Enantioselective total synthesis of (-)- and (+)-petrosin

Article abstract of DOI:10.1021/ol1022257

The enantioselective total synthesis of (-)- and (+)-petrosin is described. The union of two key segments was executed by Suzuki-Miyaura coupling. The quinolizidine rings were stereoselectively constructed via a diastereoselective Mannich reaction and an aza-Michael reaction. The 16-membered ring was constructed by ring-closing metathesis with the second-generation Grubbs catalyst.

Full text of DOI:10.1021/ol1022257

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5196-5199
Enantioselective Total Synthesis of (-)-
and (+)-Petrosin
Hiroki Toya,† Kentaro Okano,† Kiyosei Takasu,†,‡ Masataka Ihara,†,§
Atsushi Takahashi,| Haruo Tanaka,| and Hidetoshi Tokuyama*,†
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity, Aramaki,
Aoba-ku, Sendai 980-8578, Japan, and Faculty of Pharmacy and College of Science
and Engineering, Iwaki Meisei UniVersity, Iwaki, Fukushima 970-8551, Japan
tokuyama@mail.pharm.tohoku.ac.jp
Received September 17, 2010
ABSTRACT
The enantioselective total synthesis of (-)- and (+)-petrosin is described. The union of two key segments was executed by Suzuki-Miyaura
coupling. The quinolizidine rings were stereoselectively constructed via a diastereoselective Mannich reaction and an aza-Michael reaction.
The 16-membered ring was constructed by ring-closing metathesis with the second-generation Grubbs catalyst.
The bisquinolizidine alkaloid petrosin (1) isolated as a
racemate from the marine sponge Petrosia seriata by
Braekman1a and from the Xestospongia sp. by Kobayashi
and Kitagawa1b possesses activity against HIV by inhibi-
tion of reverse transcriptase and giant cell formation.1c
In 1994, Heathcock and co-workers reported the first
racemic total synthesis of (()-1 and other isomers.2 They
also revealed stereocenters of the quinolizidine ring epimerized
via formation of bisimine derivative, retro-Mannich, and Man-
nich reactions by treatment with PrNH3OAc at 95 °C.2a Since
optically active petrosin cannot be obtained either from natural
sources or by chemical synthesis, the structural stability and
differences of biological activity have not yet been fully
investigated. In this paper, we describe the enantioselec-
tive total synthesis of (-)- and (+)-petrosin and their bioac-
tivity.
In our retrosynthetic analysis, we set diester 2 as a
precursor of (-)-1 (Scheme 1). Formation of the 16-
membered ring by ring-closing metathesis (RCM) and
subsequent construction of quinolizidine rings by an
intramolecular aza-Michael reaction of a dienone deriva-
tive would lead to (-)-1. Diester 2 could be prepared from
iodide4andalkylborane5byintermolecularSuzuki-Miyaura
coupling and conversion to diene. Segments 4 and 5 would
be accessible from the common piperidine intermediate
6, which could be prepared by the Mannich reaction
from 7.
† Tohoku University.
‡ Current address: Graduate School of Pharmaceutical Sciences, Kyoto
University.
§ Current address: Drug Discovery Science Research Center, Hoshi
University.
| Iwaki Meisei University.
(1) (a) Braekman, J. C.; Daloze, D.; Macedo de Abreu, P.; Piccinni-
Leopardi, C.; Germain, G.; Van Meerssche, M. Tetrahedron Lett. 1982,
23, 4277–4280. (b) Kobayashi, M.; Kawazoe, K.; Kitagawa, I. Tetrahedron
Lett. 1989, 30, 4149–4152. (c) Goud, T. V.; Reddy, N. S.; Swamy, N. R.;
Ram, T. S.; Venkateswarlu, Y. Biol. Pharm. Bull. 2003, 26, 1498–1501.
(2) (a) Scott, R. W.; Epperson, J. R.; Heathcock, C. H. J. Am. Chem.
Soc. 1994, 116, 8853–8854. (b) Scott, R. W.; Epperson, J.; Heathcock, C. H.
J. Org. Chem. 1998, 63, 5001–5012. (c) Heathcock, C. H.; Brown, R. C. D.;
Norman, T. C. J. Org. Chem. 1998, 63, 5013–5030.
10.1021/ol1022257  2010 American Chemical Society
Published on Web 10/18/2010

10 was hydrogenated with Raney nickel in the presence of
Boc anhydride,7 and the removal of the acetyl group gave
alcohol 11. When oxidation was carried out by Swern
oxidation, a significant decrease in ee (69%) was observed.
Among various oxidation conditions, TPAP oxidation was
found to efficiently prevent racemization, and 7 was obtained
as a mixture of diastereomers (4:1).
Scheme 1. Retrosynthetic Analysis of (-)-Petrosin (1)
Next, our attention was focused on introduction of the side
chain to piperidine 7 (Scheme 3). Mannich reaction of ketene
Scheme 3. Mannich Reaction with Ketene Silyl Acetal
Synthesis of optically active hemiaminal 7 commenced
with reduction of the known malonate 83 to diol 9 (Scheme
2). Diol 9 was then subjected to lipase-mediated desymme-
Scheme 2. Synthesis of Optically Active Hemiaminal 7
silyl acetal 12 (E/Z ) ca. 5:1) smoothly proceeded in the
presence of TBSOTf to afford a mixture of product 6′
(undesired) and 6 (desired) in a ratio of 1.2:1.8 Stereochem-
istry of 6 was established based on NOE experiments after
conversion to the corresponding lactone 15 by deprotection
of the TBS group and lactonization. To improve diastereo-
selectivity, modification of nucleophile and additive effects
were thoroughly investigated. To this end, we found that
thioketene silyl acetal 13 improved selectivity (dr ) 3.4:1).
After conversion of 14 to the desired ester 6 in four steps,
we obtained 6 from 7 in comparable overall yield (36%).
With the common intermediate 6 in hand, we continued
with the elaboration to vinyl iodide 4, one of two key
segments for Suzuki-Miyaura coupling (Scheme 4). The
terminal olefin in 6 was elongated by cross metathesis with
(Z)-1,4-bis(benzyloxy)but-2-ene9 under Grubbs’ modification
with p-quinone to prevent isomerization of the C-C double
trization4 followed by protection of the other hydroxy group
as a TBS ether to provide acetate 10 in 99% ee.5,6 Acetate
(3) Saidi, M. R.; Azizi, N.; Akbari, E.; Ebrahimi, F. J. Mol. Catal. A:
Chem. 2008, 292, 44–48.
(4) (a) Wang, Y.-F.; Lalonde, J. J.; Momongan, M.; Bergbreiter, D. E.;
Wong, C.-H. J. Am. Chem. Soc. 1988, 110, 7200–7205. (b) Garc´ıa-Urdiales,
E.; Alfonso, I.; Gotor, V. Chem. ReV. 2005, 105, 313–354.
(5) Enantiomeric excess was determined by HPLC as a TBDPS
ether.
(7) Liu, T.-Y.; Long, J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.; Ding, L.-
S.; Chen, Y.-C. Org. Biomol. Chem. 2006, 4, 2097–2099.
(8) (a) Othman, R. B.; Bousquet, T.; Fousse, A.; Othman, M.; Dalla,
V. Org. Lett. 2005, 7, 2825–2828. (b) Othman, R. B.; Bousquet, T.; Othman,
M.; Dalla, V. Org. Lett. 2005, 7, 5335–5337.
(6) The absolute configuration was determined by conversion of 10 to
the previously reported product, (+)-(3S)-N-tert-butoxycarbonyl-3-hy-
droxymethyl-piperidine. See Supporting Information for details.
(9) Comin, M. J.; Parrish, D. A.; Deschamps, J. R.; Marquez, V. E.
Org. Lett. 2006, 8, 705–708.
Org. Lett., Vol. 12, No. 22, 2010
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extensive efforts, the planned RCM did not proceed at all
(Scheme 6). A careful conformation analysis suggested that
Scheme 4. Synthesis of 4 for Suzuki-Miyaura Coupling
Scheme 6. Unsuccessful Ring-Closing Metathesis
bond.10 The resulting internal double bond was selectively
hydrogenated in the presence of Et3N without debenzyla-
tion.11 Finally, removal of the TBS group followed by
iodovinylation by Parrikh-Doering oxidation to aldehyde
and Wittig reaction provided the vinyl iodide 4.
The coupling partner 18 was prepared by hydroboration
of 6 with (9-BBN)2. Without separation, alkyl borane 18 was
coupled with vinyl iodide 4 to afford the desired product 3
in excellent yield (Scheme 5).12 After desilylation, one-pot
the each Boc-protected piperidine in 2 has two side chains
located in the trans diaxial position like 20, which might hamper
the reaction of two terminal alkenes. On the other hand, the
two side chains should become axial-equatorial after construc-
tion of quinolizidine rings like 21. On the basis of these
considerations, we decided to examine the RCM after formation
of quinolizidine rings, expecting that the more closely located
two terminal alkenes would promote the RCM.
Scheme 5. Key Intermolecular Suzuki-Miyaura Coupling
Another critical issue, which had to be solved before the
RCM, was stereochemistry in quinolizidine formation. Thus,
we executed a model study on the aza-Michael reaction using
a simple substrate 2213,14 (Table 1). The Boc group was
Table 1. Construction of the Quinolizidine Skeleton
entry
reagent
solvent
temp
time
48 h
yield (%)
1
2
3
NaHCO3 aq CH2Cl2
NH3 aq
wet SiO2
rt
60 °C
-
64
64
reduction of the double bond and debenzylation, PCC
oxidation of the resultant diol to dialdehyde, and finally
Wittig methylenation yielded diene 2, a precursor of (-)-
petrosin (1).
Now the stage was set for implementation of the crucial
RCM to construct the 16-membered ring. However, despite
MeOH
12 h
(CH2Cl)2 reflux 20 min
removed with zinc bromide to give 23, which was subjected
to basic conditions (entry 1).14a However, the reaction
(10) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160–17161.
(13) We synthesized 22 from racemic 6 in 7 steps in a similar manner.
See Supporting Information for details.
(11) Locardi, E.; Boer, J.; Modlinger, A.; Schuster, A.; Holzmann, B.;
Kessler, H. J. Med. Chem. 2003, 46, 5752–5762.
(14) To the best of our knowledge, there is no example of quinolizidine
synthesis by aza-Michael reaction using R-substituted enone as a substrate.
For an example of quinolizidine synthesis in a similar system, see: (a) Pilli,
R. A.; Dias, L. C.; Maldaner, A. O. J. Org. Chem. 1995, 60, 717–722. (b)
(12) (a) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743–
8744. (b) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314–321.
Maldaner, A. O.; Pilli, R. A. Synlett 2004, 1343–1346
.
5198
Org. Lett., Vol. 12, No. 22, 2010

resulted in recovery of only the starting material. The desired
quinolizidine 24 was obtained as a single isomer when using
NH3 in methanol (entry 2).14b Furthermore, wet SiO2 in
refluxing 1,2-dichloroethane was found to give quinolizidine
24 effectively as a single isomer (entry 3).15,16 The stereo-
chemistry of 24 was tentatively assigned by good agreement
Scheme 8. Synthesis of (+)-Petrosin (1)
17
1
of H NMR for the reduced compound 25 with that of
natural petrosin.
With the stage set for the endgame, diester 2 was converted
to dienone 26 by a four-step sequence (Scheme 7). After
Scheme 7. Synthesis of (-)-Petrosin (1)
of the cyano group and debenzylation gave ent-11. (+)-Petrosin
was synthesized from ent-11 in the same manner as described
above.
Both enantiomers of petrosin and monomer unit 25 were
evaluated for inhibitory activity against syncytium formation
(Table 2).21 While a significant difference was not observed
between each enantiomer, monomer unit 25 exhibited no
Table 2. Inhibition of Syncytium Formation
sample
IC50 (µM)
(-)-petrosin
(+)-petrosin
(()-25
100.2
102.3
>400
removal of the Boc group, two quinolizidine rings were
constructed by aza-Michael reaction under the established
conditions to give 27 as a sole product. To our delight, the
expected RCM of diene 27 proceeded nicely with a
combination of the second-generation Grubbs catalyst and
p-quinone18 to afford the 16-membered compound. Finally,
reduction of the double bond in the presence of Et3N19
completed the total synthesis of (-)-petrosin (1).20
inhibitory activity against giant cell formation, indicating that
the dimeric structure would be essential for bioactivity.
In conclusion, we have accomplished an enantioselective total
synthesis of (-)- and (+)-petrosin featuring construction of qu-
inolizidine rings by an aza-Michael reaction and formation of the
16-membered ring by ring-closing metathesis. We found that the
dimeric structure was essential for anti-HIV activity. Further SAR
studies are currently underway and will be reported in due course.
(+)-Petrosin was also synthesized by modification of the
synthetic route (Scheme 8). The optically active nitrile 28 was pre-
pared via lipase-mediated desymmetrization of diol 9. Reduction
Acknowledgment. We thank Prof. Motomasa Kobayashi
(Osaka Univ.) for providing spectral data of natural petrosin.
This work was supported by the MEXT, Japan, the KAK-
ENHI, a Grant-in-Aid for Scientific Research (B) (20390003),
Tohoku University G-COE program ‘IREMC,’ and the JSPS
predoctoral fellowship to H.T.
(15) Basu, B.; Das, P.; Hossain, I. Synlett 2004, 2630–2632
.
(16) The product 24 is presumably a thermodynamic product since this
isomer was obtained as a single isomer under the basic conditions with
heating (Table 1, entry 2), in which the analogous compound underwent
epimerization (ref 14b).
(17) We synthesized the partial structure 25 from 24 by hydrogenation
with Pd/C in the presence of Et3N. See Supporting Information for de-
tails.
Supporting Information Available: Experimental pro-
1
cedures including biological evaluations and H and 13C
(18) When the reaction was performed without p-quinone, a significant
decrease in yield (45%) was observed, likely due to isomerization of the
terminal C-C double bonds (ref 10).
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) When the reaction was carried out without Et3N, a decrease in yield
(<60%) was observed.
OL1022257
(20) The optical purity of the synthetic petrosin (>99% ee) was confirmed
by Mosher’s method for a diol derived from 1, which was prepared by
reduction of two carbonyl groups, indicating that epimerization of optically
active petrosin did not proceed at all in our case.
(21) Chiba, H.; Asanuma, S.; Okamoto, M.; Inokoshi, J.; Tanaka, H.;
Fujita, K.; Omura, S. J. Antibiot. 2001, 54, 818–826.
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