Synthesis of the KLMN fragment of gymnocin-A using oxiranyl anion convergent methodology

Article abstract of DOI:10.1021/ol500788c

Synthesis of the KLMN fragment of gymnocin-A has been achieved by a [X + 2 + Y]-type convergent strategy involving the coupling of a K-ring triflate and an N-ring epoxy sulfone. Fusions of the L ring and the M ring were carried out by intramolecular S

Full text of DOI:10.1021/ol500788c

Letter
pubs.acs.org/OrgLett
Synthesis of the KLMN Fragment of Gymnocin‑A Using Oxiranyl
Anion Convergent Methodology
Takeo Sakai, Haruka Asano, Kyoko Furukawa, Rie Oshima, and Yuji Mori*
Faculty of Pharmacy, Meijo University, Yagotoyama 150, Tempaku-ku, Nagoya 468-8503, Japan
S
* Supporting Information
ABSTRACT: Synthesis of the KLMN fragment of gymnocin-A
has been achieved by a [X + 2 + Y]-type convergent strategy
involving the coupling of a K-ring triflate and an N-ring epoxy
sulfone. Fusions of the L ring and the M ring were carried out by
intramolecular SN2 substitution of a tertiary alcohol and reductive
etherification to furnish the target molecule.
arine dinoflagellates produce a number of complex
borohydride, followed by dithioacetalization, provided alcohol
1
Mbioactive molecules. Gymnocin-A was isolated from a 10 in 91% yield over two steps. The resulting alcohol was
culture of red-tide dinoflagellate Karenia mikimotoi.2 The
converted to the unsaturated ester aldehyde 12 by reaction with
ethyl propiolate followed by removal of the 1,3-dithiane. The
SmI2-mediated radical cyclization14 of acyclic 12 afforded
(3S,4R)- and (3R,4S)-hydroxy esters 13a and 13b in 71 and
22% yields, respectively. The secondary alcohol of the desired
major isomer 13a was protected with TBSOTf to afford ester
14, which was also made by recycling the undesired (3R,4S)-
isomer 13b in a four-step process. The complete isomerization
of the ester side chain of the undesired isomer was achieved by
a retro-Michael/oxa-Michael reaction15 after inversion of the
C4 hydroxyl group.16 Reduction of ester 14 with DIBALH and
Horner−Wadsworth−Emmons (HWE) olefination of the
resulting aldehyde with TolSO2CH2P(O)(OEt)2 gave trans-
vinylsulfone 15. Subsequent epoxidation with t-BOOH/t-
BuOK led to the desired trans-epoxy sulfone 16 as an 88:12
diastereomeric mixture.
structure of gymnocin-A (1) is characterized by a stunning
array of 14 contiguous ether rings (Figure 1), the third longest
marine polycyclic ether after brevisulcenal-F3 and gymnocin-B4
(17 and 15 contiguous rings, respectively). The potent
cytotoxicity (IC50 = 1.3 μg/mL) against P388 mouse leukemia
cells and the complex architecture make gymnocin-A an
attractive target for synthetic chemists.5 To date, only one
total synthesis of gymnocin-A has been achieved by Tsukano
and Sasaki using a Suzuki−Miyaura coupling strategy.6
A
structure−activity relationship study including truncated
analogues was also reported by the same group.7
Construction of such a long ladder-like structure in a highly
convergent manner is key in any total synthesis of marine
polyether toxins.8,9 We have recently reported a [X + 2 + Y]-
type convergent strategy using an oxiranyl anion coupling,
which integrates the construction of medium-ring ethers.10−12
This unique methodology has prompted us to undertake a
synthetic study of gymnocin-A, and here we report the
synthesis of the KLMN fragment.
Retrosynthesis of the KLMN fragment 2 starts with
disconnecting the C−O bond of the M ring. The unraveled
seven-membered L ring could be constructed as a ring
expansion reaction13 of the six-membered ketone 3 (Scheme
1). This cyclic ketone would be accessible by intramolecular
SN2 substitution of bulky tertiary alcohol 4, potentially a high-
risk strategy to constructing the bicyclic ether containing an
angular methyl group. Synthesis of 4 could be achieved by C−
C bond formation between advanced building block K-ring
triflate 5 and N-ring oxiranyl anion 6, both of which would be
prepared from 2-deoxy-D-ribose.
Synthesis of the other coupling partner, K-ring triflate 5, is
shown in Scheme 3. Methyl 2-deoxy-D-ribofuranoside (7) was
converted to unsaturated ester aldehyde 18 through a sequence
including silylene protection of the 1,3-diol, dithioacetalization,
oxa-Michael reaction with ethyl propiolate, and removal of the
dithioacetal. SmI2-mediated reductive cyclization of 18 on the
rigid dioxasilinane ring proceeded stereoselectively to afford
hydroxy ester 19 in 90% yield as a single diastereomer.
The ester was then reduced, and the resulting diol was
protected as a dibenzyl ether (20). After removal of the silylene
group and selective protection of the primary alcohol with a
TBDPS group, the secondary alcohol was oxidized to give
ketone 22. Introduction of an axial methyl group with MeMgBr
in Et2O afforded the desired isomer 23 in 60% yield along with
39% of its epimer. Subsequent removal of the TBDPS group
Synthesis of epoxy sulfone 16 began by tosylation and
benzylation of methyl 2-deoxy-D-ribofuranoside (7) to give 8
(Scheme 2). Reduction of the tosylate with lithium triethyl-
Received: March 17, 2014
Published: April 9, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Figure 1. Structure of gymnocin-A (1).
Scheme 1. Retrosynthetic Analysis of the KLMN Fragment 2
Scheme 2. Preparation of the N-Ring Epoxy Sulfone 16
Scheme 3. Preparation of the K-Ring Triflate 5
Union of the K-ring triflate 5 and the N-ring epoxy sulfone
16 was achieved by oxiranyl anion alkylation (Scheme 4). A
mixture of 5 and 16 was treated with n-BuLi in the presence of
HMPA at −100 °C to provide the product 24 in 67% yield
(76% conversion based on the recovered triflate). The reaction
at −80 °C resulted in a significant drop in yield to 19% because
followed by a one-pot triflation−trimethylsilylation of the
resulting diol afforded the desired K-ring triflate 5.
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Organic Letters
Letter
conditions as before, however, resulted in the formation of 3 in
only 37% yield (Table 1, entry 1). Several other conditions with
NaH were tried but failed to give satisfactory yields. The low
yield prompted us to re-examine other bases. When KHMDS
and tetramethylguanidine (TMG) were used, the reactions
were sluggish and gave even lower yields (entries 2 and 3).
Cyclization using a weaker base such as hydroxide was then
attempted to minimize decomposition of the substrate.
Reaction with 1 M aqueous NaOH in THF afforded 3 as the
sole product in 44% yield, along with 51% recovery of the
bromoketone starting material (entry 4). The low reactivity
may be due to the poor solubility of NaOH in THF. Addition
of tetra-n-butylammonium hydroxide enhanced the reaction
rate, but the yield was still moderate (entry 5). We found that
addition of a crown ether greatly improved the yield (entry 6)
and that 18-crown-6 is the best additive for the NaOH-
mediated SN2 cyclization to afford the desired product in 88%
yield (entry 7).
Cyclization using NaOH and 18-crown-6 was also examined
for the minor bromoketone isomer (10-epi-4). However, the
desired product 3 was not obtained; instead, intermolecular
substitution with hydroxide and a Favorskii rearrangement
occurred to give 25 and 26, respectively (Scheme 5). Ether ring
formation is prevented by the steric repulsion between the axial
methyl group and the N-ring moiety in the chairlike transition
state. The marked difference of reactivity between the major
isomer 4 and the minor isomer 10-epi-4 can be attributed to
their C10-configurations being S and R, respectively.
In preparation for the fusion of ring M, the six-membered
ketone 3 was homologated with trimethylsilyldiazomethane to
give the seven-membered ketone 27 in 91% yield (Scheme 6).
Methyl acetalization and reductive etherification provided
tetracyclic polyether 28, with the construction of the full
KLMN ring system. After debenzylation and protection of the
resulting triol with TBSOTf, the primary silyl ether was
selectively removed under acidic conditions. Dess-Martin
oxidation of alcohol 29 to the aldehyde, followed by a HWE
reaction, provided trans-vinyl sulfone 30. The synthesis of the
KLMN fragment 2 was completed by epoxidation of the vinyl
sulfone with t-BuOOH/t-BuOK. This epoxy sulfone will be
reacted with a triflate of the H-ring terminal fragment, the
synthesis of which is in progress.
Scheme 4. Reaction of the N-Ring Epoxy Sulfone 16 with the
K-Ring Triflate 5
Table 1. Reaction Conditions for Base-Mediated Cyclization
of 4 to 3
temp
time
(h)
yield
(%)
entry
1
base
additive
(°C)
NaH
−10
25
0
3
24
1
37
4
a
2
TMG
3
4
5
KHMDS
20
44
60
1 M aq NaOH
0
24
1
0.4 M n-Bu4NOH in
−40
MeOH
6
7
1 M aq NaOH
1 M aq NaOH
15-crown-5
18-crown-6
0
0
24
8
81
88
a
CH2Cl2 was used as a solvent.
Scheme 5. Attempting the Cyclization Reaction Using 10-
epi-4
In conclusion, we have synthesized the KLMN fragment (2)
of gymnocin-A from the N-ring epoxy sulfone 16 and the K-
ring triflate 5, which were prepared from 2-deoxy-D-ribose using
a SmI2-mediated reductive cyclization. Assembly of the two
building blocks was achieved using our [X + 2 + Y]-type
convergent strategy, where the fused cyclic ether bearing an
angular methyl group was constructed by intramolecular SN2
cyclization of a tertiary alcohol. Further studies toward the total
synthesis of gymnocin-A are continuing in our laboratory.
of the instability of the oxiranyl anion at this temperature.
Removal of the TMS group of 24 followed by bromination with
MgBr2 afforded bromoketone 4 (93%) along with a small
amount of the minor isomer 10-epi-4 (6%).
Ring fusion of 4 by intramolecular SN2 reaction to bicyclic
ether 3 containing an angular methyl group is a challenging task
as the reaction sites are an unfavorable combination of a bulky
tertiary alcohol and a secondary alkyl bromide, as dictated by
the Williamson ether synthesis. We have previously reported
that NaH is suitable for SN2 cyclization in a similar system with
a tertiary alcohol.12a The cyclization of 4 under the same
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectroscopic data, and H and 13C
NMR spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mori@meijo-u.ac.jp.
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Scheme 6. Completion of the KLMN Fragment 2 Synthesis
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by a Grant-in-Aid for
Scientific Research (C) (21590029) and a Grant-in-Aid for
Young Scientists (B) (23790027) from the Japan Society for
the Promotion of Science (JSPS).
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