A Chemoenzymatic Formal Synthesis of Epoxyquinols A and B

Article abstract of DOI:10.1055/s-0039-1690216

A formal synthesis of epoxyquinols A and B was completed in nine steps starting from benzoic acid. Enantioselectivity was established through an enzymatic arene dihydroxylation reaction performed by whole cells of Ralstonia eutropha B9 expressing benzoate

Full text of DOI:10.1055/s-0039-1690216

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
Synlett
J. A. Collins et al.
Letter
A Chemoenzymatic Formal Synthesis of Epoxyquinols A and B
Jonathan A. Collins*a
Christopher J. Gerryb,1
Madeleine M. Duncana
0
0
0
0-0
0
0
2-5
5
9
1-
5
7
7
2
O
HO
0
0
0
0-0
0
0
2-
7
6
0
2-0
4
9
2
OH
O
O
O
O
Ralstonia eutropha B9
O
a
whole cells
Department of Chemistry, Whitman College, 345 Boyer Ave.,
Walla Walla, WA 99362, USA
collinja@whitman.edu
Department of Chemistry, Amherst College, A205 Science
Center, 25 East Drive, Amherst, MA 01002, USA
H
O
OH
O
O2
HO
HO
Epoxyquinol A
b
HO
BZDO
+
O
NAD+
HO
NADH + H+
metabolism
OH
O
O
O
O
BZDO = benozoate dioxygenase
H
O
Epoxyquinol B
Received: 20.08.2019
Accepted after revision: 08.10.2019
Published online: 23.10.2019
their initial isolations from an uncharacterized soil fungus
by Osada and co-workers, were shown to be potent inhibi-
tors of angiogenesis (generation of new blood vessels).
6,7
DOI: 10.1055/s-0039-1690216; Art ID: st-2019-k0435-l
The formation of blood vessels is crucial for tumor growth,
making antiangiogenic activity a promising avenue for the
treatment of cancer.8 This has led to approval by the U.S.
Food and Drug Administration of a number of therapies
Abstract A formal synthesis of epoxyquinols A and B was completed in
nine steps starting from benzoic acid. Enantioselectivity was estab-
lished through an enzymatic arene dihydroxylation reaction performed
by whole cells of Ralstonia eutropha B9 expressing benzoate dioxygen-
ase. Subsequent formation of the enone core was facilitated by a
Dauben–Michno-type oxidative transposition of an allylic tertiary alco-
hol.
,9
based on small molecules or monoclonal antibodies for the
10–12
treatment of advanced cancers.
Further investigations
of the biological activities of epoxyquinol A and B revealed
that they inhibit TNF--induced NF-B activation through a
Key words Ralstonia eutropha, benzoate dioxygenase, chemoenzy-
matic synthesis, biocatalysis, asymmetric synthesis, epoxyquinoids
protein-crosslinking mechanism.5
,13,14
It is this inter/intra-
molecular conjugation of cysteine residues within target
proteins that has been linked to inhibition of angiogenesis
signal transduction.1
5,16
The epoxyquinoids are a structurally diverse group of
pentaketide natural products that have shown a wide array
At the time of their initial isolation and study, epoxyqui-
nols A (1) and B (2) were recognized as having a structure
and mode of action that differed significantly from those of
2–5
of biological activities.
Epoxyquinols A (1) and B (2)
(Scheme 1) are two such epoxyquinoids that, following
O
O
HO
HO
OH
OH
O
O
O
O
O
O
O
O
O
Kuwahara's intermediate
H
O
OH
O
OTBS
OTBS
endo-hetero
epoxyquinol A (1)
Oxidative
transposition
TBSO
HO
HO
TBSO
O
O
O
+
3
4
5
O
O
O
OH
HO
OH
O
OH
O
O
O
OH
O
O
O
O
O
O
Whole-cell mediated
dihydroxylation of benzoic acid
HO
HO
O
HO
H
O
exo-homo
epoxyquinol B (2)
6
Scheme 1 Retrosynthetic analysis of epoxyquinols A and B. Elements derived/conserved from ipso,ortho-dihydrodiol 6 are highlighted in red
©
2019. Thieme. All rights reserved. Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
J. A. Collins et al.
Letter
other known angiogenesis inhibitors.5–7 This, along with
the challenge of asymmetrically constructing their densely
functionalized cyclohexanone core, prompted interest from
the synthetic organic chemistry community, resulting in a
lowed by acylation of the tertiary alcohol.33 These three
steps provided diene 10 in 65% overall yield from diol 6. Al-
ternatively, it was found that the same sequence could be
performed without the intermediate purification steps,
yielding 10 from 6 in an overall isolated yield of 78%.
14,17–25
number of total syntheses.
Despite this work, we
sought to develop general routes to epoxyquinoid natural
products that would provide access to their full range of
structural diversity (substitution pattern, stereochemical
configuration, oxidation state, etc.) to facilitate their study
as potential therapeutics and biochemical probes. We envi-
sioned that this could be accomplished by starting from
chiral precursors available through enzymatic dihydroxyl-
ation of substituted arenes. Enzymatically derived cis-dihy-
dro diols have been increasingly utilized by organic chem-
ists in syntheses of natural products, including a number of
O
O
O
OTBS
O
OH
OH
HO
MeO
HO
MeO
HO
a
b
c
HO
HO
7
6
8
9
d
O
O
O
OTBS
OTBS
OTBS
1
1:12
MeO
MeO
AcO
MeO
AcO
4
6
.5:1.0 (NMR)
.5:1.0 (isolated)
AcO
O
+
e
3,4,26–28
epoxyquinoids.
Here we report the chemoenzymatic
O
11
12
10
formal synthesis of epoxyquinols A (1) and B (2) through
Scheme 2 Reagents and conditions: (a) R. eutropha B9 whole cells
79%); (b) CH N , Et O–THF, 0 °C (87%); (c) TBSOTf, Et N, CH Cl , –78 °C
25
the preparation of the disilylated enone 4. In this new
asymmetric approach to the core of this family of epoxy-
quinols, chirality is derived from a biocatalytic ipso,ortho
(
2
2
2
3
2
2
(89%); (d) Ac O, DMAP, CH Cl , r.t. (84%); (e) DMDO, acetone, –15 °C
2
2
2
(83%; 11/12 6.5:1.0)
29
cis-dihydroxylation of benzoic acid.
Epoxyquinols A (1) and B (2) are pentaketide dimers
that are produced biosynthetically from monomer 3 by way
of an oxidation, 6-electrocyclization, and a Diels–Alder
The selective epoxidation of diene 10 to give the key in-
termediate 11 was recognized early on as a challenge for
this approach. An early report by Myers et al. indicated that
some degree of control (regio and stereo) might be exerted
over direct epoxidation of diene systems derived from me-
tabolite 6.32 Our initial attempts to epoxidize the ring di-
30
cascade. Epoxyquinol A (1) is formed from an endo cy-
cloaddition between two pyran epimers (heterodimeriza-
tion), whereas epoxyquinol B (2) is generated by an exo cy-
cloaddition of the same pyran (homodimerization). The
efficiency of this sequence has compelled all developed
syntheses of these compounds to adopt it in a biomimetic
approach. Kuwahara and Imada have previously demon-
strated that monomer 3 can be prepared from the disilylat-
rectly [mCPBA, VO(acac) /tBuOOH, etc.] predominantly
2
generated epoxides 11 and 12 as components in complex
mixtures of all four possible isomers. At this point, an initial
stereochemical assignment for 11 and 12 was made based
on a comparison of their coupling constants with those re-
25
32
ed enone 4. We surmised that the key enone functionality
might be generated by an oxidative transposition of tertiary
allylic alcohol 5. Given the oxidation pattern of 5, we envi-
sioned it being readily available from the ipso,ortho-dihy-
drodiol 6, a metabolite from the enzymatic dihydroxylation
of benzoic acid. Diol 6 provides an ideal framework for the
construction of 1 and 2 because its chirality and preexisting
functionality permit rapid assembly of the desired epoxy-
quinol core. Though not as commonly employed in synthe-
sis as other cis-dihydrodiols, the use of 6 has grown in re-
cent years, and it represents an area of active research.2
The synthesis began with the dihydroxylation of benzo-
ic acid by using whole cells of Ralstonia eutropha B9
ported by Myers for two analogous epoxides. Eventually,
we discovered that treatment of diene 10 with dimethyldi-
oxirane (DMDO; 2.5 equiv, –15 °C) provided 11 and 12 as a
4.5:1.0 mixture.34 Attempts to separate the two regioiso-
mers led to an improvement in the ratio (6.5:1.0; 83%)
through a presumed preferential degradation of 12, but in
most cases, the original mixture was used without purifica-
tion. Next, we studied the oxidative transposition of the ter-
tiary allylic alcohol through a Dauben–Michno rearrange-
ment.35 We took our inspiration from a similar application
of this transformation found in the Hudlicky group’s prepa-
ration of oseltamivir.36 Cleavage of the acetyl group pro-
ceeded smoothly under basic conditions (NaOMe, MeOH,
0 °C) to give tertiary allylic alcohol 13 (68%; 83% based on
11), which was then subjected to Dauben–Michno condi-
7,28
2
9
(
Scheme 2). When a modification of the procedure of
31
Mihovilovic and co-workers was used, this reaction pro-
duced diol 6 as a single enantiomer in a yield of 79% (26.6 g
scale). The carboxyl group of metabolite 6 was converted
into its methyl ester 8 to facilitate handling and to avoid
acid-catalyzed dehydration/rearomatization. The outlined
synthetic strategy required selective manipulation of the
two alcohol groups (Scheme 1), so an orthogonal protec-
tion approach was pursued. This was accomplished by first
converting the secondary alcohol into its TBS ether 9, fol-
37
tions (CrO , Ac O) to yield enone 14 (81%) (Scheme 3). De-
3
2
spite this establishment of the viability of oxidative trans-
position with this scaffold, we were unable to find suitable
conditions for the selective reduction of the ester in the
presence of the epoxy enone. This synthetic challenge led
us to reduce the ester before the oxidative transposition
32
step. Treatment of tertiary allylic alcohol 13 with LiBH af-
4
forded diol 15 in 73% yield. Selective protection of the pri-
©
2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

C
Synlett
J. A. Collins et al.
Letter
mary alcohol gave the disilylated Dauben–Michno precur-
sor 5. Finally, the desired oxidative transposition was per-
formed to furnish intermediate 4 in 78% yield.38 This
compound was found to be identical in every respect to the
enone reported by Kuwahara in his synthesis of epoxyqui-
Endowment are thanked for the generous support of M.D. The Amherst
College Department of Chemistry and the White Family Fund are
thanked for their support of C.G.
Supporting Information
25,39
nols A (1) and B (2).
The sequence from 11 and 12 to 4
Supporting information for this article is available online at
can also be performed without intermediate purification,
affording 4 in 44% yield over four steps.
https://doi.org/10.1055/s-0039-1690216.
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References and Notes
a
(
1) New address: (i) Chemical Biology and Therapeutics Science
Program, Broad Institute, 415 Main Street, Cambridge, MA
2142, USA; (ii) Department of Chemistry and Chemical Biol-
ogy, Harvard University, 12 Oxford Street, Cambridge, MA
2138, USA.
2) Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem. Rev. 2004,
04, 2857.
O
OTBS
OTBS
OTBS
MeO
HO
HO
HO
TBSO
HO
0
c
d
O
O
O
0
13
15
5
(
(
b
e
1
3) Pandolfi, E.; Schapiro, V.; Heguaburu, V.; Labora, M. Curr. Org.
Synth. 2013, 10, 2.
O
OTBS
OTBS OTBS
epoxyquinol A (1)
and
epoxyquinol B (2)
ref. 25
MeO
(4) Mehta, G.; Sengupta, S. Tetrahedron 2017, 73, 6223.
O
O
(5) Kataoka, T. J. Antibiot. 2009, 62, 655.
(
6) Kakeya, H.; Onose, R.; Koshino, H.; Yoshida, A.; Kobayashi, K.;
Kageyama, S.-I.; Osada, H. J. Am. Chem. Soc. 2002, 124, 3496.
7) Kakeya, H.; Onose, R.; Yoshida, A.; Koshino, H.; Osada, H. J. Anti-
biot. 2002, 55, 829.
O
O
14
4
(
Scheme 3 Reagents and conditions: (a) NaOMe, MeOH, 0 °C (68%; 83%
based on 11); (b) Ac O, CrO , CH Cl , 0 °C (81%); (c) LiBH , THF, 0 °C,
73%); (d) TBSCl, imidazole, CH Cl (82%); (e) Ac O, CrO , CH Cl , 0 °C (78%)
2
3
2
2
4
(8) Paper, D. H. Planta Med. 1998, 64, 686.
(
2 2 2 3 2 2
(9) Nishida, N.; Yano, H.; Nishida, T.; Kamura, T.; Kojiro, M. Vasc.
Health Risk Manage. 2006, 2, 213.
(
10) Cook, K. M.; Figg, W. D. CA Cancer J. Clin. 2010, 60, 222.
In conclusion, we have developed a chemoenzymatic
(11) El-Kenawi, A. E.; El-Remessy, A. B. Br. J. Pharmacol. 2013, 170,
formal synthesis of epoxyquinols A (1) and B (2) starting
from an enzymatic desymmetrization of benzoic acid. Or-
thogonal protection of the resulting ipso,ortho-dihydrodiol
allowed an epoxidation and Dauben–Michno oxidative
transposition to establish the epoxy enone core of the for-
mal intermediate 4 in 23% overall yield and with only three
chromatographic purifications. When appended to Kuwahara’s
synthesis, this constitutes preparations of 1 and 2 in 13
steps with overall yields of 8 and 4%, respectively, starting
from benzoic acid. To our knowledge, this is the shortest re-
ported synthesis of 1 and 2 [compared with Porco et al. (14
steps) and the groups of Kuwahara, Mehta, and Hayashi (15
7
12.
(12) Zirlik, K.; Duyster, J. Oncol. Res. Treat. 2018, 41, 166.
(13) Kamiyama, H.; Usui, T.; Sakurai, H.; Shoji, M.; Hayashi, Y.;
Kakeya, H.; Osada, H. Biosci., Biotechnol., Biochem. 2008, 72,
1
894.
(
14) Li, C.; Bardhan, S.; Pace, E. A.; Liang, M.-C.; Gilmore, T. D.; Porco,
J. A. Org. Lett. 2002, 4, 3267.
15) Kamiyama, H.; Kakeya, H.; Usui, T.; Nishikawa, K.; Shoji, M.;
Hayashi, Y.; Osada, H. Oncol. Res. 2008, 17, 11.
(16) Kamiyama, H.; Usui, T.; Uramoto, M.; Takagi, H.; Shoji, M.;
Hayashi, Y.; Kakeya, H.; Osada, H. J. Antibiot. 2008, 61, 94.
17) Shoji, M.; Yamaguchi, J.; Kakeya, H.; Osada, H.; Hayashi, Y.
Angew. Chem. Int. Ed. 2002, 41, 3192.
18) Shoji, M.; Kishida, S.; Takeda, M.; Kakeya, H.; Osada, H.; Hayashi,
Y. Tetrahedron Lett. 2002, 43, 9155.
19) Shoji, M.; Imai, H.; Mukaida, M.; Sakai, K.; Kakeya, H.; Osada, H.;
Hayashi, Y. J. Org. Chem. 2004, 70, 79.
(20) Shoji, M.; Imai, H.; Shiina, I.; Kakeya, H.; Osada, H.; Hayashi, Y.
J. Org. Chem. 2004, 69, 1548.
21) Shoji, M.; Hayashi, Y. Eur. J. Org. Chem. 2007, 2007, 3783.
22) Li, C.; Porco, J. A. J. Org. Chem. 2005, 70, 6053.
(
(
(
(
14,17–25
steps)].
The efficiency and novelty of this approach is
derived from the use of diol 6 as a chiral building block with
unique functionality that permits rapid construction of the
epoxyquinol core. The synthetic flexibility of the ipso,ortho-
dihydrodiols makes our strategy adaptable to syntheses of
other epoxyquinols. Further application of enzymatically
derived diols in syntheses of diverse epoxyquinoid frame-
works is ongoing in our laboratory, and will be reported in
due course.
(
(
(
(
(
(
23) Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 3569.
24) Mehta, G.; Islam, K. Tetrahedron Lett. 2004, 45, 3611.
25) Kuwahara, S.; Imada, S. Tetrahedron Lett. 2005, 46, 547.
26) Taher, E. S.; Banwell, M. G.; Buckler, J. N.; Yan, Q.; Lan, P. Chem.
Rec. 2018, 18, 239.
Acknowledgment
(
27) Hudlicky, T. ACS Omega 2018, 3, 17326.
(
28) (a) Lewis, S. E. Chem. Commun. 2014, 50, 2821. (b) Palframan, M.
J.; Kociok-Köhn, G.; Lewis, S. E. Chem. Eur. J. 2012, 18, 4766.
29) Reiner, A. M.; Hegeman, G. D. Biochemistry 1971, 10, 2530.
The authors would like to thank Professor Marko Mihovilovic (TU
Wien) for providing the mutant R. eutropha B9 strain used in this
work. Whitman College and the the Luis B. Perry Summer Research
(
©
2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

D
Synlett
J. A. Collins et al.
Letter
(
(
30) Fujita, K.; Ishikawa, F.; Kakeya, H. J. Nat. Prod. 2014, 77, 2707.
31) Fischer, T. M.; Leisch, H.; Mihovilovic, M. Monatsh. Chem. 2010,
41, 699.
32) Myers, A. G.; Siegel, D. R.; Buzard, D. J.; Charest, M. G. Org. Lett.
001, 3, 2923.
2858, 1768, 1741, 1234, 1123, 1055 cm–1. 1H NMR (400 MHz,
CDCl3):  = 6.03 (ddd, J = 10.0, 3.7, 2.8 Hz, 1 H), 5.79 (ddd,
J = 10.0, 1.7, 1.7 Hz, 1 H), 4.65 (dd, J = 2.7, 1.7 Hz, 1 H), 4.35 (d,
J = 3.8 Hz, 1 H), 3.85 (s, 3 H), 3.40 (m, 1 H), 2.11 (s, 3 H), 0.90 (s,
1
(
(
13
2
9 H), 0.07 (s, 3 H), 0.01 (s, 3 H). C NMR (101 MHz, CDCl ):
3
33) Methyl (1S,6R)-1-(Acetoxy)-6-{[tert-butyl(dimethyl) silyl]
oxy}cyclohexa-2,4-diene-1-carboxylate (10)
 = 170.68, 169.27, 136.89, 122.89, 80.69, 69.14, 53.64, 52.80,
47.69, 25.59, 21.02, 17.90, –4.65, –5.33. HRMS (ESI+): m/z [M +
+
DMAP (0.25 g, 1.92 mmol) was added to a solution of silyl ether
H] calcd for C16H27O Si: 343.1571; found: 343.1572.
6
9
(0.22 g, 0.77 mmol) in CH Cl (2 mL) under argon. Ac O (0.2
(35) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682.
(36) Werner, L.; Machara, A.; Hudlicky, T. Adv. Synth. Catal. 2010,
352, 195.
(37) Methyl (1S,2S,6R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-5-oxo-
7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate (14)
2
2
2
mL, 1.54 mmol) was then added dropwise over 5 min while the
mixture turned light orange and then bright red. The solution
was then stirred for 6 h at r.t. The reaction was slowly quenched
with H O (0.5 mL), and the mixture was partitioned between
2
hexanes (10 mL) and H O (1 mL). The layers were separated, and
Preparation of oxidizing solution: Ac O (1.0 mL, 10.58 mmol)
2
2
the organic phase was washed with sat. aq NH Cl (2 × 1.0 mL),
was added to CrO3 (388 mg, 3.88 mmol) under argon, and the
mixture was warmed to 75 °C and stirred for 8 min. The result-
ing dark-brown solution was cooled to r.t. then further cooled in
an ice bath before being diluted with CH Cl (3 mL).
4
sat. aq NaHCO (2 × 1.0 mL), and brine (1 × 1.0 mL). The organic
3
phase was dried (MgSO ), filtered, and concentrated under
4
reduced pressure. Purification of the crude oil by flash column
chromatography [silica gel, hexane–EtOAc (10:1)] gave a clear
2
2
Oxidative transposition: A solution of tertiary alcohol 13 (800
20
colorless oil; yield: 0.211 g (84%); []D +9.25 (c 1.03, EtOAc);
Rf = 0.55 (hexane–EtOAc, 1:3).
mg, 2.66 mmol) in CH Cl (6 mL) under argon was chilled in an
2
2
ice bath. The oxidizing solution was added dropwise over 3 min.
The resulting dark-brown mixture was stirred for 5 min and
then the reaction was quenched by slow addition of EtOH (6
IR (neat): 2952, 2929, 2856, 1765, 1737, 1238, 1058, 829, 775
–1 1
cm
. H NMR (400 MHz, CDCl ):  = 6.18 (ddd, J = 9.6, 1.8, 0.8
3
Hz, 1 H), 6.03 (ddd, J = 9.6, 5.1, 0.7 Hz, 1 H), 5.92 (dddd, J = 9.6,
mL) and solid NaCO (1.0 g). The mixture was allowed to warm
3
5
4
.1, 2.2, 1.2 Hz, 1 H), 5.83 (dddd, J = 9.6, 2.6, 0.9, 0.9 Hz, 1 H),
.95 (dd, J = 2.4, 2.4 Hz, 1 H), 3.75 (s, 3 H), 2.08 (s, 3 H), 0.90 (s, 9
to r.t. and stirred for 20 min. The dark-brown mixture was then
filtered through a pad of Celite and partitioned between Et O
2
13
H), 0.10 (s, 3 H), 0.04 (s, 3 H). C NMR (101 MHz, CDCl ):
(125 mL) and H O (40 mL). The phases were separated and the
3
2

= 170.63, 170.17, 131.68, 125.73, 125.66, 122.54, 80.11, 70.93,
organic layer was washed with H O (3 × 30 mL), sat. aq NaHCO3
2
5
2.55, 25.65, 20.89, 18.01, –4.30, –5.02. HRMS (ESI+): m/z [M +
(2 × 30 mL), and brine (1 × 5 mL). The organic phase was dried
+
Na] calcd for C16H26NaO Si: 349.1442; found: 349.1441.
(MgSO ), filtered, and concentrated under reduced pressure.
5
4
(
34) Methyl
(1S,2R,3S,6S)-3-(Acetoxy)-2-{[tert-butyl(dimethyl)
Flash column chromatography (EtOAc–hexane, 1:10) gave
enone 14 as a colorless oil; yield: 640 mg (81%) []D +252.18 (c
20
silyl]oxy}-7-oxabicyclo[4.1.0]hept-4-ene-3-carboxylate (11)
and
dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]hept-4-ene-2-car-
boxylate (12)
Preparation of DMDO solution: DMDO was prepared by the pro-
cedure reported by Taber et al. (CAUTION! DMDO is a volatile
peroxide and should be handled with care: the preparation and
reactions of DMDO should be carried out behind a safety shield
under a hood; see Ref. 40 for details). The preparation was
repeated four times to produce sufficient DMDO solution (~100
mL, 60 mM in acetone). The DMDO solution was stored in a
sealed round-bottomed flask at –15 °C until use.
Methyl
(1R,2S,3R,6R)-2-(Acetoxy)-3-{[tert-butyl
0.90, EtOAc); R = 0.51 (hexane–EtOAc, 5:1).
f
(
IR (neat): 3003, 2954, 28889, 1728, 1693, 1246, 1093, 1080,
–1 1
854, 795 cm . H NMR (400 MHz, CDCl ):  = 6.69 (d, J = 1.6 Hz,
3
1 H), 5.20 (s, 1 H), 3.85 (s, 3 H), 3.71 (dd, J = 3.7, 1.6 Hz, 1 H),
3.53 (m, 1 H), 0.88 (s, 9 H), 0.24 (s, 3 H), 0.14 (s, 3 H). C NMR
40
13
(101 MHz, CDCl ):  = 194.33, 165.61, 143.63, 130.23, 63.00,
3
56.86, 52.73, 25.58, 18.00, –4.54, –4.80. HRMS (ESI+): m/z [M +
+
Na] calcd for C14H22NaO Si = 321.1129; found: 321.1129.
5
(38) (1R,5S,6S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-4-({[tert-
butyl(dimethyl)silyl]oxy}methyl)-7-oxabicyclo[4.1.0]hept-3-
en-2-one (4)
Epoxidation: Acetate 10 (0.660 g, 2.02 mmol) was cooled in an
ice bath and a solution of DMDO in acetone (84 mL, 5.05 mmol,
Preparation of oxidizing solution: Ac O (0.27 mL, 2.92 mmol)
2
was added to CrO3 (110 mg, 1.10 mmol) under argon, and the
mixture was warmed to 75 °C and stirred for 10 min. The
resulting dark-brown solution was then taken off the heat,
allowed to cool to r.t., and then further cooled in an ice bath.
Once chilled, the solution was diluted with CH Cl (3 mL).Oxida-
~60 mM) was added in one portion. The mixture was swirled to
dissolve the substrate and the flask was stoppered and placed in
a freezer at –15 °C for 2 d until the reaction was complete (TLC).
The solution was then concentrated under reduced pressure to
give epoxides 11 and 12 [yield: 0.678 g (98%)] in a ratio of 4.5:1
2
2
tive transposition
(NMR). Flash column chromatography [silica gel, hexane–EtOAc
: A solution of tertiary alcohol 5 (141 mg, 0.36 mmol) in CH Cl2
2
(
5:1) + 2% Et N] gave an enriched mixture of 11 and 12 as a clear
(2 mL) under argon was chilled to 0 °C in an ice bath. Once
chilled, the solution was treated by dropwise addition of the
oxidizing solution (1.5 mL) over 5 min. The resulting dark-
brown mixture was stirred for 45 min. The reaction was then
quenched by slow addition of MeOH (1 mL), and the mixture
was warmed to r.t. and stirred for 10 min. The resulting mixture
was partitioned between Et O (50 mL) and H O (5 mL). The
3
colorless oil [yield: 0.574 g (83%)] in a ratio of 6.5:1.0.
1
Rf = 0.45 (EtOAc–hexane, 1:3). H NMR (400 MHz, CDCl ):
1
1
3

= 6.36 (dd, J = 9.8, 0.7 Hz, 1 H), 6.14 (ddd, J = 9.8, 2.6, 0.6 Hz, 1
H), 4.19 (d, J = 2.0 Hz, 1 H), 3.74 (s, 3 H), 3.44 (ddd, J = 4.2, m2.1,
.6 Hz, 1 H), 3.40 (dd, J = 4.1, 2.7 Hz, 1 H), 2.11 (s, 3 H), 0.93 (s, 9
0
2
2
13
H), 0.17 (s, 3 H), 0.08 (s, 3 H). C NMR (101 MHz, CDCl ):
organic layer was washed with sat. aq NaHCO3 (3 × 5 mL) and
3

4
1
= 169.95, 169.73, 134.01, 126.61, 78.97, 72.29, 56.74, 52.68,
7.36, 25.59, 20.89, 18.01, –4.78, –5.24.
2
brine (1 × 1 mL) then dried (MgSO ), filtered, and concentrated
4
under reduced pressure. Flash column chromatography [silica
gel, hexane–EtOAc (100:1)] gave a colorless oil; yield: 108 mg
20
35
Rf = 0.45 (EtOAc–hexane, 1:3). IR (neat): 2955, 2931, 2895,
(78%); []D +125.71 (c 1.32) [Lit. +129.1 (c 1.35, CHCl )];
3
©
2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

E
Synlett
J. A. Collins et al.
Letter
Rf = 0.74 (hexane–EtOAc, 3:1).
IR (neat): 2954, 2930, 2886, 2858, 1684, 1472, 1464, 1254,
 = 193.25, 158.01, 120.25, 63.91, 62.97, 57.34, 52.99, 25.80,
25.57, 18.31, 17.95, –4.13, –4.69, –5.43, –5.54. HRMS (ESI+): m/z
–1
1
+
1
082, 832 cm . H NMR (400 MHz, CDCl ):  = 6.10 (ddd, J = 3.6,
[M + H] calcd for C19H37O Si : 385.2225; found: 385.2229.
3
4
2
1
.7, 0.7 Hz, 1 H), 4.57 (s, 1 H), 4.42 (dd, J = 16.7, 1.9 Hz, 1 H), 4.16
(39) Imada, S. Master’s Thesis; Tohoku University: Japan, 2005.
(40) Taber, D. F.; DeMatteo, P. W.; Hassan, R. A. Org. Synth. 2013, 90,
350.
(ddd, J = 16.7, 1.7, 0.5 Hz, 1 H), 3.63 (dd, J = 3.6, 1.3 Hz, 1 H), 3.45
(ddd, J = 3.6, 1.9, 1.0 Hz, 1 H), 0.92 (s, 9 H), 0.92 (s, 9 H), 0.21 (s,
13
3
H), 0.18 (s, 3 H), 0.08 (s, 6 H). C NMR (101 MHz, CDCl ):
3
©
2019. Thieme. All rights reserved. Synlett 2019, 30, A–E