Total synthesis of auripyrones A and B and determination of the absolute configuration of auripyrone B

Article abstract of DOI:10.1002/anie.200906662

(Figure Presented) The winner takes it aldol: The total synthesis of auripyrones A and B was achieved using a diastereoselective aldol-type reaction with 2, 6-diethyl-3, 5-dimethyl-4-pyrone as a key step. The stereostructure and absolute configura-tion of auripyrone B has also been determined.

Full text of DOI:10.1002/anie.200906662

Angewandte
Chemie
DOI: 10.1002/anie.200906662
Natural Product Synthesis
Total Synthesis of Auripyrones A and B and Determination of the
Absolute Configuration of Auripyrone B**
Ichiro Hayakawa, Takuma Takemura, Emi Fukasawa, Yuta Ebihara, Natsuki Sato,
Takayasu Nakamura, Kiyotake Suenaga, and Hideo Kigoshi*
Compounds containing the g-pyrone functional group have
been isolated from marine animals (Figure 1).[1] These com-
pounds show valuable biological activities: for example,
peroniatriols I (1) and II (2) exhibited significant cytotoxicity
against L1210 cells.[2] Also, vallartanone B (3)[3] and onchi-
dione (4)[4] are chemical defense compounds of mollusks.
Therefore, the development of a method to synthesize g-
pyrone-containing compounds is an important topic in natural
product synthesis.
Figure 2. Structures of auripyrone A and B.
In 1996, auripyrones A (5) and B (6) were isolated from
the sea hare Dolabella auricularia (Aplysiidae) by Yamada
and co-workers (Figure 2).[5] Auripyrones A (5) and B (6)
exhibited cytotoxicity against HeLa S3 cells with IC50 values of
0.26 and 0.48 mgmLꢀ1, respectively. The relative stereochem-
istry of the two compounds, except for the configuration of
C2’ in auripyrone B (6), were deduced using detailed
spectroscopic analysis to be structures 5 and 6. The main
structural features of auripyrones are a g-pyrone ring and a
spiroacetal moiety.
In 2006, Perkins and Lister achieved the first total
synthesis of auripyrone A (5), the key reaction of which was
spiroacetalization.[6] This synthesis determined the absolute
configuration of auripyrone A (5). Very recently, Jung and
Salehi-Rad reported the total synthesis of auripyrone A (5)
using a tandem non-aldol aldol/Paterson aldol process as a
key step.[7] However, the configuration of auripyrone B (6) at
the C2’ position remained unknown. Therefore, we decided to
complete the syntheses of auripyrones A (5) and B (6) and to
determine the absolute configuration of auripyrone B (6).
Our retrosynthetic analyses of auripyrones A (5) and B
(6) are shown in Scheme 1. We expected that a spiroacetal-
ization of triketone 7, as was utilized in the total synthesis by
Perkins and Lister,[6] would provide auripyrones A and B.
Triketone 7 might be obtained from an aldol reaction between
C1–C13 segment 8 and C14–C20 segment 9. The five
contiguous chiral centers in C1-C13 segment 8 could be
prepared by a crotylboration and diastereoselective aldol-
type reaction[8] between 2,6-diethyl-3,5-dimethyl-4-pyrone
(12) and the optically active aldehyde 13 as the key steps.
Recently, we reported the diastereoselective aldol-type
reaction between 2,6-diethyl-3,5-dimethyl-4-pyrone (12) and
different aldehydes (Scheme 2).[8] This reaction has the
advantages of affording straightforward access even to
complex molecules and the construction of two stereogenic
centers at once.
Figure 1. Marine natural products that contain the g-pyrone frame-
work.
[*] Dr. I. Hayakawa, T. Takemura, E. Fukasawa, Y. Ebihara, N. Sato,
T. Nakamura, Dr. K. Suenaga,[+] Prof. Dr. H. Kigoshi
Department of Chemistry, Graduate School of Pure and Applied
Sciences, University of Tsukuba
1-1-1 Tennodai, Tsukuba 305-8571 (Japan)
Fax: (+81)29-853-4313
E-mail: kigoshi@chem.tsukuba.ac.jp
[+] Present address: Department of Chemistry, Faculty of Science and
Technology, Keio University
3-14-1 Hiyoshi, Kohoku, Yokohama, Kanagawa 223-8522 (Japan)
[**] This work was supported by Grants-in-Aid for Scientific Research
(B), and Scientific Research on Priority Area “Creation of Biolog-
ically Functional Molecules” from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) (Japan). We thank
the Kaneka Corporation for their gift of methyl d-(R)-b-hydroxyiso-
butanoate.
The starting point for this work was the construction of
C1-C13 segment 20 (Scheme 3). The diastereoselective aldol-
type reaction between 2,6-diethyl-3,5-dimethyl-4-pyrone
(12)[9] and the known compound, optically active aldehyde
14,[10] afforded the desired compound 15 in 47% yield along
with other diastereomers (21% yield).[8] The stereochemistry
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906662.
1
of 15 was determined using H–1H coupling constants and
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Scheme 3. Synthesis of the C1-C13 segment (20). Reagents and
conditions: a) NaHMDS, THF, ꢀ788C, 47% yield; b) TBSCl, imida-
zole, DMF, 99% yield; c) HCO2H, Et2O, RT; d) 25% NH3 aq., MeOH,
RT, 92% yield over 2 steps; e) (COCl)2, DMSO, iPr2NEt, CH2Cl2,
ꢀ788C then 08C, 99% yield; f) 18, BF3·OEt2, THF, ꢀ408C then NaOH,
H2O2, 71% yield; g) isovaleryl chloride, DMAP, pyr, RT, quantitative
yield; h) OsO4, NMO, acetone/H2O (1:1), RT, 90% yield; i) NaIO4,
acetone/H2O (1:1), RT, 72%. Tr=triphenylmethyl, NaHMDS=sodium
hexamethyldisilazide, THF=tetrahydrofuran, TBS=tert-butyldimethyl-
silyl, DMF=N,N-dimethylformamide, DMSO=dimethyl sulfoxide,
DMAP=4-dimethylaminopyridine, pyr=pyridine, NMO=N-methyl-
morpholine oxide.
Scheme 1. Retrosynthetic analyses of auripyrones A (5) and B (6).
C14–C20 segment 22 was prepared as follows. Aldehyde
21 was synthesized from commercially available (S)-2-methy-
1-butanol using a previously reported method.[14] The aldol
reaction between aldehyde 21 and 3-pentanone, and protec-
tion of the resulting secondary hydroxy group afforded C14–
C20 segment 22 as a diastereomeric mixture (Scheme 4). This
segment 22 was used for the next reaction without separation
because the configurations of these newly generated stereo-
centers were either lost by oxidation or epimerization in the
subsequent steps.
Scheme 2. Aldol-type reaction of 2,6-diethyl-3,5-dimethyl-4-pyrone (12)
NaHMDS=sodium hexamethyldisilazide, THF=tetrahydrofuran.
NOESY correlations of the corresponding acetonide deriva-
tive.[8] The secondary hydroxy group in compound 15 was
protected as a TBS ether to afford compound 16. The trityl
group was removed, and the primary hydroxy group was
oxidized by Swern oxidation to give aldehyde 17. The Brown
crotylboration reaction[11] between aldehyde 17 and boronate
18 afforded homoallylic alcohol 19 as a single diastereomer.[12]
Acylation of the secondary hydroxy group in 19 and
subsequent dihydroxylation of the terminal olefin gave a
diol in 90% yield. Oxidative cleavage of the resulting
dihydroxy group with NaIO4 afforded aldehyde 20 as a C1–
C13 segment. This two-step procedure was superior to the
direct Lemieux-Johnson conditions[13] in both yield and
reproducibility because of the instability of aldehyde 20.
Scheme 4. Synthesis of the C14-C20 segment (22). Reagents and
conditions: a) (COCl)2, DMSO, iPr2NEt, CH2Cl2, ꢀ788C then 08C, 30%
yield; b) LDA, 3-pentanone, THF, ꢀ788C, 89% yield; c) TESCl, imida-
zole, DMF, RT, 95% yield. DMSO=dimethyl sulfoxide, LDA=lithium
diisopropylamide, THF=tetrahydrofuran, TES=triethylsilyl,
DMF=N,N-dimethylformamide.
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With both C1–C13 segment 20 and C14–C20 segment 22
in hand, we attempted the coupling reaction between 20 and
22. Although g-pyrone compounds are readily deprotonated
at the a-alkyl group by LDA, LHMDS, NaHMDS, and
KHMDS, which often results in the formation of by-products,
the Paterson aldol reaction[15] by Sn(OTf)2 and Et3N gave
coupling compound 23 as a diastereomeric mixture in good
yield (Scheme 5). Selective removal of the TES group in 23
Figure 3. Spiroacetalization of triketone 24.
equatorial position (hemiacetal 24b) so as to avoid a 1,3-
diaxial interaction between the C12 and C14 methyl groups of
24a.
Scheme 5. Completion of the synthesis of auripyrone A (5). Reagents
and conditions: a) Sn(OTf)2, Et3N, CH2Cl2, ꢀ788C, 99% yield;
b) AcOH/THF/H2O (4:1:4), RT, 73% yield; c) Dess–Martin period-
inane, CH2Cl2, RT, 83% yield; d) HF·pyr/THF/pyr (5:7:3), 608C, 22%
yield. OTf=trifluoromethanesulfonate, Ac=acetyl, THF=tetrahydro-
furan, pyr=pyridine.
Next, we attempted the synthesis of (2’S)- and (2’R)-
auripyrone B. First, we tried to remove the acyl group in
auripyrone A (5). However, whilst we could not obtain a de-
acylated derivative, we did obtain a bis(pyrone) compound.
Then, we attempted to convert homoallylic alcohol 19 into
auripyrone B using our synthetic strategy for auripyrone A
(5; Scheme 6). An esterification reaction between compound
19 and (S)-2-methylbutyric acid (25)[16] under the conditions
described by Yamaguchi et al.[17] afforded compound 26.
Dihydroxylation of the terminal olefin in 26 gave a diol, and
the resulting dihydroxy group was oxidatively cleaved to
afford aldehyde 27. The Paterson aldol reaction[15] of alde-
hyde 27 and C14-C20 segment 22 afforded the coupling
product 28 as a diastereomeric mixture. The TES group in 28
was removed, and oxidation of the dihydroxy group afforded
triketone 29 as a mixture of the keto and enol forms, a
precursor for the spiroacetalization reaction. Removal of the
TBS group in triketone 29 by HF·pyr and a spontaneous
spiroacetalization afforded (2’S)-auripyrone B (30).
The (2’R)-auripyrone B (33) was also prepared from 19 in
the same manner with (R)-2-methylbutyric acid (31)[16]
(Scheme 7).
gave a diol that was converted into triketone 24 using Dess–
Martin periodinane; triketone 24 was an equilibrium mixture
of the keto and enol forms. Cleavage of the TBS ether group
in triketone 24 by HF·pyr and a spontaneous spiroacetaliza-
tion reaction afforded auripyrone A (5). Synthetic auripyr-
one A (5) gave spectral data (1H NMR and 13C NMR
spectroscopy, HRMS, and optical rotation) that were in full
agreement with those of the natural compound,[5] thus
completing the total synthesis.
Stereocontrol of the C14 methyl group in the spiroacetal-
ization to afford auripyrone A (5) can be explained as follows
(Figure 3). Triketone 24 was transformed into hemiacetals
24a and 24b. The stereochemistry of C13 in hemiacetals 24a
and 24b was controlled by the double anomeric effect. The
C14 methyl group in hemiacetal 24a was epimerized into the
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Scheme 7. Completion of the synthesis of (2’R)-auripyrone B (33).
Reagents and conditions: a) 31, 2,4,6-trichlorobenzoyl chloride, Et3N,
DMAP, toluene, ꢀ788C to 08C, 94% yield. DMAP=4-dimethylamino-
pyridine.
Figure 4. Absolute stereochemistry of auripyrone B (6).
In conclusion, we have achieved the total synthesis of
auripyrones A (5; 2.6% overall yield in 13 steps) and B (6;
2.8% overall yield in 13 steps) by using a diastereoselective
aldol-type reaction with 2,6-diethyl-3,5-dimethyl-4-pyrone
(12) as a key step. From this synthetic work, we determined
the stereostructure and absolute configuration of auripyro-
ne B (6). Further application of the diastereoselective aldol-
type reaction with 2,6-diethyl-3,5-dimethyl-4-pyrone (12) is
currently underway in our group.
Scheme 6. Completion of the synthesis of (2’S)-auripyrone B (30).
Reagents and conditions: a) 21, 2,4,6-trichlorobenzoyl chloride, Et3N,
DMAP, toluene, ꢀ788C to 08C, 93% yield; b) OsO4, NMO, acetone/
H2O (1:1), RT, 94% yield; c) NaIO4, acetone/H2O (1:1), RT, 82% yield;
d) Sn(OTf)2, Et3N, CH2Cl2, ꢀ788C, 99% yield; e) AcOH/THF/H2O
(4:1:4), RT, 90% yield; f) Dess–Martin periodinane, CH2Cl2, RT, 95%
yield; g) HF·pyr/THF/pyr (5:7:3), 608C, 17% yield. DMAP=4-dimethyl-
aminopyridine, NMO=N-methylmorpholine oxide, OTf=trifluorome-
thanesulfonate, Ac=acetyl, THF=tetrahydrofuran, pyr=pyridine.
Received: November 26, 2009
Revised: January 19, 2010
Published online: February 23, 2010
Keywords: aldol reactions · auripyrones · diastereoselectivity ·
.
natural products · total synthesis
With both diastereomers (2’S)-auripyrone B (30) and
(2’R)-auripyrone B (33) in hand, we compared the H NMR
1
spectra of their synthetic samples with those reported for the
natural sample of auripyrone B (6).[18] Although the chemical
shifts of the acyl group protons (H4’, H5’) in (2’R)-auripyr-
one B (33) were clearly different from those of the natural
auripyrone B (6), the data for (2’S)-auripyrone B (30) were in
good agreement with those of the natural product. Compar-
ison of the optical rotation of synthetic (2’S)-auripyrone B
(30) with that of natural samples identified the absolute
configuration: the optical rotation of synthetic (2’S)-auripyr-
one B (30) {½aꢁ2D5 = + 43 (c = 0.29, CHCl3)} corresponded to
the reported values {½aꢁ2D6 = + 39 (c = 0.14, CHCl3)}. There-
fore, this synthesis established the stereochemistry and
absolute configuration at C2’ of auripyrone B (6; Figure 4).
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