Enantioselective total synthesis of aperidine

Article abstract of DOI:10.1021/ol200728w

An efficient total synthesis of aperidine was accomplished using a Rh-catalyzed C-H insertion of a cis-dihydrobenzofuran ring. To circumvent the facile epimerization of the cis-dihydrobenzofuran ring, we designed and prepared the C-H insertion precursor d

Full text of DOI:10.1021/ol200728w

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2789–2791
Enantioselective Total Synthesis
of Aperidine
Toshiyuki Wakimoto,*,§,† Kakeru Miyata,† Hitoshi Ohuchi,† Tomohiro Asakawa,†
Haruo Nukaya,† Yoshihide Suwa,‡ and Toshiyuki Kan*,†
School of Pharmaceutical Sciences, University of Shizuoka and Global COE Program,
52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan, and Suntory Holdings Limited,
1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8593, Japan
wakimoto@mol.f.u-tokyo.ac.jp; kant@u-shizuoka-ken.ac.jp
Received March 17, 2011
ABSTRACT
An efficient total synthesis of aperidine was accomplished using a Rh-catalyzed CÀH insertion of a cis-dihydrobenzofuran ring. To circumvent the
facile epimerization of the cis-dihydrobenzofuran ring, we designed and prepared the CÀH insertion precursor diazoamide by Raines’ protocol.
Finally, the efficient incorporation of a guanidine group and mild deprotection conditions yielded this labile natural product.
Aperidine (1)1 and hordatine A (2)2 were isolated from
beer as muscarinic M3 receptor antagonists (Figure 1).
Recently, we reported their absolute structures and de-
scribed their antagonist activity toward the R1 adrenocep-
tor as well.3 To evaluate their potential as lead compounds
for drug development,4 an ample supply and flexible
preparation methods for 1 and 2 are strongly required.
In previous studies of the enantioselective total synthesis of
the trans-isomer 2,3 selective formation of the cis-isomer 1
was unfortunately prevented by the facile isomerization
between these two diastereomers. In general, the higher
thermodynamic stability of the trans configuration during
isomerization renders the trans-isomer predominant in
neolignans, and the cis-isomer is rarely observed in Nature.
Therefore, few reports have described the synthesis of
cis-dihydrobenzofuran rings, reflecting the scarcity
and instability of natural products containing cis-
dihydrobenzofuran.5
Figure 1. Structure and synthetic strategy for 1.
† University of Shizuoka and Global COE Program.
‡ Suntory Holdings Limited.
Recently, we developed a novel methodology to con-
struct optically active trans-dihydrobenzofuran rings via
rhodium carbenoid-mediated intramolecular CÀH inser-
tion of aryl diazoesters in the presence of a chiral
auxiliary.6 Utilizing this methodology, we accomplished
§ Present address: Graduate School of Pharmaceutical Sciences, The
University of Tokyo, Bunkyo-ku, Tokyo 113À0033, Japan.
(1) (a) Yokoo, Y.; Fujii, W.; Hori, H.; Nagao, K.; Suwa, Y.;
Taniyama, K.; Tsuji, K.; Yoshida, T.; Nukaya, H. Alcohol.: Clin. Exp.
Res. 2004, 28, 129S–133S. (b) Yamaji, N.; Yokoo, Y.; Iwashita, T.;
Nemoto, A.; Koike, M.; Suwa, Y.; Wakimoto, T.; Tsuji, K.; Nukaya, H.
Alcohol.: Clin. Exp. Res. 2007, 31, S9–S14.
(5) Natori, Y.; Tsutsui, H.; Sato, N.; Nakamura, S.; Nambu, H.;
Shiro, M.; Hashimoto, S. J. Org. Chem. 2009, 74, 4418–4421.
(6) For a review on CÀH insertion reactions: (a) Doyle, M. P.;
Mckervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synth-
esis with Diazo Compounds: From Cyclopropanes to Ylides; Wiley: New
York, 1998. (b) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103,
2861–2904.
(2) Stoessl, A. Tetrahedron Lett. 1966, 21, 2287–2292.
(3) Wakimoto, T.; Nitta, M.; Chiba, T.; Yiping, Y.; Tsuji, K.; Kan,
T.; Nukaya, H.; Ishiguro, M.; Koike, M.; Yokoo, Y.; Suwa, Y. Bioorg.
Med. Chem. Lett. 2009, 19, 5905–5908.
(4) Apers, D.; Vlietinck, A.; Pieters, L. Phytochem. Rev. 2003, 2, 201–
217.
r
10.1021/ol200728w
2011 American Chemical Society
Published on Web 04/22/2011

the total synthesis of several natural products.7 The highly
cis-selective construction from the diazoester itself using
Rh2(S-PTAD)4 and Rh2(S-PTTL)4 was reported, respec-
tively, by the Davies8 and Hashimoto5 groups. On the basis
of these findings, we envisioned that optimization and
refinement of the reaction conditions to 3 would provide
an optically active cis-dihydrobenzofuran ring of 1, as
showninScheme 1. Herein, we describeanenantioselective
synthesis of (À)-aperidine (1) with improvements to the
synthetic route employed for 2.3
proceeded, accompanied by the concomitant epimerization
at the R-position of the ester group, to give 9 (Scheme 2).
Consequently, we were confronted with the formidable
task of avoiding competitive epimerization, which gener-
ated the trans configuration in preference to the conver-
sions required for introduction of the agmatine units.
Therefore, construction of the cis-dihydrobenzofuran ring
in a later stage of the total synthesis, at least after introduc-
tion of the side chains, was required.
Scheme 2. Epimerization of 6 under Acidic and Basic
Conditions
Scheme 1. Construction of cis-Dihydrobenzofuran Ring of 6
To construct the cis-dihydrobenzofuran ring, a precur-
sor of the CÀH insertion reaction was preparedfrom4 bya
previously described method.7a The side chain was incor-
porated using the Heck reaction of 4 with methyl acrylate
to provide the trans-cinnamic ester derivative 5. After
installing a diazo group by treating with p-acetamidoben-
zenesulfonyl azide (p-ABSA) and DBU, a CÀH insertion
reaction was investigated using several rhodium catalysts
and conditions. The rhodium carbenoid-mediated intra-
molecular CÀH insertion reaction proceeded with an
increasing cis selectivity upon decreasing the temperature.
A diazoamide with embedded side chains could poten-
tially ameliorate the disadvantages of the above-described
approach through a sequence of conversions after the
CÀH insertion reaction. However, attempts to promote
CÀH insertion of the diazoamide possessing protected
guanidine groups were unsuccessful. These results sug-
gested that a side chain could be incorporated as a pro-
tected butanol amine, i.e., 9 (Scheme 3). After hydrolysis of
the diester 5, condensation of the resultant carboxylic acid
with 9 gave the amide 10. Although the diazo transfer
reaction proceeded smoothly in 5, the same reaction with
the amide 10 did not give the desired diazo compound due
to the lower pKa of the R amide group. Recently, Raines
and co-workers reported an efficient conversion to a diazo
group from an azide functionality using a novel phosphine
reagent 13.11 Considering its high reactivity and the mild
required reaction conditions, this procedure would be
suitable for incorporating the diazo group into 10. After
bromination of the ester 10 through the silylketene acetal
intermediate, displacement of the bromide with NaN3 gave
the desired R-azide amide 12. Upon treatment of 12 with
13, phosphine-mediated activation of the azide group and
amide bond formation proceeded smoothly to form an
acyl triazene intermediate 14. Without purification of 14,
subsequent transformation by treatment with aqueous
NaHCO3 successfully furnished the diazoamide 15.
9
Furthermore, the Hashimoto catalyst Rh2(S-PTTL)4
gave the best results among several catalysts tested to
furnish predominantly a cis-dihydrobenzofuran ring 6
(Scheme 1).
With the desired dihydrobenzofuran 6 in hand, we
turned our attention to incorporation of the agmatine unit 7.
Treatment of 6 with the di-Boc-agmatine 710 and AlMe3,
however, resultedinepimerizationatthe C-2position prior
to the desired amide bond formation to give 8. This
reaction presumably proceeded through the p-quinone-
methide intermediate, which was promoted by the Lewis
acid AlMe3. Next, hydrolysis of 6 by treatment with LiOH
(7) (a) Kurosawa, W.; Kan, T.; Fukuyama, T. Synlett 2003, 1028–
1030. (b) Kurosawa, W.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc.
2003, 125, 8112–8113. (c) Koizumi, Y.; Kobayashi, H.; Wakimoto, T.;
Furuta, T.; Fukuyama, T.; Kan, T. J. Am. Chem. Soc. 2008, 130, 16854–
16855.
The desired diazoamide 15 in hand, we then focused
on constructing the cis-dihydrobenzofuran ring. Upon
(8) Reddy, R. P.; Lee, G. H.; Davies, H. M. Org. Lett. 2006, 8, 3437–
3440.
(9) Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.;
Hashimoto, S. Org. Lett. 2002, 4, 3887–3890.
(11) Myers, E. D.; Raines, R. T. Angew. Chem., Int. Ed. 2009, 48,
(10) Drake, B.; Patek, M.; Lebl, M. Synthesis 1994, 579–582.
2359–2363.
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Org. Lett., Vol. 13, No. 10, 2011

Scheme 3. Preparation of CÀH Insertion Precursor 15
Scheme 4. Completion of the Total Synthesis of 1
purification was performed by the sequential combination
of gel filtration and HPLC separation.14 All spectral data
of 1 (1H, 13C NMR, IR, and HRMS) were identical to
those of the natural product, and the optical rotation,
[R]25D = À54 (c 0.14, MeOH), agreed well with reported
value of previously the (2R,3S)-1, [R]25 = À57 (c 0.2,
D
MeOH).
In conclusion, an enantioselective total synthesis of
aperidine (1) was accomplished in 10 steps from the readily
available arylacetic acid derivative 4. Our stereoselec-
tive synthesis featured the cis-selective construction of a
dihydrobenzofuran ring utilizing a Rh-catalyzed CÀH
insertion of the diazoamide 15, which was efficiently
synthesized by Raines’ protocol. After incorporation of a
guanidine group by the Mitsunobu reaction, all protecting
groups were efficiently removed by treatment with BCl3 at
low temperatures, even in the presence of an unstable
cis-dihydrobenzofuran ring. The final deprotection step
did not proceed with noticeable epimerization, suggesting
that electrostatic interactions between the embedded gua-
nidine and phenol of 1 may play a critical role in main-
taining the cis-configuration despite an inherent preference
for the epimer and generation of the trans-isomer 2.3 Thus,
we achieved the first asymmetric synthesis of 1 using
careful manipulations.
treatment of 15 with 4 mol % Hashimoto catalyst Rh2
(S-PTTL)4 at À78 °C, the CÀH insertion reaction pro-
ceeded smoothly to exclusively afford the cis-dihydroben-
zofuran 16 in 75% yield in a completely stereoselective
manner (Scheme 4). The reaction proceeded even in the
presence of the amide group, which could have decreased
the activity of the catalyst. Because the labile cis-dihydro-
benzofuran 16 can readily undergo epimerization under
acidic as well as basic conditions, extra mild conditions
were required for further conversion. After cleavage of
both TBS ethers of 16 by NH4F, a guanidine moiety was
incorporated into 17 by the Mitsunobu reaction.12 Upon
treatment of the di-Boc guanidine 18 in the presence of
the corresponding alcohol 17 with DEAD and PPh3,
smooth amination proceeded to provide the protected
aperidine 19.
After numerous attempts to circumvent the facile epi-
merization during the final deprotection step, we found
that simultaneous cleavage of the Bn ether and Boc groups
Acknowledgment. This work was financially supported
in part by the Uehara Memorial Foundation and by a
Grant-in-Aid for Scientific Research on Priority from the
Ministry of Education, Culture, Sports, Science and Tech-
nology (MEXT), Japan.
13
of 19 could be performed by treatment with BCl3
at À78 °C, and careful workup provided 1. Presumably,
Lewis acid- mediated cleavage of the Bn ether proceeded
by BCl3, and HCl-mediated hydrolysis of the Boc group
proceeded after addition of MeOH to the reaction mixture.
After removal of the solvent and resultant B(OMe)3,
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(12) (a) Mitsunobu, O. Synthesis 1981, 1–28. (b) Hughes, D. L. Org.
React. 1992, 42, 335–656.
(13) Williams, D. R.; Brown, D. L.; Benbow., J. W. J. Am. Chem.
(14) Detailed experimental procedures and spectral data are de-
scribed in the Supporting Information.
Soc. 1989, 111, 1923–1925.
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