Model Reactions for the Enantioselective Synthesis of γ-Rubromycin: Stereospecific Intramolecular Photoredox Cyclization of an ortho-Quinone Ether to a Spiroacetal

Article abstract of DOI:10.1021/acs.orglett.8b01475

A model study for the enantioselective total synthesis of γ-rubromycin has revealed a promising approach for constructing the chiral, nonracemic bicyclic spiroacetal via the stereospecific photoredox reaction of 1,2-naphthoquinone ether.

Full text of DOI:10.1021/acs.orglett.8b01475

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Model Reactions for the Enantioselective Synthesis of
γ‑Rubromycin: Stereospecific Intramolecular Photoredox Cyclization
of an ortho-Quinone Ether to a Spiroacetal
Fumihiro Wakita, Yoshio Ando, Ken Ohmori, and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan
S
* Supporting Information
ABSTRACT: A model study for the enantioselective total synthesis of γ-rubromycin has revealed a promising approach for
constructing the chiral, nonracemic bicyclic spiroacetal via the stereospecific photoredox reaction of 1,2-naphthoquinone ether.
Scheme 3. Stereospecific Photoredox Reaction (Previous
icyclic spiroacetals constitute one of the key structural
Work)
Bmotifs in various bioactive natural products, and their
Scheme 1. Bicyclic Spiroacetals
Scheme 2. γ-Rubromycin and Photoredox Approach
On the other hand, an intriguing stereochemical challenge
arises, when only a single stereogenicity is present at the
spiroacetal center, such as in olean (2). An ingenious access is
represented by the Mori synthesis of 2. The strategic use of
extra stereogenic centers (see a in Scheme 1) enabled the
requisite stereocontrol and were eventually removed.3
Although an interesting methodology for the construction of
spiroacetals such as 2 has recently emerged via enantioselective
acetalization (b in Scheme 1),4 there are still needs for
developing optional approaches.5
stereocontrolled construction has been attracting considerable
attention from synthetic chemists.1 As represented by the
structure of 1, a bee pheromone, most natural products
correspond to the thermodynamically preferred isomer in view
of steric and stereoelectronic effects, where synthetic routes
may be rationally designed (see Scheme 1).2
Received: May 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01475
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Organic Letters
Letter
Scheme 4. Preparation of 1,2-Naphthoquinone 9
Scheme 5. 1,5-Hydrogen Abstraction vs 1,7-Hydrogen
Abstraction
Table 1. Photoredox Reaction of γ-Rubromycin Model 9
Scheme 6. Resolution of 7 and Preparation of (−)-9
entry
light source
time
10 [%]
11 [%]
a
1
2
fluorescent light (32 W)
Xe lamp (300 W)
156 h
20 min
55
71
trace
12
b
a
b
Recovery = 9%. Recovery = 8%.
Table 2. Enantiospecific Photoredox Reaction (Solvent
Effect)21
We became intrigued by this challenge in the context of the
synthetic project toward γ-rubromycin (3),6−9 an antibiotic
having a spiroacetal center as the sole stereogenicity (Scheme
2). The absolute configuration of 3 was assigned as (S) by
quantum chemical CD calculation;6b however, it has never
been verified by chemical synthesis.
To address this issue, we devised the idea of the “photoredox
approach”, i.e., photoinduced conversion of 1,2-naphthoqui-
none ether A into spiroacetal B, which is an intramolecular
redox reaction, in that the C2 position of chromane A becomes
oxidized, while the quinone moiety is reduced to the
hydroquinone level in B. Our hope was that the C−H
oxidation would proceed in a stereoretentive manner.
entry
solvent
yield [%]
enantiomeric excess, ee [%]
1
2
3
4
5
6
7
8
CH3CN
toluene
THF
acetone
CH2Cl2
MeOH
EtOH
69
10
33
34
46
64
51
44
53
12
13
42
31
77
61
45
i-PrOH
This idea stems from our recent finding, a stereospecific
photoredox reaction of 1,4-naphthoquinone C that was
exploited in the asymmetric synthesis of spiroxin C (Scheme
3):10,11 Upon photoirradiation of C, intramolecular C−H
abstraction generates biradical E, which undergoes single
electron transfer (SET) to zwitterion F and following
oxycyclization gives D. Most importantly, this sequence
proceeds in a stereospecific manner with retention of
configuration, which could be attributed to the biaryl-like
B
DOI: 10.1021/acs.orglett.8b01475
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Pleasingly, the model experiments addressing these ques-
tions gave us affirmative answers, which will be described in
this communication.
As a model substrate, 1,2-naphthoquinone 9 was prepared
(Scheme 4). Lawsone was combined with aldehyde 413 by
reductive alkylation14 to give hydroxynaphthoquinone 5 in
76% yield. Protection of the hydroxy group in 5 by MOM
group afforded naphthoquinone 6 in 93% yield. Hydrogenation
of 6 to the corresponding hydroquinone followed methylation
in a one-pot reaction gave naphthalene 7 in 91% yield. After
removal of the MOM group in 7, the resulting phenol 8 was
oxidized to give 1,2-naphthoquinone 9 as an orange solid in
88% yield, ready for examining the photoredox reaction.
Gratifyingly, photoirradiation of 1,2-naphthoquinone 9
indeed provided spiroacetal 10 as the photoredox product
(Table 1).15 Exposure of 9 to normal room light (32 W
fluorescent light, CH3CN, rt) gave spiroacetal 10 in 55% yield,
although very long reaction time was required (ca. 1 week,
entry 1 in Table 1). However, the reaction time was greatly
shortened when a xenon lamp (>380 nm, 300 W) was
employed, and the yield was improved to 71% (entry 2 in
Table 1).16 Under these conditions, a small amount of bicyclic
compound 11 was coproduced17 via Norrish−Yang cycliza-
tion.18
Figure 1. HPLC analysis of rac-10 and (R)-(−)-10.
Table 3. Temperature Effect in the Enantiomeric Excess
(ee) of (R)-(−)-1021
temperature time yield
enantiomeric
entry
solvent
MeOH
MeOH
MeOH
[°C]
[h]
[%]
excess, ee [%]
1
2
3
4
0
−40
−78
−78
1
2
3
3
65
70
34
68
82
87
98
98
MeOH, CH3CN
(v/v = 3/1)
Scheme 5 shows a rationale for the formation of the desired
product 10 and the undesired product 11. Upon light
irradiation and excitation of 1,2-naphthoquinone 9, the
productive pathway for 10 is initiated by the intramolecular
1,5-hydrogen abstraction, giving biradical I. Subsequent
intramolecular SET generates zwitterion II, which is trapped
by the proximal phenol to give the oxycyclization product 10.
On the other hand, 1,7-hydrogen abstraction gives biradical
III, which, after Norrish−Yang cyclization, yields side product
11. This site selectivity of the hydrogen abstraction (1,5- vs
1,7-) reflects the conformational flexibility of the system. Other
byproducts arising from a possibly competing 1,6-hydrogen
abstraction were not observed. This process seems unlikely,
because of the higher bond dissociation energy of the relevant
unactivated C−H bond.10
scaffold in E and F: The stereodeteriorating internal C−C
bond rotation is slower relative to the sequence, E → F → D.
We wondered if such a stereospecific reaction scenario
would apply for the conversion of A → B (vide supra, Scheme
2) and realized that three major challenges needed to be
addressed:
(1) Suitability of 1,2-naphthoquinones as substrates of the
photoredox reaction.12
(2) C−H oxidation at the C2 position of chromane A.
(3) Stereospecificity in a conformationally mobile system as
A.
The third point seemed particularly challenging, as the
reaction sites are indirectly connected through a one-carbon
tether, providing a system much more dynamic than the biaryl-
like structure stated above.
Focusing our attention to the configurational integrity of this
photoredox reaction, an enantiomerically pure sample of 1,2-
naphthoquinone 9 was prepared from the resolved enantiomer
Scheme 7. Rationale for Stereoretentive Photoredox Reaction
C
DOI: 10.1021/acs.orglett.8b01475
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Organic Letters
Letter
of 7 obtained by preparative HPLC on a chiral stationary
phase.19 Hence, according to the procedure in Scheme 6, (+)-7
was converted to the model substrate (−)-9. The absolute
stereochemistry of (+)-7 and (−)-9 were assigned as (S).20
1,2-Naphthoquinone (−)-9, thus obtained, was irradiated
with a xenon lamp (CH3CN, at room temperature (rt)), which
gave spiroacetal (−)-10 in 69% yield (Table 2, entry 1).21 The
enantiomeric excess (ee) of (−)-10 was 53% ee, as assessed by
HPLC analysis on a column with chiral stationary phase (see
the HPLC analysis in Figure 1).19 As will be discussed later
(vide infra, Scheme 8), the absolute configuration of the major
enantiomer (−)-10 was (R), proving that the photochemical
reaction proceeded preferentially in a retentive manner.
STEREOCHEMICAL PROOF
The assignment of the stereochemistry of key compound
(−)-10 was realized after conversion to ester 14. The absolute
■
Scheme 8. Absolute Configuration of (−)-10 and X-ray
a
Structure of 14
In order to improve the configurational integrity, we
optimized various reaction parameters and started with a
solvent screening. It turned out that the solvent effect is
substantial, in that polar solvents22 led to both higher ee and
yield of (−)-10 (Table 2, entries 1 and 6, as the solvents
CH3CN and MeOH). Notably, when methanol was used
(Table 2, entry 6), (−)-10 was isolated in 77% ee. By contrast,
other protic solvents, such as ethanol and isopropyl alcohol, led
to lower yield and ee (Table 2, entries 7 and 8).
By lowering the reaction temperature, we were able to
further raise the ee of 10 (Table 3).21 At −78 °C, pleasingly,
almost complete stereochemical retention was observed (98%
ee) (Table 3, entry 3). Unfortunately, the yield decreased
substantially (34%), because of the low solubility of (−)-9 in
methanol at low temperature, forming precipitates. Using
CH3CN as a cosolvent (MeOH:CH3CN = 3:1, Table 3, entry
4), the reaction remained homogeneous, even at −78 °C, and
photoirradiation smoothly converted quinone (−)-9 to
spiroacetal (−)-10 in 68% yield with almost perfect configura-
tional integrity (98% ee; see the HPLC analysis in Figure 1).19
Scheme 7 shows our rationale for the observed stereo-
chemical outcome of the reaction. In an ideal case, after the
initial photoexcitation and 1,5-hydrogen abstraction in G, the
following sequential process, H → I → J, proceeds rapidly
enough, relative to the bond rotation on the tether moiety, and
leads to the stereoretentive spiroacetal formation. On the other
hand, erosion of the configurational integrity occurs in the case
where the bond rotation competes and the inverted con-
formers K and/or L intervene. Under unoptimized conditions,
the configurational integrity was lost, which could easily be
explained by the conformational flexibility of the compound.
With our optimized reaction conditions, we secured high
chemical yield and excellent configurational integrity for the
reaction of (−)-9 → (−)-10. We gained insight into the key
factors responsible for the observed outcome and our
interpretation is as follows:
a
Disordered atoms are omitted for clarity.
stereochemistry was confirmed as (R) by the X-ray diffraction
(XRD) analysis of camphanate 14 (see Scheme 8).
In summary, we have developed a promising approach to the
enantioselective total synthesis of γ-rubromycin via the
photoredox reaction of 1,2-naphthoquinone at the C2 position
on chromane, allowing the enantiospecific construction to the
spiroacetal moiety. Further studies toward the total synthesis is
actively pursued in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01475.
Full experimental procedure, characterization data, and
NMR spectra for all new compounds (PDF)
Accession Codes
CCDC 1837042 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
(1) Polar solvents have a tendency to give better yields,
which could be attributed to the acceleration of the
electron-transfer step to form the zwitterionic species.23
(2) Protic solventsin particular, methanollead to
excellent ee values, probably because of the strong
solvation effect via hydrogen bonding in H and/or I,
thus reducing the conformational flexibility of the
relevant intermediate(s).
(3) Lower reaction temperatures significantly improve the
optical purity, which could be ascribed to the retardation
of conformational changes, while the reaction rate itself
is not affected.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ksuzuki@chem.titech.ac.jp.
ORCID
Yoshio Ando: 0000-0002-0063-7672
Ken Ohmori: 0000-0002-8498-0821
Keisuke Suzuki: 0000-0001-7935-3762
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.8b01475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
A.; Palle, V. P.; Kamboj, R. K. International Patent No. WO 124828
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(15) The structure of spiroacetal 10 was identified by extensive 2D
NMR experimentation. For details, see the Supporting Information.
(16) Even when the reaction was performed for a longer time under
the same conditions (60 min), 1,2-quinone 9 still slightly remained,
while the yields of the product 10 and byproduct 11 were almost
unchanged.
ACKNOWLEDGMENTS
■
This research was supported by JSPS KAKENHI Grant Nos.
JP16H06351 and JP26810018, and Grant for Basic Science
Research Projects from The Sumitomo Foundation. We are
grateful to Prof. Hidehiro Uekusa and Dr. Haruki Sugiyama
(Tokyo Institute of Technology) for X-ray diffraction analysis.
We thank one of the referees, who suggested a kinetic isotope
effect, which will be examined in due course.
(17) Bicyclic compound 11 was obtained as a single diastereomer.
For details, see the Supporting Information.
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