Total synthesis of (+)-gregatin B and e

Article abstract of DOI:10.1021/ol402472q

The first total synthesis of (+)-gregatin E and a new total synthesis of (+)-gregatin B are described. Key features of our synthetic approach involve a palladium-catalyzed cyclization-methoxycarbonylation of optically active propargylic acetate and a Suzuki-Miyaura coupling or CuTC-mediated coupling reaction. The absolute configuration of (+)-gregatin E (5R,5′S) is proposed.

Full text of DOI:10.1021/ol402472q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Total Synthesis of (þ)-Gregatin B and E
000–000
Taichi Kusakabe, Yasuko Kawai, and Keisuke Kato*
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba,
2
74-8510, Japan
kkk@phar.toho-u.ac.jp
Received August 27, 2013
ABSTRACT
The first total synthesis of (þ)-gregatin E and a new total synthesis of (þ)-gregatin B are described. Key features of our synthetic approach involve
a palladium-catalyzed cyclizationꢀmethoxycarbonylation of optically active propargylic acetate and a SuzukiꢀMiyaura coupling or CuTC-mediated
0
coupling reaction. The absolute configuration of (þ)-gregatin E (5R,5 S) is proposed.
Gregatins, aspertetronins, and penicilliols are natural
products isolated from Cephalosporium gregatum, Asper-
gillus rugulosus, and Penicillium daleae, respectively, which
1
possess 4-oxo-3-furancarboxylate skeletons. Initially, the
core structures of these compounds were believed to be
furan-2(5H)-ones 1 (Figure 1). However, the originally
proposed structure has been revised twice. Most recently,
BurghartꢀStoll and Br u€ ckner reported the total synthesis
and structural revision of gregatins AꢀD and aspertetro-
nins A and B, together with a plausible structural revision
Figure 1. Original 1, revised 2, and rerevised structure of
gregatins 3.
1
b,2
1
based on H NMR spectroscopic com-
of gregatin E
3
parison to related compounds. The absolute and relative
configurations of gregatin E have not yet been determined.
4b
-dihydro-4-oxo-3-furancarboxylate skeleton 3. For the
5
construction of the diene moiety of the side chain, this
II
Previously, we reported the Pd -catalyzed cyclizationꢀ
4
a
methoxycarbonylation of propargylic acetates and its
application to the construction of the 2,5,5-trialkyl-4,
3a
precedent utilized dehydration of the corresponding
homoallylic alcohols. This method may not be suitable
for the synthesis of (þ)-gregatin E (3a) bearing an addi-
tional hydroxy group in the side chain. In this paper, we
would like to report the first total synthesis of (þ)-gregatin
E (3a) and a new total synthesis of (þ)-gregatin B based on
(
1) (a) Ballantine, J. A.; Ferrito, V.; Hassall, C. H.; Jones, V. I. P.
J. Chem. Soc. 1969, 56–61. (b) Kobayashi, K.; Ui, T. Tetrahedron Lett.
975, 4119–4122. (c) Kimura, T.; Takeuchi, T.; Kumamoto-Yonezawa,
1
Y.; Ohashi, E.; Ohmori, H.; Masutani, C.; Hanaoka, F.; Sugawara, F.;
Yoshida, H.; Mizushina, Y. Bioorg. Med. Chem. 2009, 17, 1881–1816.
(
2) Zhan, Z.-J.; Jin, J.-P.; Ying, Y.-M.; Shan, W.-G. Helv. Chim. Acta
011, 94, 1454–1458.
3) (a) Burghart-Stoll, H.; Br u€ ckner, R. Eur. J. Org. Chem. 2012,
012, 3978–4017. (b) Burghart-Stoll, H.; Br u€ ckner, R. Org. Lett. 2011,
3, 2730–2733.
2
(4) (a) Kato, K.; Yamamoto, Y.; Akita, H. Tetrahedron Lett. 2002,
43, 6587–6590. (b) Kato, K.; Nouchi, H.; Ishikura, K.; Takaishi, S.;
Motodate, S.; Tanaka, H.; Okudaira, K.; Mochida, T.; Nishigaki, R.;
Shigenobu, K.; Akita, H. Tetrahedron 2006, 62, 2545–2554.
(
2
1
1
0.1021/ol402472q r XXXX American Chemical Society

our carbonylation chemistry and Pd- or Cu-mediated
5
coupling reactions.
Scheme 2. Preparation of Diacetate (S)-8
Scheme 1. Retrosynthetic Analysis of (þ)-Gregatins B and E
Retrosynthetically, gregatins B and E (3a and 3c) can
be obtained by the coupling reaction of a vinyl iodide with
a vinyl stannane or borate, which may be derived from
Scheme 3. Synthesis of Vinyl Stannane 5 (right half)
2-butyne and (R)-6 (Scheme 1). The 4-oxo-3-furancarbox-
ylate skeleton of (R)-6can be constructed by Knoevenagelꢀ
Claisen type condensation of the corresponding γ-acetoxy-
β-ketoester, which can be obtained by hydrolysis of the
4
orthoester (R)-7. The synthesis of (R)-7 can be achieved
II
by Pd -catalyzed cyclizationꢀmethoxycarbonylation of
optically active propargyl acetate (S)-8.
Since the configuration of gregatin E (3a) was unknown
0
(
C5 and C5 ), we assumed the same absolute configura-
3
tion at C5 as established for gregatins AꢀD. Thus, the
total synthesis started with the preparation of the optically
active propargyl acetate (S)-8 in seven steps according
6
to the reported procedure (Scheme 2). Asymmetric di-
hydroxylation of the Weinreb amide 9 derived from
methacrylic acid gave diol (R)-10 in 90% yield with 92%
ee. Silylation of (R)-10 followed by reduction with DIBAL
afforded the aldehyde (R)-12 in 91% yield (two steps).
CoreyꢀFuchs homologation and subsequent desilylation
gave the corresponding diol, which was converted to
propargyl acetate (S)-8 in 75% yield (four steps).
8
tentatively assumed that DMSO acted as a ligand to
prevent the dimerization. The acetoxymethyl group in
(
R)-14 was transformed into the desired terminal alkyne
via a three-step sequence: hydrolysis of (R)-14, followed by
The synthesis of the vinyl stannane (R)-5a is detailed
in Scheme 3. The oxidative cyclizationꢀcarbonylation
oxidation toaffordthe corresponding aldehyde, which was
9
II
of propargyl acetate (S)-8 mediated by Pd in DMSO/
treated with OhiraꢀBestmann reagent to afford terminal
alkyne (R)-7 in 74% yield (three steps). According to our
MeOH afforded cyclic orthoester (R)-14 in 79% yield
as the sole product. When the reaction was performed
in MeOH, dimeric ketone 15 was obtained in 10% yield
4
b
previously reported procedure, the 4-oxo-3-furancar-
boxylate skeleton was constructed via a two-step sequence:
acid treatment of the orthoester (R)-7 followed by
KnoevenagelꢀClaisen type condensation to give the 4-oxo-
7
together with (R)-14 (59%). Although we do not have
a clear explanation for the solvent effects at this stage, we
3
-furancarboxylate 6in 71% yield (two steps). Regioselective
palladium-catalyzed hydrostannylation of 6 afforded vinyl
10
stannane (R)-5a in 82% yield.
(
5) (a) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
748–2749. (b) Wang, M.; Lin, Z. Organometallics 2010, 29, 3077–3084.
c) Burghart-Stoll, H.; Kapferer, T.; Br u€ ckner, R. Org. Lett. 2011, 13,
2
(
Since the absolute configuration of the secondary alco-
0
1
016–1019.
hol in the side chain (C5 ) was unknown, both enantiomers
(
537. (b) Avenoza, A.; Cativiela, C.; Peregrina, J. M.; Sucunza, D.;
6) (a) Knight, D. W.; Qing, X. Tetrahedron Lett. 2009, 50, 3534–
3
Zurbano, M. M. Tetrahedron: Asymmetry 2001, 12, 1383–1388.
(8) Diao, T.; White, P.; Guzei, I.; Stahl, S. S. Inorg. Chem. 2012,
11898–11909.
(9) (a) Ohira, S. Synth. Commun. 1989, 19, 561–564. (b) M u€ ller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521–522.
(10) Darwish, A.; Lang, A.; Kim, T.; Chong, J. M. Org. Lett. 2008,
10, 861–864.
(
7) (a) Cyclizationꢀcarbonylationꢀcyclization coupling reactions of
propargyl acetates; Yasuhara, S.; Sasa, M.; Kusakabe, T.; Takayama,
H.; Kimura, M.; Mochida, T.; Kato, K. Angew. Chem., Int. Ed. 2011, 50,
3
912ꢀ3915. (b) The use of (CH
3 2 2
CN) PdCl resulted in decreased yields
of (R)-14 (67%).
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 4. Synthesis of Iodoalkene 4 (left half)
Scheme 6. Total Synthesis of (þ)-Gregatin E (3a) and Its
Diastereomer 3b
a
Scheme 5. Preliminary Experiments for the Coupling Reaction
a
Table 1. Total Synthesis of (þ)-Gregatin B (3c)
a
3 4
Conditions: (A) (Ph P) Pd, CuI, THF, reflux, 7 h, 41%; (B) CuTC
(1.5 equiv), NMP, 0ꢀ10 °C, 5 h, 82%.
of the vinyl iodide [(R)-4a and (S)-4a] were prepared
1
independently (Scheme 4). Hydrostannylation of known
1
1
2
silyl ether 16 followed by treatment with iodine, and
subsequent desilylation, afforded (R)-4a and (S)-4a in
good yields.
entry
5
4
conditions
yield (%)
3c/3d
With vinyl stannane (R)-5a and vinyl iodides (R)-4a and
S)-4a in hand, the stage was now set for the coupling
1
2
3
4
(()-5a
(()-5a
(()-5b
(þ)-5b
4b
4b
4c
4d
(A)
(B)
(A)
(C)
46
84
60
80
1/1.2
7.7/1
>99/1
>99/1
(
reaction. In preliminary experiments (Scheme 5), the Stille
13
coupling reaction of (()-5a with vinyl iodide (()-17 was
investigated [(Ph P) Pd, CuI, refluxed for 7 h in THF]. An
3
4
a
inseparable mixture of (()-18a and (()-18b (1:1) was
obtained in 41% yield along with a mixture of unidentified
compounds. The yield was improved (82%) using the
Conditions: (A) PdCl (CH
2
3
CN)
2
(10 mol %), CuI (20 mol %),
P)
DMF, rt, 6.5 h; (B) CuTC (1.7 equiv), NMP, 0 °C, 2.5 h; (C) Pd(Ph
10 mol %), TBAF (1.5 equiv), THF, 10 °C, 13 h.
3
4
(
5
CuTC-mediated coupling reaction. Unfortunately, fluoride-
mediated desilylation (TBAF, HFꢀpyridine, and
Next, similar coupling reactions were investigated for
the synthesis of (þ)-gregatin B (3c) (Table 1). Stille cou-
HFꢀEt N) of the mixture of (()-18a and (()-18b failed.
3
1
6
A mixture of (()-3a and (()-3b was obtained in 25% yield,
due to the instability of the products under the current
reaction conditions.
pling reaction of (()-5a with vinyl iodide 4b gave a
mixture of (()-3c and (()-3d in 46% yield (ratio =
5
c,17
1:1.2) (entry 1).
The yield was improved by using the
Thus, we turned our attention to the reaction of un-
protected vinyl iodides (R)-4 and (S)-4 (Scheme 6).
Although the Stille coupling reaction of (()-5a with vinyl
CuTC-mediated coupling reaction, but (()-3d was still
produced as a minor product (entry 2). As mentioned
above [Scheme 5, condition (A)], isomerization of the
olefinic configuration was not observed when using steri-
cally bulky vinyl iodide (()-17. Therefore, we next inves-
tigated the Stille coupling reaction of 4c with sterically
bulky vinyl iodide (()-5b prepared from (()-5a (entry 3).
(()-3c was obtained in 60% yield without isomerization.
Using the SuzukiꢀMiyaura coupling reaction, the yield of
(þ)-3c was improved (80%) without erosion of the double
1
4
iodide (()-4a failed, the CuTC-mediated coupling reac-
tion gave good results. (þ)-Gregatin E (3a) and its diaste-
reomer (þ)-3b were obtained from (S)-4a and (R)-4a
1
8
1
in 77% and 84% yields, respectively. The H NMR data
of these diastereomers matched those provided in the
1
b
1
13
literature. Although the H- and C NMR spectra of
(
1
5
þ)-3a were extremely similar to those of (þ)-3b, the
absolute configuration of natural (þ)-gregatin E was
0
proposed to be (5R, 5 S) based on the melting point.
(16) Alexakis, A.; Duffault, J. M. Tetrahedron Lett. 1988, 29, 6243–6246.
(
17) The similar isomerization during the Stille or Suzuki coupling
reaction has been reported. Reaction of (Z)-alkenyl halides: (a) Lu,
G.-P.; Voigtritter, K. R.; Cai, C.; Lipshutz, B. H. Chem. Commun. 2012,
48, 8661–8663. (b) Lu, G.-P.; Voigtritter, K. R.; Cai, C.; Lipshutz, B. H.
J. Org. Chem. 2012, 77, 3700–3703. For the reaction of (E)-alkenyl
halides, see ref 5c.
(
(
11) Darwish, A.; Chong, J. M. Tetrahedron 2012, 68, 654–658.
12) Robinson, J. E.; Brimble, M. A. Org. Biomol. Chem. 2007, 5,
2
572–2582.
(
(
(
13) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508–519.
14) Complex mixture was obtained.
15) See the Supporting Information.
(18) Jackson, S. K.; Banfield, S. C.; Kerr, M. A. Org. Lett. 2005, 7,
1215–1218.
Org. Lett., Vol. XX, No. XX, XXXX
C

bond stereochemistry (entry 4). Spectroscopic data of
both (þ)-3c and (()-3d were in full agreement with those
reported by Br u€ ckner and Burghart-Stoll.
The detailed reaction mechanism for the isomerization
during the coupling reaction is now under investigation in
our laboratory.
In conclusion, the first total synthesis of (þ)-gregatin
E (3a) and a new total synthesis of (þ)-gregatin B (3c)
have been achieved. The furanone skeleton was effec-
Acknowledgment. This work was supported by a JSPS
KAKENHI grant (no. 24790026).
II
tively constructed based on Pd -catalyzed cyclizationꢀ
methoxycarbonylation of optically active propargyl acetate
(
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, copy of NMR spectra. This
material is available free of charge via Internet at http://
pubs.acs.org.
S)-8. The (E,E)-diene moiety was successfully prepared by
II
a Pd - or CuTC-mediated coupling reaction with retention
of the olefinic configuration. This methodology is applicable
for the synthesis of penicilliols A and B bearing a hydroxy
group in the (E,E)-diene side chain.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX