install all of the necessary carbon atoms more rapidly with high Z-selectivity. To test this hypothesis, we devel-
oped a mole-scale protocol for the preparation of phosphonate 3 (Scheme 1)37. Ester 1 was reduced to the aldehyde
and subjected to this phosphonate and KOtBu to form Z-enoate 2 in 80% yield as a single isomer. Subsequently,
this enoate underwent acid-catalyzed acetonide deprotection-transesterification to provide the unsaturated lactone
4 in 77% yield in a 9-gram scale. Following our previous route, this lactone was transformed into amine 7 in 4
steps according to our earlier work.8, 9
O
N
O
N
O
O
O
CO2Et
O
O
a
b
c
d,e
CO2Me
RHN
BocHN
BocHN
O
Boc
Boc
1
2
4
5
P
CO2Et
6: R=Boc
7: R=H
O
f
2
3
O
O
HO
g
h
N
O
N
O
O
AcO
CO2Et
j
O
O
O
9
CO2Et
OR
S28
N
OH
10: R=Et
11: R=H
8
i
N
Cl
O
O
Ru
X
N
O
O
N
O
O
Cl
k
O
O
O
NO2
O
O
N
H
N
H
13: X=O
14: X=CH2
12
nitro-Grela catalyst
l
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Scheme 1. a) DIBALH (2 equiv), DCM, -78 °C, 4 h, then 3 (1.5 equiv), KOtBu (1.45 equiv), THF, -78 °C, 45 h,
80%; b) AcOH, 80 °C, 25 h, 77%; c) H2, PtO2 (1 mol %), EtOH, 23 °C, quant. (dr = 10:1); d) allyl-MgCl (2.0
equiv), THF, -78 °C, 96%; e) Et3SiH (10 equiv), BF3•OEt2 (4.0 equiv), CF3CH2OH (8.0 equiv), DCM, -78 °C;
then Boc2O (0.5 equiv), -78®23 °C, 45% (dr = 10:1); f) TFA/DCM (1:9), 23 °C, used directly; g) 1,1’-carbon-
yldiimidazole (1.2 equiv), DCM, 23 °C, 1 h, then morpholine (2–5 equiv), 23 °C, 2 h, 97%; h) DIBALH (1.1
equiv), DCM, -78 °C, 3 h; then (o-tBuPhO)2P(=O)CH2CO2Et (1.5 equiv), KOtBu (1.45 equiv), THF, -78 °C, 8 h,
78%; i) NaOH (2.1 equiv), MeOH/H2O 1:1.1, 0 °C, 2 h, 85%; j) HATU (1 equiv), iPr2NEt (3 equiv), 11 (1 equiv),
THF or DCM, 0 °C, 30 min, 60%; k) methacrolein (24 equiv), nitro-Grela catalyst (5 mol %), 40 °C, 8 h, 60%; l)
Ph3PCH3Br (1.5 equiv), KOtBu (1.49 equiv), THF, 0 °C, 3 h, 69%.
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In the previous synthesis of fragment S28 (Scheme 1; also in Scheme S1) en route to FR901464 and
meayamycin, an acetyl group was installed on the allylic hydroxy group.38 However, for the synthesis of meaya-
mycin B, this requires additional two steps to form the carbamate (S22®14®meayamycin B). During previous
structure-activity relationship studies, a more direct route was developed for various analogs35 using (S)-(-)-ethyl
lactate 8 as an inexpensive chiral starting material, but this route had never been used for the synthesis of meaya-
mycin B. Ester 8 was exposed to CDI and morpholine to afford morpholine carbamate 9 in 97% yield, which
underwent DIBALH reduction and subsequent HWE reaction with (o-tBuPhO)2P(=O)CH2CO2Et39 to afford Z-
enoate 10 in 78% yield. Hydrolysis of 10 with aqueous NaOH afforded acid 11 in 85% yield. With acetate S28,
amide bond formation with amine 7 using HATU isomerized the Z-olefin S19 to the more stable E-isomer in
approximately 10% yield.35 When acid 11 was subjected to the same conditions, this isomerization was more
prominent, in a 1:2 ratio favoring the undesired E olefin. We hypothesized that the faster isomerization of the
olefin, when starting with acid 11, might be caused by the greater participation effect of the carbonyl oxygen in
the carbamate group of Z-15 (Scheme 2A), allowing for isomerization upon the activation of the carboxylic acid
with HATU via intramolecular 1,4-addition (Z-15 ®16) followed by rotation and elimination (16®E-15).
A
O
O
O
O
N
N
O
N
O
N
O
O
N
O
O
N
16
Z-15
O
N
O
O
N
N
O
O
O
N
O
N
O
O
O
N
E-15
16
B
MOMO
O
MOMO
O
O
+
7
N
H
OH
17
Scheme 2: (A) Proposed mechanism for isomerization. (B) A control experiment with methoxymethyl ether 17
This hypothesis is supported by preliminary studies with the methoxymethyl ether (MOM) analog 17, the
olefin of which did not isomerize under the same conditions (Scheme 2B; manuscript in preparation). To gain
further insights, the coupling reactions were performed between acid 11 and cyclohexylamine in various solvents
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and at various temperatures. The olefin isomerization observed during the formation of amide 12 did not occur
under these conditions, possibly due to a greater accessibility of the amino group compared to that of amine 7
whose amino group may be in the axial orientation; the higher nucleophilicity may have favorably competed with
the intramolecular 1,4-conjugate addition described above. These results support our hypothesis about the origin
of E/Z isomerization during the amide coupling.
8
9
These results also led to our next hypothesis that the olefin isomerization might be mitigated if the charged
transition state for the conversion of Z-15 to 16 could be destabilized. In effect, the use of less polar solvents such
as THF and DCM for the coupling of acid 11 and amine 7 improved the stereochemical integrity of the olefin.
Lowering the temperature during addition of the acid to HATU below 0 °C did not affect the isomerization ratio.
Using an excess of the amine also suppressed the olefin isomerization, but this was not practical due to the difficult
recovery of amine 7. Nonetheless, this result indicated that the presence of the amine in excess in relation to the
in-situ activated carboxylic acid was advantageous. To create such conditions without using amine 7 in excess,
acid 11 was added to the amine in a dropwise fashion, competing against and minimizing the olefin isomerization.
Several other methods were tested; activation with DCC or mixed anhydrides via chloroformates showed no de-
sired product. Other non-classical methods were also attempted, including use of boric acid derivatives40 and the
Corey-Nicolaou method.41 All of these methods failed or resulted in inefficient product formation with unidenti-
10
11
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1
fied side products, which, from H-NMR analysis, appear to be 1,4-addition products of the activated complex,
prior to amide bond formation. Ultimately, for the optimized conditions to minimize this undesired isomerization,
a mixture of acid 11 and iPr2NEt was added dropwise to a pre-mixed solution of amine 7 and HATU at 0 °C in
THF or DCM to give the desired Z-enamide 12 in 50% yield with negligible isomerization. This amide was then
cross-coupled with methacrolein in the presence of nitro-Grela precatalyst to generate aldehyde 13 in 40% yield.
Addition of this aldehyde to in-situ prepared Ph3P=CH2 afforded the most advanced left fragment 14 in 83% yield.
We then turned our attention to the right hand fragment 29 and recognized several problems for scaling
up our previous scheme (Scheme S1). First, the Zr/Ag-promoted alkynylation, although stereoselective, required
stoichiometric amounts of these heavy metals.42 Second, the use of a selenium reagent was not cost effective.8, 9
Third, the formation of the tetrahydropyran ring required a stoichiometric quantity of Hg(OAc)2.9 Importantly,
this scheme was lengthy (11 linear steps from propargyl alcohol). To develop a more concise scheme for 29 with
less hazardous reagents, we began the preparation of this right fragment with ketone 18 ($3.35/mol, Sigma Al-
drich). This ketone was first converted to the TMS ether 19 using TMSCl and NaI in ~90% yield in a 130-gram
quantity in sufficient purity to be used without purification for the next step. This material could be purified by
distillation for long term storage. The yield suffered when less NaI was used. Although most Lewis acids (e.g.,
BF3•OEt2) failed to catalyze the Mukaiyama-type aldol condensation between 19 and acrolein, Kobayashi's
method43 afforded 64 grams of alcohol 20 (75% yield). Notably, we were able to reduce the amount of
Yb(OTf)3•6H2O ($12/mmol, Sigma-Aldrich) from 10 mol% as suggested in the original literature43 to 0.08 mol%
without sacrificing the yield. Regioselective b-elimination using Piv2O and NaOAc gave enone 21 in 77% yield
(Route A; cost: $44/mmol of 21, Sigma Aldrich). Intermediate 21 was also synthesized via a Wittig reaction from
ylide 25 in 24% yield (Route B; cost $57/mmol of 21, Sigma-Aldrich). The low yield was presumably due to the
stabilized nature of the ylide 25, as shown in structure 25a.44 Although the Wittig reaction was not efficient, the
ylide 25 could be synthesized from inexpensive reagents and required only extractions to purify.
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A: Aldol approach
OH
O
a
b
c
d
e
4
5
6
7
8
9
O
OH
TMSO
OTMS
O
OH
OH OH
OH OH
23
O
20
OH
18
19
24
21
rac-22
i
see text
Br
O
PPh3
g
f
h
10
11
12
13
14
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OH
O
OH
O
25
O
B: Wittig approach
O
OH
27
Ph3P
j
Nu
OH
25a
O
O
O
O
P
O
k
O
O
Li
OH
O
HO
HO
O
O
26
29
28
Nu
C: Final Coupling
O
O
N
O
O
O
N
O
O
l
O
O
+
29
O
O
N
H
HO
N
H
O
14
meayamycin B
Scheme 3. A: a) TMSCl (2.5 equiv), Et3N (3.0 equiv), NaI (2.3 equiv), MeCN, 23 °C, 4 h, 90%.; b) acrolein (2.0
equiv), Yb(OTf)3•6H2O (0.08 mol %), toluene/water/EtOH (4:10:1), 23 °C, 3 d, 70%; c) Piv2O (1.0 equiv), NaOAc
(0.3 equiv), DCE, 60 °C, 24 h, 70%; d) NaBH4 (1.5 equiv), MeOH, 0 °C, 1 h, 95%.; e) (+)-diisopropyl tartrate
(8.0 mol %), Ti(OiPr)4 (6.0 mol %), TBHP (1.9 equiv), DCM, -20 °C, 12 h, 38%. B: f) Br2 (1 equiv), MeOH, 0 °C
to 23 °C, 3 h, 99%; g) PPh3 (1.05 equiv), toluene, 23 °C, 7 h; then aqueous NaOH, 64%; h) acrolein (2.0 equiv),
DCM, reflux, 24 h, 28%; i) tetrapropylammonium perruthenate (6.0 mol %), 4-methylmorpholine N-oxide (3.0
equiv), DCM, 23 °C, 2 h; j) camphorsulfonic acid (1.1 equiv), DCM, 23 °C, 6 h, 70% (2 steps); k) CH2Br2 (1.2
n
equiv), BuLi (2.2 equiv), THF, -78®23 °C, 6 h, 73%. C: l) nitro-Grela catalyst (2 mol%), DCE, 40 °C, 52 h,
20%.
Our attempts to enantioselectively convert enone 21 to epoxyketone 27 in one step were unsuccessful.
For example, La-BINOL-Ph3As-based45 enantioselective epoxidation required as much as 30 mol% of (R)-BINOL
ligand to form the epoxyketone in 30% yield and 70% ee. The cinchona alkaloid-catalyzed asymmetric Darzens
condensation46 did not provide the desired product even after protecting the tertiary hydroxy group as a TMS or
THP ether, presumably due to the 1,3-conjugated diene system. Kinetic resolution of racemic epoxy alcohols by
an intramolecular epoxide opening catalyzed by [CoIII(salen)] complex,47,48 have been used successfully for the
preparation of chiral pyrans by others. However, this method failed to convert racemic epoxide 27 to the enantio-
enriched ketone 28. These failures prompted us to explore a new area of chiral Brønsted acid catalyzed reactions.49,
50 After preparation and silica gel chromatography purification of (R)-BINOL phosphoric acid, epoxide 27 was
converted to ketone 28 in 32% yield with an ee of >90%. However, this transformation was not reproducible, as
different batches of chiral phosphoric acid produced different results. The poor reproducibility may stem from
metal impurities.51 After further investigation, the most promising outcome was 43% ee with a mixture of MgCl2
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and 26 (1:2) (Scheme 3), though extensive efforts to improve upon this enantioselectivity failed. We also explored
enzymatic kinetic resolution of secondary alcohols 28 and 29 using lipases Aand B and vinyl acetate, to no avail.52
In light of these failed attempts and non-reproducible data, a longer but reproducible and scalable ap-
proach was pursued: the reduction of enone 21 and subsequent Sharpless kinetic resolution of alcohol 22 afforded
epoxyalcohol 2353 in 90% ee and 36% yield. This epoxyalcohol was oxidized54 to form epoxyketone 27 in ~23%
yield over 3 steps. This ketone underwent facile anti-Baldwin/Nicolaou-type cyclization under acidic conditions55
to form cyclic ketone 28 in 77% yield. The ketone was subjected to nucleophilic attack through the putative bi-
dentate chelation model to provide the right fragment 29 in 73% yield as a single diastereomer. This fragment was
coupled with the left fragment 14 to afford meayamycin B in 20% yield on the average (Scheme 3C; also see the
previous work38).
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Due to the low yield and difficulty with scaling the Sharpless kinetic resolution of alcohol 22 we turned
our attention to the reduction of the prochiral enone 21 to the enantioenriched allylic alcohol (S)-22 (Scheme 4).
Despite advances in the field of enantioselective reduction of carbonyls, our efforts to synthesize (S)-22 resulted
in unsatisfactory enantioselectivities; for example, the Corey-Bakshi-Shibata reduction56 produced (S)-22 with
45:55 er (56% yield). Neither the Noyori asymmetric reduction57 nor the Brown asymmetric reduction58 provided
the desired product. These failures prompted us to develop a new enantioselective reduction of 21. Diastereose-
lective reduction of chiral β–hydroxyketones have been reported by Shapiro59 and Evans.60 On the basis of these
works, we asked whether the β-hydroxy functionality of 21 could be exploited to induce enantioselectivity to
afford (S)-22. Recent studies61 have indicated that under mild basic conditions, boric acid can chelate 1,2-diols.
Thus, we hypothesized that under similar reaction conditions, 21 could form a mixed borate ester 30 (Scheme 4)
with a chiral bidentate ligand, which would be reduced in a one-pot procedure to obtain the enantioenriched diol
(S)-22.
Scheme 4. Hypothesis for enantioselective reduction of prochiral ketone.
With this admittedly vague hypothesis, several chiral compounds were evaluated as potential ligands (Ta-
ble 1). While L1–L4 were discouraging for this transformation (Entries 1–5), the use of axially chiral ligand L5
with NaBH4 produced (S)-22 in 84% yield with 12:88 er (Entry 6). With 50 mol% of the ligand, the er was
essentially the same (Entry 7). With lower loading of the ligand, the er values gradually decreased (Entries 8–11).
This trend may be attributed to the competing background racemic reduction of ketone 21 with NaBH4. Although
a stoichiometric amount of L5 was optimal, we did not find this to be a setback because the ligand could be readily
recycled with ~90% recovery (see Supporting Information for detail).
Encouraged by the result with the B(OH)3-L5-NaBH4 system, we wished to investigate the bulkier BINOL
derivatives L6 and L7, which did not induce any appreciable enantioselectivity (Entries 12 and 13). This may be
because the added steric bulk hindered the formation of the mixed borate ester with the substrate. Similar axially
chiral reducing agents BINAL-H with stoichiometric amounts of the chiral ligand gave good enantioselectivity
with ketones in the literature,62 but this method did not reduce ketone 21 the desired alcohol. The procedure was
streamlined by eliminating B(OH)3 from the reaction conditions; simply premixing L5 and NaBH4 in MeCN for
1 h at 23 °C, followed by reduction at -78 to 4 °C over 12 h led to (S)-22 with 2:98 er (Entry 14). Furthermore,
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we were able to reduce the amount of (R)-BINOL to 20 mol % without sacrificing the er (Entry 15). Thus, the
optimal ligand was determined to be L5 for the enantioselective reduction of ketone 21.
5
6
7
Table 1. Screening of chiral ligands to induce enantioselectivity.
8
9
10
11
12
13
14
15
16
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18
19
20
21
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Entry
Ligand (L*)
Amount
(equiv)
Yield (%)*
e.r. #
1
2
3
4
5
6
7
–
–
1
85
80
76
68
71
83
84
50:50
50:50
45:55
50:50
50:50
12:88
13:87
L1
L2
L3
L4
L5
L5
1
1
1
1
0.5
8
L5
0.2
84
17:83
20:80
32:68
40:60
55:45
52:48
2:98
9
L5
L5
L5
L6
L7
L5
L5
0.1
0.05
0.025
0.2
79
81
83
70
73
58
79
10
11
12
13
0.2
14**
15**
0.5
0.2
7:93
Reaction conditions: (a) B(OH)3, NaHCO3, L5 (1:1:1), THF, NaBH4, 23 °C, 1 h; then 21 (1 equiv), THF, -78 to 4 °C, 12 h.
*Isolated yield. #(R)-22: (S)-22
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** Reaction was performed in MeCN instead of THF without B(OH)3. See Supporting Information for details.
3
4
5
6
7
8
To probe the generality of this enantioselective reduction, we treated prochiral ketone with the premixed
solution of L5 (0.2 equiv) and NaBH4 (0.3 equiv) but the racemate was obtained (Table 2, Entry 1). Thus, we
revisited our previous strategy to form the hypothesized intermediate 30 indicated in Scheme 4. Here, we at-
tempted to form this intermediate by using stoichiometric amounts of L5 and BH3. With these modified conditions,
prochiral ketones 31–35 were subjected to the 1:1 BH3/L5 mixture in THF for 1 h at 23 °C and the resulting
mixture was cooled to -78 °C and exposed to NaBH4 (0.3-0.4 equiv) to obtain alcohol 36–40 (Table 2). Lower
loading of BH3 and L5 resulted in lower enantioselectivities (Entries 2 and 3). Although 1 equiv of L5 was nec-
essary to achieve high enantioselectivity, L5 could be recovered by filtration and recrystallization. Though high
enantioselectivities could not be obtained with substrates without a hydroxy group (Entries 8-10), a- or b-hy-
droxyketones resulted in high enantioselectivites (Entries 2, 4, 5). Greater amounts of NaBH4 eroded the enanti-
oselectivity (Entry 6 vs 7), probably due to a background racemic reduction to a greater degree. To render the
method catalytic, we tested addition of stoichiometric amount of a sacrificial alcohol (e.g., tBuOH, iPrOH), to no
avail. To slow the background racemic reduction, we investigated milder reducing agents such as NaBH3CN and
iPrOH under various conditions, again to no avail. Due to the lower cost of BINOL ($0.17 per mmol, VWR)
compared to other commercially available catalytic reducing agents, this stoichiometric method may offer an in-
expensive alternative to CBS or Noyori reduction for a- or b-hydroxyketones.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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29
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36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Enantioselective reduction of ketones
BH3•THF/L5
O
OH
R'
NaBH4
R
R'
R
31–35
36–40
Br
O
O
O
OH
Ph
Ph
OH
31
32
33
O
O
Ph
Cl
Ph
35
34
Entry Ketone L5
(equiv)
0.2
NaBH4 Yield
(equiv) (%)*
e.r.
1b
2
3
4
5
6
7
8
9
31
31
31
21
32
32
32
33
34
0.3
0.4
0.4
0.4
0.4
0.3
1.2
0.3
0.3
77
69
76
72a
71
78
88
45
49
50:50
7:93
1
0.5
1
21:79
2:98
1
4:96
0.5
0.5
1
12:88
35:65
49:51
41:59
1
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1
2
10
35
1
0.3
40
47:53
3
4
5
Reaction conditions: (a) BH3•THF, L5 (1:1), THF, 1 h; then ketone, THF, NaBH4, -78 to 24 °C, 12 h.
*Yield based on the 1H NMR analyses of crude material.
6
7
a isolated yield. b premixed NaBH4 and L5 method
8
9
1
11
To study the mechanism, we analyzed the premixed solution of L5 and NaBH4 by H and B NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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28
29
30
31
32
33
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35
36
37
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44
45
46
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49
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60
1
spectroscopy. The H NMR spectrum suggested a mixture of symmetric and asymmetric species, likely B1
(Scheme 5), when a substoichiometric amount of NaBH4 was present (Spectrum 24, Supporting Information). We
believe the small amount of the symmetric species is L5. Three boron species (d-20, 5.6, and 9.1 ppm) were
observed (Spectrum 25, Supporting Information). Heating the reaction mixture to 130 °C did not lead to cycliza-
tion to form B2 (Spectra 26 and 27, Supporting Information). When additional 1.7 equivalents of NaBH4 was
present (i.e., 2.5 equivalents of NaBH4), a single boron species (d -19 ppm, q, J = 92.8 Hz) was observed in the
11B NMR spectrum besides NaBH4 (Spectrum 28, Supporting Information). Moreover, only a symmetric species
was observed by H NMR (Spectrum 29, Supporting Information). We propose that L5 reacted with the sub-
stoichiometric amount of NaBH4 to form asymmetric B1 which then reacts with additional NaBH4 to form B3
(Scheme 5).
1
1
We were unable to obtain H NMR spectrum of a mixture of L5 and BH3•THF due to its poor stability
13
when exposed to the air to remove THF. Furthermore, C NMR spectra were not obtained because the mixure
was not stable over prolonged time necessary to obtain 13C NMR. We propose that B4 may be formed when L5
and BH3•THF (1:1) are mixed.
NaBH4
NaBH4
OH
OH
OBH3Na
OH
OBH3Na
OBH3Na
0.8 equiv
1.7 equiv
L5
B1
B3
heat
BH3
O
O
BH
BH2Na
O
O
B4
B2
Scheme 5. Observed species generated in THF.
We then carried out the subsequent epoxidation of (S)-22 with mCPBA and found that epoxide 23 was
obtained as a single diastereomer in 57% yield. The result may be rationalized by the proposed model by Sharpless,
in which the O-C—C=C dihedral angle is estimated to be ~120°.63 Based on this model, the allylic hydroxy group
directs the peracid-mediated oxidation to furnish 23 (Scheme 6). The stereochemical outcome of this epoxidation
is consistent with the transition state TSmajor; the 1,3-allylic strain64 in transition state TSminor disfavors the for-
mation of the alternative diastereomer 41. This improved route bypassed the low yielding Sharpless kinetic reso-
lution strategy.
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2
3
4
5
6
7
R
H
O
R
Ar
H
H
Et
H
O
O
O
HO
HO
O
Et
H
H
H
H
O
Ar
1.3-allylic strain
TSmajor
TSminor
8
OH
9
R=
OH
OH
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
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29
30
31
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34
35
36
37
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41
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45
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49
50
51
52
53
54
55
56
57
58
59
60
O
Cl
O
R
R
Ar=
23
41
Scheme 6. Rationale for observed diastereoselectivity.
In conclusion, the use of phosphonate 2 shortened the synthetic scheme for 8 by 3 steps, excluding the
preparation of this phosphonate. The overall yield from 1 to 5 is higher (63%) than that of the previous scheme
(45%). Importantly, the new scheme for the right fragment 29 exploited a new enantioselective reduction of enone
21 to allylic alcohol (S)-22 involving inexpensive and recyclable reagent L5. The present synthesis is more concise
(current and previous schemes: $204/mmol and $753/mmol for the right fragment 29, respectively) and requires
less hazardous reagents. With this improvement, better access to the left-hand and right-hand fragments allows
meayamycin B35 to be synthesized in 11 steps in the longest linear sequence and 24 total steps. The overall yield
of meayamycin B was 0.82% and 0.24% from commercially available starting materials 21 and 1, respectively.
Experimental Section
General Information and Reagents. All reactions were carried out with freshly distilled solvents under anhy-
drous conditions, unless otherwise noted. All of the flasks used for carrying out reactions were dried in an oven
at 80 °C prior to use. Unless otherwise stated, all reactions that required heating used an oil bath as the heating
source with a thermometer submerged in the bath to monitor temperature. Unless specifically stated, the temper-
ature of a water bath during the evaporation of organic solvents using a rotary evaporator was about 35±5 °C. All
of the syringes in this study were dried in an oven at 80 °C and stored in a desiccator over Drierite®. Tetrahydro-
furan (THF) was distilled over Na metal and benzophenone. Dichloromethane (DCM) was distilled over calcium
hydride. Acetonitrile was distilled over calcium hydride and stored over 3Å molecular sieves. Yields refer to
chromatographically and spectroscopically (1H NMR) homogenous materials, unless otherwise stated. All reac-
tions were monitored by thin-layer chromatography (TLC) carried out on 0.25-mm Merck silica gel plates (60F-
254) using UV light (254 nm) for visualization or anisaldehyde in ethanol or 0.2% ninhydrin in ethanol, or 2.4%
phosphomolybdic acid/1.4% phosphoric acid/5% sulfuric acid w/v in water as developing agents and heat for
visualization. Silica gel (230–400 mesh) was used for flash column chromatography. A rotary evaporator was
connected to a water aspirator that produced a vacuum pressure of approximately 60 mmHg when it was connected
to the evaporator. NMR spectra were recorded on a Bruker Advance spectrometer at 300 MHz, 400 MHz, 500
MHz, 600 MHz or 700 MHz. The chemical shifts are given in parts per million (ppm) on a delta (δ) scale. The
solvent peak was used as a reference value, for 1H NMR: CHCl3 = 7.27 ppm, CH3OH = 3.31 ppm, DMSO = 2.50
ppm, acetone = 2.05 ppm, for 13C{1H} NMR: CDCl3 = 77.00 ppm, CD3OD = 49.00 ppm, DMSO-d6 = 49.10 ppm,
and acetone-d6 = 29.40 ppm. The following abbreviations are used to indicate the multiplicities: s = singlet; d =
doublet; t = triplet; q = quartet; m = multiplet; br = broad. High-resolution mass spectra were recorded on a VG
7070 spectrometer or Micromass QTOF instrument. Low-resolution mass spectra [LCMS (ESI)] were recorded
on a Shimadzu LCMS-2020. Infrared (IR) spectra were collected on a Mattson Cygnus 100 spectrometer. Samples
for acquiring IR spectra were prepared as a thin film on a NaCl plate by dissolving the compound in DCM and
then evaporating the DCM.
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3-(tert-butyl) 4-methyl (4S,5R)-2,2,5-trimethyloxazolidine-3,4-dicarboxylate (1)
4
5
6
Refer to the paper9 for synthesis and spectroscopic data.
7
8
9
tert-butyl
ylate (2)
(4R,5R)-4-((Z)-3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)-2,2,5-trimethyloxazolidine-3-carbox-
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DIBALH (1.0 M in hexanes, 87.0 mL) was added to a stirred solution of 1 (22.10 g, 49.10 mmol) in DCM (100
mL) at -78 °C dropwise via a syringe under a nitrogen atmosphere over 1 h. After the addition, the mixture was
stirred at the same temperature for 3 h (Flask A). A stirred solution of 3 (12.30 g, 49.60 mmol) in THF (Flask B)
at 0 °C was treated with KOtBu (5.06 g, 45.1 mmol) under a nitrogen atmosphere. After 20 min at the same
temperature, the mixture was transferred to the solution of Garner’s aldehyde (Flask A) at -78 °C by cannula. The
resulting mixture was slowly warmed to 25 °C and stirred at this temperature for 45 h. The reaction mixture was
quenched with aqueous potassium sodium tartrate (1M, 200 mL) at room temperature. The mixture was stirred
for 30 min at room temperature and extracted with EtOAc (3 ´ 250 mL). The combined organic layers were
washed with brine (50 mL), dried over Na2SO4, filtered through a cotton plug, and concentrated in vacuo. The
residue was purified by flash chromatography (2®8% EtOAc in hexanes) on silica gel (400 mL) to afford the
ester 2 (11.80 g, 80% yield) as a colorless oil. Data for ester 2: Rf = 0.48 (20% EtOAc in hexanes); [a]D24 +47.6
(c 1.0, CHCl3); IR (neat): nmax = 3421, 2980, 2933, 1786 (C=O), 1701 (C=O), 1454, 1378, 1306, 1255, 1221, 1177,
1133, 1087, 1027 cm-1; 1H NMR (400 MHz, 348K, C6D6): d = 5.67 (d, 1H, J = 6.6 Hz), 5.08 (app t, 1H, J = 7.8
Hz), 3.99 (q, 2H, J = 7.2 Hz), 3.83 (qd, 1H, J = 7.8, 6.6 Hz), 1.86 (s, 3H), 1.75 (s, 3H), 1.63 (s, 3H), 1.40 (s, 9H),
1.40–1.38 (m, 3H), 0.97 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (100 MHz, 348K, C6D6): d = 167.5, 152.7, 143.2,
95.1, 79.6, 76.4, 62.7, 60.9, 29.0, 27.5, 26.5, 21.2, 19.2, 14.8 ppm; HRMS (ESI-TOF) m/z: [(M-Boc+H)+H]+
Calcd for C12H22NO3 228.1600; found 228.1603.
tert-butyl ((2R,3R)-2,5-dimethyl-6-oxo-3,6-dihydro-2H-pyran-3-yl)carbamate (4)
A solution of ester 2 (8.80 g, 26.9 mmol) in AcOH (125 mL) was heated to 80 ºC under air atmosphere. The
mixture was stirred at the same temperature for 25 h. The solvent was removed in vacuo, and the residue was
purified by flash chromatography (5®40% EtOAc in hexanes) on silica gel (300 mL) to afford the unsaturated
lactone 4 (5.00 g, 77% yield) as a white solid. Spectroscopic data for unsaturated-lactone 4 matched that in the
previous literature.8
tert-butyl ((2R,3R,5S)-2,5-dimethyl-6-oxotetrahydro-2H-pyran-3-yl)carbamate (5)
Refer to the paper8 for synthesis and spectroscopic data.
tert-butyl ((2R,3R,5S)-6-allyl-6-hydroxy-2,5-dimethyltetrahydro-2H-pyran-3-yl)carbamate (S18)
Refer to the paper8 for synthesis and spectroscopic data.
tert-butyl ((2R,3R,5S,6S)-6-allyl-2,5-dimethyltetrahydro-2H-pyran-3-yl)carbamate (6)
Refer to the paper8 for synthesis and spectroscopic data.
(2R,3R,5S,6S)-6-allyl-2,5-dimethyltetrahydro-2H-pyran-3-amine (7)
Refer to the paper8 for synthesis and spectroscopic data.
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(S)-1-ethoxy-1-oxopropan-2-yl morpholine-4-carboxylate (9)
3
4
5
6
7
8
9
Refer to the paper for synthesis and spectroscopic data.38
(S,Z)-5-ethoxy-5-oxopent-3-en-2-yl morpholine-4-carboxylate (10)
Refer to the paper for synthesis and spectroscopic data.38
(S,Z)-4-((morpholine-4-carbonyl)oxy)pent-2-enoic acid (11)
Refer to the paper for synthesis and spectroscopic data.38
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(S,Z)-5-(((2R,3R,5S,6S)-6-allyl-2,5-dimethyltetrahydro-2H-pyran-3-yl)amino)-5-oxopent-3-en-2-yl mor-
pholine-4-carboxylate (12)
An oven-dried, 50-mL, single-necked, round-bottomed flask equipped with a Teflon-coated magnetic stir bar, a
rubber septum and a nitrogen inlet was charged with amine 7 (2.22 mmol), CH2Cl2 (5 mL), and O-(7-azabenzotri-
azol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (844 mg, 2.22 mmol), followed by N, N′- diiso-
propylethylamine (1.15 mL, 6.66 mmol) via a syringe. The resulting mixture was stirred at 23 °C for 5 min and
then a solution of carboxylic acid 11 (2.22 mol) in CH2Cl2 (2 mL) was added dropwise. The resulting pale-yellow
solution was stirred 23 °C for 20 h. Saturated aqueous ammonium chloride (10 mL) was added, and the mixture
was extracted with CH2Cl2 (3 ´ 10 mL). The combined organic layers were washed with brine (20 mL), dried over
anhydrous Na2SO4, filtered through a cotton plug, and concentrated in vacuo. The crude residue was purified by
flash chromatography (30®55% EtOAc in hexanes) on silica gel (70 mL) to afford the amide 12 (421 mg, 50%
yield) as a colorless oil. Data for amide 12: Rf = 0.48 (80% EtOAc in hexanes); [α]D17 -24.8 (c 1.0, MeOH); IR
(film): 3419, 3072, 2931, 1687 (C=O), 1658 (C=O), 1523, 1437, 1373, 1332, 1278, 1246, 1116 cm–1; H NMR
1
(400 MHz, 293 K, CDCl3) δ 6.19–6.09 (m, 1H), 5.92 (dd, 1H, J = 11.6, 7.8 Hz), 5.84–5.74 (m, 1H), 5.69 (dd, 1H,
J = 11.6, 1.2 Hz), 5.11 (dd, 1H, J = 17.2, 1.6 Hz), 5.05 (dd, 1H, J = 10.2, 0.8 Hz), 3.98–3.92 (m, 1H), 3.69–3.64
(m, 5H), 3.53 (dt, 1H, J = 7.1, 2.7 Hz), 3.46 (t, 4H, J = 5.1 Hz), 2.37–2.30 (m, 1H), 2.16–2.09 (m, 1H), 1.96–1.94
(m, 2H), 1.79–1.75 (m, 1H), 1.41 (d, 3H, J = 6.5 Hz), 1.15 (d, 3H, J = 6.5 Hz), 1.02 (d, 3H, J = 7.3 Hz) ;13C{1H}
NMR (100 MHz, 293 K, CDCl3) δ 165.0, 155.0, 144.5, 134.9, 122.3, 116.9, 80.8, 77.4, 76.1, 70.3, 66.7, 47.1,
37.5, 36.0, 29.0, 20.3, 18.0, 15.1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd. for C20H32N2O5Na 403.2209; Found
403.2220.
(S,Z)-5-(((2R,3R,5S,6S)-2,5-dimethyl-6-((E)-3-methyl-4-oxobut-2-en-1-yl)tetrahydro-2H-pyran-3-
yl)amino)-5-oxopent-3-en-2-yl morpholine-4-carboxylate (13)
A 10-mL, single-necked, round-bottomed flask equipped with a Teflon-coated magnetic stir bar, a nitrogen inlet
and a rubber septum was charged with amide 12 (270 mg, 0.95 mmol), methacrolein (1.20 mL, 14.0 mmol) and
nitro-Grela Grubbs catalyst (6.3 mg, 9.4 µmol). The resulting mixture was stirred at 45 °C for 22 h, and additional
nitro-Grela Grubbs catalyst (6.3 mg, 9.4 µmol) was added. The stirring was continued for 13 h and the mixture
was concentrated in vacuo. The residue was purified by flash chromatography (30®80% EtOAc in hexanes) on
silica gel (15 mL) to afford the aldehyde 13 (185 mg, 60%) as a colorless oil. Data for aldehyde 13: Rf = 0.27
(80% EtOAc in hexanes); [α]D 17 -9.9 (c 1.0, DCM); IR (film): nmax = 3354, 2969, 2925, 2857, 2717, 1687 (br,
unresolved, C=O), 1518, 1426, 1301, 1276, 1242, 1118, 1071, 1023 cm–1; 1H NMR (400 MHz, 293 K, CDCl3) δ
9.41 (s, 1H), 6.56 (app t, J = 6.8 Hz, 1H), 6.38 (d, J = 8.8 Hz, 1H), 6.14 (dq, J =13.6, 6.8 Hz, 1H), 5.94 (dd, J =
11.6, 8.0 Hz, 1H), 5.74 (d, J = 11.6 Hz, 1H), 3.95–3.92 (m, 1H), 3.70–3.64 (m, 6H, 11,15-H), 3.47–3.34 (m, 4H),
2.60–2.52 (m, 1H) 2.43–2.36 (m, 1H), 1.81–1.77 (m, 1H), 1.75 (s, 3H), 1.63–1.56 (m, 2H), 1.41 (d, J = 6.5 Hz,
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The Journal of Organic Chemistry
3H), 1.16 (d, J = 6.5 Hz, 3H), 1.07 (d, J = 7.5 Hz, 3H) ;13C{1H} NMR (100 MHz, 293 K, CDCl3) δ 195.0, 165.1,
154.9, 150.5, 143.9, 140.6, 122.4, 79.7, 76.1, 70.1, 66.6, 46.8, 35.8, 32.8, 31.6, 20.2, 17.7, 15.1, 9.5; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd. for C22H35N2O6 423.2495; Found 423.2484.
4
5
6
7
8
(S,Z)-5-(((2R,3R,5S,6S)-2,5-dimethyl-6-((E)-3-methylpenta-2,4-dien-1-yl)tetrahydro-2H-pyran-3-
yl)amino)-5-oxopent-3-en-2-yl morpholine-4-carboxylate (14)
9
An oven-dried, 50-mL, single-necked, round-bottomed flask equipped with a Teflon-coated magnetic stir bar, a
rubber septum and a nitrogen inlet was charged with methyltriphenylphosphonium bromide (803 mg, 2.25 mmol)
and THF (8.0 mL). The solution was cooled in an ice-water bath, and a solution of KOtBu in THF (1M, 1.90 mL,
1.90 mmol) was added via a syringe. The mixture was stirred for 10 min at the same temperature. A solution of
aldehyde 13 (183 mg, 0.57 mmol) in THF (7.0 mL) was added to the mixture via cannula, and the stirring was
continued for 30 min. After 30 min H2O (5.0 mL) was added and the mixture was concentrated in vacuo. After
removal of THF, the mixture was extracted with EtOAc (3 ´ 20 mL). The combined organic layers were washed
with brine (20 mL), dried over anhydrous Na2SO4, filtered through a cotton plug, and concentrated in vacuo. The
crude residue was purified by flash chromatography (10®50% EtOAc in hexanes) on silica gel (20 mL) to afford
the diene 14 (124 mg, 69% yield) as a colorless oil. Spectroscopic data for diene 14 matched that in the previous
literature.38
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2,2,4,4,8,8-hexamethyl-6-methylene-3,7-dioxa-2,8-disilanonane (19)
A 2-L round-bottomed flask equipped with a Teflon-coated magnetic stir bar containing ketone 18 (25.2 mL,
203.50 mmol) was purged with argon. Et3N (85.0 mL, 612 mmol) and TMSCl (65.0 mL, 510 mmol) were added
to the flask at 23 °C and the mixture was stirred at the same temperature for 30 min. A solution of NaI (66.801 g,
448 mmol; dried overnight under high vacuum in a 140 °C sand bath) in dry MeCN (500 mL; dried over 4Å
molecular sieves overnight) was added to the reaction mixture over 1 h at the same temperature. The mixture was
stirred for an additional 3.5 h, then diluted with ice-cold H2O (1.5 L). The mixture was extracted with EtOAc (3
× 250 mL). The combined organic layers were dried over Na2SO4, filtered through a cotton plug, and concentrated
in vacuo. The resulting crude residue of enol ether 19 (53.002 g, quantitative yield) was >90% pure by 1H NMR
spectroscopic analysis and used after the crude material was passed through a plug of neutral aluminum with 90
% EtOAc in hexanes before the next step. Data for enol ether 19: IR (film): nmax = 2961, 1620, 1321, 1251, 1042
cm-1; 1H NMR (400 MHz, CDCl3, 293 K): δ 4.07 (br s, 1H), 4.05 (br s, 1H), 2.19 (s, 2H), 1.26 (s, 6H), 0.19 (s,
9H), 0.10 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3, 293 K): δ 157.1, 92.9, 73.9, 51.9, 30.1, 2.8, 0.17; HRMS of
19 was not obtainable.
2,6-dihydroxy-2-methyloct-7-en-4-one (20)
Toluene (13.4 mL) and acrolein (5.0 mL, 75 mmol) were added to a 250-mL round-bottomed flask equipped with
a Teflon-coated magnetic stir bar containing 19 (13.030 g, 50.00 mmol). The flask was cooled on an ice-water
bath (0 °C external temperature), then a solution of Yb(OTf)3•6H2O (25.0 mg, 40.3 μmol) in H2O/EtOH (1:10 v/v,
36.6 mL) was added. The mixture was stirred at room temperature for 3 d and then concentrated in vacuo. The
crude residue was purified by flash chromatography (10®60% EtOAc in hexanes) on silica gel (1.5 L) to afford
hydroxy ketone 20 as a colorless oil (6.031 g, 70% yield). Data for hydroxy ketone 20: Rf = 0.18 (40% EtOAc in
hexanes); IR (film): nmax = 3410 (br O-H), 2974, 2932, 1701 (C=O), 1378, 1144 cm-1; 1H NMR (400 MHz, 1%
CD3OD in CDCl3, 293 K): δ 5.91 (ddd, J = 16.4, 10.4, 5.6 Hz, 1H), 5.33 (dt, J = 17.2, 2.4 Hz, 1H), 5.17 (dt, J =
10.4, 2.0 Hz, 1H), 4.62-4.57 (m, 1H), 2.67–2.66 (m, 4H), 1.27 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, 293 K):
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δ 212.3, 139.2, 115.2, 69.9, 68.6, 54.4, 50.7, 29.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C9H17O3 173.1178;
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Found 173.1184.
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1-bromo-4-hydroxy-4-methylpentan-2-one (24)
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Ketone 18 (10.01 g, 86.10 mmol) in MeOH (60.0 mL) was added to a 250-mL round-bottomed flask equipped
with a Teflon-coated magnetic stir bar, and the stirred solution was cooled to 0 °C. To the mixture was added Br2
(4.40 mL, 86.10 mmol) dropwise using a syringe, and the resultant mixture was slowly warmed to 23 °C over 3
h. The mixture was poured into H2O (200 mL) and extracted with DCM (50 mL × 4). The combined organic layers
were dried over Na2SO4, filtered through a cotton plug, and concentrated in vacuo to afford bromoketone 24 as a
pale-yellow oil (16.601 g, 99% yield). Data for bromo ketone 24: Rf = 0.57 (60% EtOAc in hexanes); IR (film):
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max = 3433 (br O-H), 2975, 2249, 1715 (C=O), 1465, 1382, 1173, 1057, 978, 911, 733 cm-1; 1H NMR (400 MHz,
1% CD3OD in CDCl3, 293 K): δ 3.91 (s, 2H), 2.83 (s, 2H), 1.28 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3, 293
K): δ 203.0, 70.0, 50.9, 35.4, 29.4; HRMS (ESI-TOF) m/z: [M-OH+H]+ Calcd. for C6H12BrO 179.0066; Found
178.9959.
4-hydroxy-4-methyl-1-(triphenyl-l5-phosphaneylidene)pentan-2-one (25)
A 250-mL round-bottomed flask equipped with a Teflon-coated magnetic stir bar was treated with bromoketone
24 (10.02 g, 51.31 mmol), benzene (80.0 mL), PPh3 (14.22 g, 53.86 mmol), and the resulting solution was stirred
at 23 °C for 7 h. The mixture was poured into H2O (1 L) and extracted with DCM (100 mL × 3). The aqueous
layer was treated with 4 M NaOH (15.0 mL, 60.0 mmol) and extracted with DCM (100 mL × 4). The combined
organic layers were dried over Na2SO4, filtered through a cotton plug, and concentrated in vacuo to afford crude
ylide 25. This ylide was washed with hexanes (100 mL × 3) until TLC analysis showed absence of PPh3 to obtain
ylide 25 as a yellowish white solid (12.302 g, 64% yield). Data for ylide 25: Rf = 0.24 (40% EtOAc in hexanes);
IR (film): nmax = 3266 (br O-H), 3057, 2967, 1675 (C=O), 1528, 1437, 1404, 1282, 1106, 998 cm-1; 1H NMR (300
MHz, 1% CD3OD in CDCl3, 293 K): δ 7.67–7.43 (m, 15H), 3.80–3.71 (d, J = 25.6 Hz, 1H), 2.43 (s, 2H), 1.24 (s,
6H); 13C{1H} NMR (100 MHz, CDCl3, 293 K): δ 192.8, 133.1 (d, J = 10.0 Hz), 132.4 (d, J = 2.5 Hz), 129.0 (d, J
= 11.3 Hz), 126.1 (d, J = 90.0 Hz), 70.2, 55.1 (d, J = 103.8 Hz), 50.3 (d, 13.8), 29.7; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd. for C24H26O2P 377.1665; Found 377.1675. m.p.: 184.5–185.2 °C.
(E)-2-hydroxy-2-methylocta-5,7-dien-4-one (21)
(Method A): To a 250-mL round-bottomed flask equipped with a Teflon-coated magnetic stir bar and a reflux
condenser was added ylide 25 (12.320 g, 32.75 mmol), DCM (105 mL) at 23 °C, to which acrolein (4.3 mL, 64
mmol) was added dropwise. The mixture was refluxed at 40 °C for 24 h, and then concentrated in vacuo. The
resulting crude residue was purified by flash chromatography (10®50% EtOAc in hexanes) on silica gel (200
mL) to afford enone 21 as a pale-yellow oil (1.41 g, 28% yield).
(Method B): A 1-L round-bottomed flask equipped with a Teflon-coated magnetic stir bar was treated with hy-
droxy ketone 20 (24.292 g, 141.07 mmol), DCE (40 mL), Ac2O (13.35 mL, 141.1 mmol) and NaOAc (3.472 g,
42.33 mmol). The mixture was stirred in a 60 °C oil bath for 24 h. The mixture was cooled to 23 °C, then diluted
with EtOAc (250 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic layer was separated,
dried over Na2SO4, filtered through a cotton plug, and concentrated in vacuo. The crude residue was purified by
flash chromatography (10®50% EtOAc in hexanes) on silica gel (1 L) to afford enone 21 as a pale-yellow oil
(15.238 g, 70% yield).
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(Method C): A 25-mL round-bottomed flask equipped with a Teflon-coated magnetic stir bar was treated with
hydroxy ketone 20 (110 mg, 0.60 mmol), DCE (1.0 mL), Piv2O (0.14 mL, 0.70 mmol) and NaOAc (25.1 mg, 0.30
mmol). The mixture was stirred in a 60 °C oil bath for 24 h. The mixture was cooled to 23 °C, then diluted with
DCM (5.0 mL) and saturated aqueous sodium bicarbonate (5.0 mL). The organic layer was separated, dried over
Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (10®50%
EtOAc in hexanes) on silica gel (10 mL) to afford enone 21 as a pale-yellow oil (77.1 mg, 83% yield). Data for
enone 21: Rf = 0.33 (40% EtOAc in hexanes); IR (film): nmax = 3437 (br O-H), 2973, 1678 (C=O), 1204, 1110 cm-
1; 1H NMR (400 MHz, 1% CD3OD in CDCl3, 293 K): δ 7.18 (dd, J = 15.6 Hz, 10.8 Hz, 1H), 6.51 (dt, J = 17.2
10.8 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 5.72 (d, J = 17.2 Hz, 1H), 5.60 (d, J = 10.0 Hz, 1H), 2.75 (s, 2H), 1.27
(s, 6H); 13C{1H} NMR (100 MHz, CDCl3, 293 K): δ 202.0, 143.7, 135.1, 131.1, 127.5, 69.9, 50.7, 29.6; HRMS
(ESI-TOF) m/z: [M-CH3]+ Calcd. for C9H14O2 139.0759; Found 139.0756.
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(E)-2-methylocta-5,7-diene-2,4-diol (22)
A 250-mL round-bottomed flask equipped with a Teflon-coated magnetic stir bar was treated with enone 21
(2.40 g, 15.4 mmol) and MeOH (60 mL). The mixture was cooled to 0 °C and NaBH4 (1.16 g, 30.8 mmol) was
added over 15 min. The mixture was stirred at the same temperature for 30 min, then diluted with saturated
aqueous NH4Cl (50 mL). MeOH was removed in vacuo, then the resulting mixture was extracted with Et2O (3 ×
40 mL). The organic layer was washed with aqueous NH3 (5 mL x 2), brine (10 mL), dried over Na2SO4, filtered
through a cotton plug, and concentrated in vacuo. Allylic alcohol 22 was used directly in the next step (2.30 g,
95% yield). Data for allylic alcohol 22: Rf = 0.30 (40% EtOAc in hexanes); IR (film): nmax = 3369, 3088, 3040,
2973, 2935, 1654, 1605, 1467, 1380, 1326, 1253, 1153, 1058, 1004, 952, 908, 857, 768 cm-1; 1H NMR (400
MHz, 1% CD3OD in CDCl3, 293 K): δ 6.36-6.20 (m, 2H), 5.72 (dd, J = 14.8, 6.4 Hz, 1H), 5.21 (dd, J = 16.4,
2.0 Hz, 1H), 4.93 (dd, J = 10.0, 2.0 Hz, 1H), 4.57-4.52 (m, 1H), 1.78 (dd, J = 14.8, 10.8, 1H), 1.58 (dd, J = 14.8,
2.4, 1H), 1.33 (s, 3H), 1.26 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, 293 K): δ 136.5, 136.3, 130.5, 117.6,
71.6, 70.2, 47.8, 31.8, 27.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C9H17O2 157.1223; Found 157.1229.
Enantioselective reduction of (E)-2-hydroxy-2-methylocta-5,7-dien-4-one (21)
(Method A): A clean and dry 10-mL round-bottomed flask was treated with NaHCO3, H3BO3 and Ligand (L*)
(1:1:1) and stirred in 10:1 MeOH/water mixture (2 mL) at 23 °C. After 1 h, the mixture was concentrated in vacuo
and water was removed by adding MeOH (4 mL ´ 3) and concentrating under reduced pressure to obtain a white
solid, to which was added enone 21 (31 mg, 0.2 mmol) in 1 mL THF and stirred at 23 °C. After 1 h, the solution
was cooled to -78 °C and NaBH4 (2.3 mg, 0.06 mmol, 0.3 equiv) was added. The mixture was slowly warmed to
23 °C over 12 h and was quenched with saturated aqueous NH4Cl (1.0 mL), and THF was removed in vacuo. The
resulting mixture was extracted with Et2O (3 × 5 mL). The combined organic layers were washed with brine, conc.
NH3 and dried over Na2SO4, filtered through a cotton plug, and concentrated in vacuo. The crude residue was
purified by flash chromatography (5®30% EtOAc in hexanes) on silica gel (10 mL) to afford (S)-22 as a clear
oil. A solution of (S)-22 was prepared in 5% iPrOH in hexanes (1mg/mL). The enantiomeric ratio was determined
by chiral HPLC with (S,S)-Whelk-O 1 column [eluent: 5:95 iPrOH/hexanes; 1.0 mL/min flow rate, detection: 231
nm; tR 7.7min, tR 8.2 min. The results are summarized in Table 1.
(Method B): A clean and dry 10-mL round-bottomed flask was treated with (R)-1,1’-binaphthol (L5) (0.04 mmol,
20 mol%) and stirred with NaBH4 (0.5 equiv) in MeCN (2 mL) at 23 °C. After 1 h, the mixture was concentrated
in vacuo to obtain a white solid, which was resuspended in dry THF (1 mL) and cooled to -78 °C. This mixture
was treated with enone 21 (31 mg, 0.2 mmol) in THF (0.5 mL), and the resulting mixture was slowly warmed to
0 °C over 16 h. The mixture was quenched with saturated aqueous NH4Cl (1.0 mL), and THF was removed in
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vacuo. The resulting mixture was extracted with Et2O (3 × 5 mL). The combined organic layers were washed with
conc. NH3 (2 mL) to remove any B(OH)3, dried over Na2SO4, filtered through a cotton plug, and concentrated in
vacuo. The crude residue was purified by flash chromatography (5®30% EtOAc in hexanes) on silica gel (10
i
mL) to afford allylic alcohol (S)-22 as a clear oil. A solution of (S)-22 was prepared in 5% PrOH in hexanes
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(1mg/mL). The enantiomeric ratio was determined by chiral HPLC with (S,S)-Whelk-O 1 column [eluent: 5:95
iPrOH/hexanes; 1.0 mL/min flow rate, detection: 231 nm; tR 7.7min, tR 8.2 min. The results are summarized in
Table 1.
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(Method C): A 500-mL round-bottomed flask was treated with (R)-1,1’-binaphthol (L5) (18.9 g, 66 mmol, 1.0
equiv) and dry THF (120 mL) and cooled to 0 °C. 1 M BH3•THF in THF (66.0 mL, 1 equiv) was added to the
resulting solution dropwise over 20 min, and the mixture was stirred for 1 h at the same temperature. Enone 21
(66 mmol) in THF (120 mL) was added dropwise over 45 min at 0 °C. After an additional 1 h, the mixture was
cooled to -78 °C and treated with NaBH4 (832 mg, 0.3 equiv) in 4 portions over 2 h and allowed to warm to 23
°C over 12 h. The reaction mixture was then quenched with sat. NH4Cl (100 mL) at 0 °C and stirred for 30 min.
The mixture was concentrated in vacuo to remove THF, followed by vacuum filtration to remove a precipitated
white solid. The obtained white precipitate was recrystallized from hot hexanes to recover (R)-1,1’-binaphthol
(L5) (12.1 g, 42 mmol, 63% recovery). The aqueous layer was extracted with Et2O (2 × 100 mL). The combined
organic layers were washed with conc. NH3 (20 mL) to remove any B(OH)3, dried over Na2SO4, filtered through
a cotton plug, and concentrated in vacuo. The crude residue was purified by flash chromatography (5®30%
EtOAc in hexanes) on silica gel (400 mL) to afford alcohol (S)-22 (7.30 g, 71%) as clear oil. A solution of the
product was prepared in 5% iPrOH in hexanes (1mg/mL). The enantiomeric ratio was determined by chiral HPLC
with (S,S)-Whelk-O 1 column [For compound (S)-22: eluent: 5:95 iPrOH/hexanes; 1.0 mL/min flow rate, detec-
tion: 231 nm; tR 7.7min, tR 8.2 min.
Data for allylic alcohol (S)-22 [α]D 21 -3.5 (c 1.0, DCM).
(E)-5-hydroxy-5-methyl-1-phenylhex-1-en-3-one (31)
A 50-mL round-bottomed flask equipped with a Teflon-coated magnetic stir bar and a reflux condenser was treated
with ylide 25 (376 mg, 1 mmol) and DCM (5 mL) at 23 °C, to which PhCHO (2 mmol) was added dropwise. The
mixture was refluxed at 40 °C for 4 h, and then concentrated in vacuo. The resulting crude residue was purified
by flash chromatography (10®50% EtOAc in hexanes) on silica gel (200 mL) to afford enone 31 as pale-yellow
oil (151 mg, 74% yield). Data for enone 31: Rf = 0.56 (40% EtOAc in hexanes); IR (film): nmax = 3459 (br O-H),
3030, 2970, 1675 (C=O), 1501, 1200, 1130 cm-1; 1H NMR (400 MHz, 1% CD3OD in CDCl3, 293 K): δ 7.60 (d, J
= 16.2 Hz, 1H), 7.57–7.55 (m, 2H), 7.42–7.40 (m, 3H), 6.76 (d, J = 16.2 Hz, 1H), 2.86 (s, 2H), 1.32 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3, 293 K): δ 201.7, 143.8, 134.3, 130.9, 129.2, 128.6, 127.0, 70.1, 51.0, 29.6.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C13H17O2 205.1150; Found 205.1158.
(E)-2-methyl-6-phenylhex-5-ene-2,4-diol (36)
A 10-mL round-bottomed flask was treated with (R)-1,1’-binaphthol (L5) (28 mg, 01 mmol, 1.0 equiv) and dry
THF (0.3 mL) and cooled to 0 °C. 1 M BH3•THF in THF (0.1 mL, 1 equiv) was added to the resulting solution
dropwise, and the mixture was stirred for 1 h at the same temperature. Enone 31 (0.1 mmol) in THF (0.2 mL) was
added dropwise at 0 °C. After an additional 1 h, the mixture was cooled to -78 °C and treated with NaBH4 (2 mg,
0.3 equiv) and allowed to warm to 23 °C over 12 h. The reaction mixture was then quenched with sat. NH4Cl (1
mL) at 0 °C and stirred for 30 min. The mixture was concentrated in vacuo to remove THF, followed by vacuum
filtration to remove a precipitated white solid. The aqueous layer was extracted with Et2O (2 × 5 mL). The
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combined organic layers were washed with conc. NH3 (0.5 mL) to remove any B(OH)3, dried over Na2SO4, filtered
through a cotton plug, and concentrated in vacuo. The crude residue was purified by prep TLC (5®30% EtOAc
in hexanes) to afford alcohol (S)-36 (14.7 mg, 86 % ee, 67 %) as clear oil.. Data for allylic alcohol 36: Rf = 0.40
(40% EtOAc in hexanes); IR (film): nmax = 3369, 3088, 3030, 2973, 2935, 1654, 1503, 1464, 1390, 1329, 1244,
1153, 1058, 1004, 957 cm-1; 1H NMR (400 MHz, 1% CD3OD in CDCl3, 293 K): δ 7.38 (d, J = 7.2 Hz, 1H), 7.33
(app t, J = 7.2, Hz, 2H), 7.23 (d, J = 7.2 Hz, 2H), 6.63 (d, J = 16.0 Hz, 1H), 6.25 (dd, J = 16.0, 6.4 Hz, 1H), 4.72
(d, J = 8.0 Hz, 1H), 3.37 (br. s, 1H), 2.85 (br. s, 1H) 1.88 (dd, J = 14.4, 10.8 Hz, 1H), 1.68 (dd, J = 14.4, 2.4 Hz,
2H), 1.39 (s, 3H), 1.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, 293 K): δ 136.8, 132.3, 129.9, 128.7, 127.8,
126.6, 71.8, 70.9, 48.2, 32.1, 27.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C13H19O2 207.1307; Found
207.1301.
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(S)-3-methyl-1-((2S,3S)-3-vinyloxiran-2-yl)butane-1,3-diol (23)
(Method A): A 250-mL round-bottomed flask equipped with a Teflon-coated magnetic stir bar containing enanti-
oenriched 22 (2.30 g, 14.7 mmol) was purged with argon. DCM (60 mL) and 4Å molecular sieves (3.10 g) were
added to the flask. The mixture was cooled to -20 °C (external temperature), then Ti(OiPr)4 (0.38 g, 1.34 mmol),
t
(+)-diisopropyl tartrate (0.50 g, 2.10 mmol) and BuOOH solution in isooctane (1.4 mL, 8.0 mmol) were added
sequentially at the same temperature. The mixture was stirred at the same temperature for 13 h, then diluted with
1 M NaOH (50 mL), Celite ® (3.0 g), Na2SO4 (3.0 g), NaCl (3.0 g). The mixture was stirred for 40 min, then
filtered through a pad of Celite® and Florisil mixture. The filtrate was concentrated in vacuo, and the resulting
crude residue was purified by flash chromatography (10®70% EtOAc in hexanes with 1% NEt3) on silica gel
(200 mL) to afford unreacted allylic alcohol 22 and epoxy alcohol 23 as clear oils (1.38 g, ca. 55%) with impurities
of titanium and tartrate. The recovered 22 was resubjected to the same conditions to afford 23 (1.80g, ca. 71%
after 2 cycles) as a clear oil with minor impurities. The impure epoxy alcohol 23 was used in the next step without
further purification. The % ee was not determined at this stage due to the presence of impurities. Data for epoxy
alcohol 23: Rf = 0.35 (60% EtOAc in hexanes); The compound was not characterized due to impurities.
(Method B): A 25-mL round-bottomed flask equipped with a Teflon-coated magnetic stir bar containing enanti-
oenriched 22 (43 mg, 0.28 mmol) was dissolved in DCM (2 mL) and was cooled to 0 °C (external temperature).
To the stirred solution was added NaHCO3 (46 mg, 0.55 mmol) and mCPBA (52 mg, 0.30 mmol) sequentially
and stirred at the same temperature for 1 h, then stirred at 23 °C for 1 h. The reaction was then quenched with
saturated Na2S2O3 solution and extracted with DCM (10 mL × 3) and the combined organic layers were dried over
Na2SO4, filtered through a cotton plug, and concentrated in vacuo. The crude residue was purified by flash chro-
matography (5®50% EtOAc in hexanes) on silica gel (15 mL) to afford epoxy alcohol 23 as a clear oil (27 mg,
57% yield).Data for epoxy alcohol 23: [α]D 21 -2.8 (c 0.9, DCM).
(5R,6R)-5-hydroxy-2,2-dimethyl-6-vinyltetrahydro-4H-pyran-4-one (28)
A 250-mL round-bottomed flask equipped with a Teflon-coated magnetic stir bar containing 23 (911 mg) was
treated with DCM (200 mL), 4Å molecular sieves (3.30 g), TPAP (101 mg, 0.29 mmol), and NMO (2.50 g, 18.4
mmol) at 23 °C. The mixture was stirred at the same temperature for 40 min, then filtered through a plug of silica.
The filtrate was concentrated to approximately 200 mL of DCM remaining in the flask. To the flask was added
CSA (860 mg, 3.70 mmol) at 23 °C. The mixture was stirred at the same temperature for 19 h, then Et3N (1 mL)
was added. The mixture was concentrated in vacuo, and the crude residue was purified by flash chromatography
(10®30% EtOAc in hexanes) on silica gel (50 mL) to afford ketone 28 as a clear oil (650 mg, 92% ee, 70% yield,
over 2 steps). Data for ketone 28: Rf = 0.35 (30% EtOAc in hexanes); [α]D 20 +28.1 (c 1.0, DCM); IR (film): nmax
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= 3474 (br, O-H), 2975, 2934, 1723 (C=O), 1374, 1240, 1107, 1080 cm-1; H NMR (400 MHz, 1% CD3OD in
CDCl3 , 293 K): δ 6.04 (ddd, J = 16.8, 10.4, 5.2 Hz, 1H), 5.47 (app. d, J = 16.8 Hz, 1H), 5.33 (app. d, J = 10.4
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Hz, 1H), 3.95-5.20 (m, 2H), 2.66 (d, J = 13.2 Hz, 1H), 2.50 (d, J = 13.2 Hz, 1H), 1.43 (s, 3H), 1.20 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3, 293 K): δ 207.4, 135.5, 118.0, 77.9, 76.7, 76.4, 51.5, 30.8, 23.6; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd. for C9H15O3 171.1021; Found 171.1006.
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A 25-mL round-bottomed flask equipped with a Teflon-coated magnetic stir bar containing ketone 28 (200 mg,
1.18 mmol) was purged with N2. To the flask was added THF (12.0 mL) and CH2Br2 (246 mg, 1.42 mmol). The
flask was cooled to -78 °C, then nBuLi (1.60 mL, 2.60 mmol) was added. The mixture was stirred for 7 h, while
warming the cooling bath to 20 °C. The reaction mixture was quenched with saturated aqueous NH4Cl (15.0 mL),
and THF was removed in vacuo. The resulting mixture was extracted with Et2O (3 × 15 mL). The combined
organic layers were dried over Na2SO4, filtered through a cotton plug, and concentrated in vacuo. The crude resi-
due was purified by flash chromatography (5®30% EtOAc in hexanes) on silica gel (40 mL) to afford epoxide
29 as a white solid (157 mg, 73% yield). Data for epoxide 29 [α]D 20 +68.3 (c 1.2, DCM). Spectroscopic data for
epoxide 29 matches that in the previous literature.9
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Supporting Information
A scheme of the previous synthetic route, copies of HPLC chromatograms, 1H, 11B, and 13C NMR spectra.
Corresponding Author
koide@pitt.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Prof. Dennis P. Curran in our department for allowing us to use the (S,S)-Whelk-O 1 HPLC column and E. Benjamin
Hay and Thomas Allen for helping us. We thank Dr. Damodaran Krishnan and Dr. Bhaskar Godugu in our department for
assisting with NMR and mass spectroscopic (NIH grant 1S10RR017977-01) analyses, respectively. We also thank Dr. Thomas
Colacot (Johnson Matthey Catalysis & Chiral Technologies) for PtO2 as a gift. This work was supported in part by the US
National Institutes of Health (R01 CA120792 and 3P50 CA097190 0751).
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