Total synthesis and absolute stereochemistry of seragakinone A

Article abstract of DOI:10.1002/anie.201006528

(Chemical Equation Presented) Cyclic transformation: The key transformations of the asymmetric total synthesis of the marine-derived natural product seragakinone A are two N-heterocyclic carbene catalyzed benzoin cyclizations that result in the construction of two rings and a pinacol-type rearrangement to install the angular prenyl substituent.

Full text of DOI:10.1002/anie.201006528

DOI: 10.1002/anie.201006528
Natural Product Synthesis
Total Synthesis and Absolute Stereochemistry of Seragakinone A**
Akiomi Takada, Yoshimitsu Hashimoto, Hiroshi Takikawa, Katsuyoshi Hikita, and
Keisuke Suzuki*
Dedicated to Professors Gilbert Stork, Samuel J. Danishefsky, and Mamoru Ohashi
Seragakinone A (1), an antifungal and antibacterial com-
pound, is produced by an unidentified marine fungus that is in
symbiosis with rhodophyta Ceratodictyon spongiosum and
was collected at Seragaki beach, Okinawa.[1] The intriguing
structure of 1 features a densely oxygenated pentacyclic core
having an angular prenyl substituent, and it was determined
by using extensive spectroscopic studies and single-crystal X-
ray analysis; however the absolute configuration was unas-
signed. The three major challenges in this synthesis are: 1) the
construction of the pentacyclic framework, 2) the stereose-
lective introduction of a prenyl unit into the sterically
hindered angular position, and 3) the regio- and stereocon-
trolled installation of multiple oxygen functionalities. Herein,
we describe the first total synthesis of ent-1, which proved to
be enantiomeric to the natural product and thus allowed
assignment of the absolute structure of seragakinone A.
Scheme 1. Retrosynthetic analysis of (ꢀ)-seragakinone A (ent-1).
Retrosynthetic analysis of ent-1 (Scheme 1) started with a
disconnection of the A ring, which could be constructed using
a benzoin-forming reaction and an aldol reaction as a key
annulation. A key feature of our approach is the use of an
isoxazole as a 1,3-diketone equivalent.[2] This allowed a
disconnection of ent-1 into two isoxazole-containing frag-
ments, 2 and 3. Dione 2 could be formed from diene 4 by the
[3]
ꢀ
ꢀ
at C4a C5 and C2’ C3’. Based on our previous study, we
planned to install the angular prenyl group in 4 through an
isoxazole-assisted, stereospecific pinacol-type 1,2-shift, which
allowed a further disconnection to give the stereogenic ketol
5. This ketol could be formed by an asymmetric benzoin
cyclization[4] of ketoaldehyde 6, and a final disconnection
suggested nitrile oxide 7[5] and quinone monoacetal 8 as
starting materials.
=
regio- and stereoselective oxygenation of the two C C bonds
[*] A. Takada, Y. Hashimoto, Dr. H. Takikawa, K. Hikita,
Prof. Dr. K. Suzuki
Department of Chemistry, Tokyo Institute of Technology
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
Fax: (+81)3-5734-2788
Scheme 2 shows the preparation of prenyl ketone 4,
beginning with the conversion of the known bromide 9[6] into
nitrile oxide 7. Bromide 9 was treated with n-butyllithium,
and the resulting lithium species was trapped with DMF to
afford the corresponding aldehyde. This aldehyde was
converted into nitrile oxide 7 by treatment with hydroxyl-
amine and subsequent exposure to NCS in the presence of
triethylamine.[5] The regioselective 1,3-dipolar cycloaddition
of nitrile oxide 7 with quinone monoacetal 8, with subsequent
E-mail: ksuzuki@chem.titech.ac.jp
[**] We thank Prof. Dr. Jun’ichi Kobayashi (Hokkaido Univ.) and Prof. Dr.
Hideyuki Shigemori (Tsukuba Univ.) for kindly providing a com-
parison sample of 1. We are grateful to Sachiyo Kubo for X-ray
analysis, and Dr. Haruko Takahashi for HSCCC purification.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006528.
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Notably the stereochemical integrity was preserved
during the migration. The HPLC analysis using a chiral
stationary phase confirmed the enantiopurity (99% ee) of 11.
The key prenyl ketone 4 was then synthesized by cross-
metathesis (excess 2-methyl-2-butene and Grubbs II cata-
lyst).[13] Reduction of ketone 4 with NaBH4 afforded alcohol
13 as a single isomer (Scheme 3), and the unambiguous
Scheme 2. Prenyl ketone 4. Reagents and conditions: a) nBuLi, THF,
Et2O, ꢀ788C, 1 h, then DMF, ꢀ78!08C, (95%); b) NH2OH·HCl,
K2CO3, MeOH, H2O, 08C, 1 h (98%); c) NCS, Et3N, CHCl3, 08C,
30 min (90%); d) 8, toluene, RT, 11 h then MnO2, 808C, 10 min
(75%); e) TsOH·H2O, MeOH, RT, 2 h, then 2m H2SO4 aq., THF, RT,
10 h (91%); f) 12 (10 mol%), Et3N (10 mol%), THF, RT, 4 h (86%,
99% ee); g) allylmagnesium bromide, THF, ꢀ788C, 20 min (92%);
h) CH3SO2Cl, Et3N, CH2Cl2, 08C, 10 min (83%); i) 2-methyl-2-butene,
Grubbs II catalyst (8 mol%), CH2Cl2, 408C, 14 h (89%). DMF=N,N’-
dimethylformamide, NCS=N-chlorosuccinimide, Ts=4-toluenesul-
fonyl.
dehydrogenation (MnO2)[7] and hydrolysis of the resulting
cyclic acetal gave ketoaldehyde 6, which was then ready for
the key benzoin cyclization. Pleasingly, when using the
modified Rovis triazolium salt 12[4d,8] (10 mol%) in the
presence of triethylamine (10 mol%), the proposed reaction
of 6 proceeded with excellent enantioselectivity to give the
cyclic ketol (R)-5 in high yield (86%, 99% ee).[9]
Scheme 3. Ketone 18. Reagents and conditions: a) NaBH4, THF,
MeOH, 08C, 10 min (92%); b) BnBr, NaH, nBu4NI, THF, RT, 2.5 h
(94%); c) 20 (20 mol%), Oxone, K2CO3, nBu4NHSO4, CH2(OMe)2,
MeCN, H2O (pH 6), 08C, 24 h (92%, d.r. 8.2:1); d) PPTS, 1,4-dioxane,
H2O, 708C, 12 h (78%); e) PhI(OAc)2, KOH, MeOH, 08C, 2 h (64%);
f) TPAP, NMO, 4 ꢀ molecular sieves, CH2Cl2, RT, 3 h (86%).
NMO=4-methylmorpholine N-oxide, PPTS=pyridinium p-toluenesul-
fonate, TPAP=tetra-n-propylammonium perruthenate.
Nucleophilic addition of allylmagnesium bromide to
ketone 5 selectively afforded cis-diol 10 as a single diastereo-
mer,[10] ready for the key pinacol rearrangement. In contrast
to the model system reported previously,[3a] the attempted 1,2-
shift failed under a variety of acidic conditions (e.g. BF3·OEt2,
TfOH), because of the decomposition of the acetal moiety.
Hoping to achieve the key regioselective activation of the
assignment of the absolute configuration was made by
derivatization of 13 into the corresponding camphanate
ester, which was then used in X-ray analysis.[14,15] Benzylation
of alcohol 13 produced ether 14, thus setting the stage for the
stereocontrolled tetrahydrofuran ring construction. Since
simple oxidation of the prenyl side chain failed to give a
significant level of diastereoselection (e.g. 15/2’-epi-15 = 1:1.4,
with m-chloroperoxybenzoic acid), we opted instead for
reagent control. Shi epoxidation[16] catalyzed by ketone
hydrate 20 (20 mol%) proved effective, thereby furnishing
the desired epoxide 15 in high selectivity (92%, 15/2’-epi-15 =
8.2:1). After separation, epoxide 15 was treated with PPTS in
aqueous 1,4-dioxane, which induced hydration of the epoxide
angular hydroxy group, we examined the conditions required
[11]
=
for methanesulfonylation mediated by sulfene (CH2 SO2).
Pleasingly, a rapid 1,2-shift occurred upon treatment of diol 10
with triethylamine and methanesulfonyl chloride (08C,
10 min), thereby giving the desired ketone 11 in 83%
yield.[3a,9] Although the intermediate mesylate was not
detected, this outcome is consistent with the selective
ꢀ
sulfonylation of the C5a OH and then an isoxazole-assisted
ionization followed by a 1,2-shift of the allyl group.[12]
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and tetrahydrofuran ring formation with subsequent hydro-
lysis to give ketone 16. The Moriarty a-hydroxylation[17] of
ketone 16 proceeded stereoselectively when using diacetoxy-
iodobenzene (KOH, methanol) to afford a-hydroxy dimeth-
ylacetal 17 as a single diastereomer. The stereochemistry of 17
was verified by X-ray analysis.[15] TPAP oxidation[18] of 17
provided ketone 18, which was then ready for the A ring
formation.
We had planned to react ketone 18 with the dianion,
generated from isoxazole 21,[19] but all attempts failed to give
the corresponding adduct. Since ketone 18 did not undergo
attack even by simpler nucleophiles (e.g. MeLi, MeMgBr), we
assumed that the failure was a result of an equilibrium
between 18 and hemiacetal 19. Attempted protection of the
tertiary alcohol in 18 was not possible, for example, treatment
of ketone 18 with TMSOTf (2,6-lutidine, CH2Cl2) only
effected the silylation of the hemiacetal 19.
At this juncture, an indirect protocol was devised
(Scheme 4). After bis-silylation of diol 17, exposure of bis-
silyl ether 22 to (HF)xpy allowed selective desilylation of the
secondary silyl ether to give mono-alcohol 23, which was
oxidized to furnish ketone 24. Pleasingly, ketone 24 under-
went nucleophilic attack by the dianion generated from 21,
thus affording alcohol 25 in 69% yield. Desilylation of 25 and
then hydrolysis of the resulting acetal gave a ketone. Dess–
Martin oxidation[20] of the primary alcohol afforded ketoal-
dehyde 26.
Benzoin cyclization of 26 proceeded nicely using triazo-
lium salt 27[21] (20 mol%) and DBU (20 mol%) in MeOH
(RT, 30 min), to give ketol 28 in 90% yield with excellent
diastereoselectivity (d.r. 15:1). The stereochemistry of 28 was
verified by single-crystal X-ray analysis.[15]
Hydrogenation of 28 in the presence of PdCl2 effected
debenzylation and reductive cleavage of two isoxazoles to
give enaminone 29, and Dess–Martin oxidation[20] of the
secondary alcohol gave ketone 30. Conventional acidic
conditions proved ineffective for the hydrolysis of the two
enaminones in 30 to yield the corresponding 1,3-diketones.
After a series of trials the hydrolysis of the C11–C12
enaminone was realized by diazotization using tBuONO,[22]
and a basic workup (1m NaOH) hydrolyzed the C13–C3
enaminone to give 1,3-diketone 31.[23] The final step was the
selective demethylation, which was achieved by using NaI and
CeCl3·7H2O.[24–26] The synthetic material was identical in all
respects (1H, 13C NMR, IR, HRMS) to the natural sample
30
except for the sign of optical rotation: ½aꢁD ¼ꢀ144 (c = 1.00,
26
MeOH), lit. ½aꢁD ¼ + 146 (c = 1.0, MeOH), thereby allowing
assignment of the synthetic material as the antipode of the
natural product.
In summary, we have achieved the first asymmetric total
synthesis of (ꢀ)-seragakinone A. Noteworthy features of the
synthesis include: 1) the benzoin-forming reactions, which
worked well to effect two separate cyclizations, including one
catalytic enantioselective reaction, 2) the pinacol-type rear-
Scheme 4. Endgame. Reagents and conditions: a) TMSOTf, 2,6-lutidine, CH2Cl2, 08C, 30 min (94%); b) (HF)xpy, THF, ꢀ78!08C, 8 h (99%);
c) Dess–Martin periodinane, NaHCO3, CH2Cl2, RT, 5 h (97%); d) 21 (3 equiv), nBuLi (6 equiv), THF, ꢀ788C, 2 h then 24, THF, ꢀ788C, 30 min
(69%); e) TsOH·H2O, H2O, THF, reflux, 4.5 h (82%); f) Dess–Martin periodinane, CH2Cl2, RT, 1 h (90%); g) 27 (20 mol%), DBU (20 mol%),
MeOH, RT, 30 min (90%, d.r. 15:1); h) H2 (balloon), PdCl2, MeOH, H2O, AcOH, RT, 2 h (96%); i) Dess–Martin periodinane, CH2Cl2, RT, 1 h
(80%); j) tBuONO, CF3CO2H, DMSO, RT, 21 h then 1m NaOH aq., RT, 1.5 h; k) NaI, CeCl3·7H2O, CH3CN, reflux, 33 h (49%, 2 steps).
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMSO=dimethyl sulfoxide, py=pyridine, Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl.
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of this reaction, we are tempted to propose that such a
rangement that was effective for installing the angular prenyl
substituent and, 3) determination of the absolute configura-
tion of the natural product.
=
mechanism applies also to a “sulfene” intermediate (CH2 SO2).
Received: October 18, 2010
Published online: February 3, 2011
Keywords: antibiotics · cyclization · natural products ·
.
organocatalysis · total synthesis
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ꢀ
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ꢀ
facile ionization and a 1,2-shift, whereas coordination of an LA
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ꢀ
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[25] Other demethylation methods (e.g. BBr3, BCl3, nBu4NI, and
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