New perspective for natural products synthesis: Concise synthesis of (+)-Sch 642305 by chiral auxiliary multiuse methodology

Article abstract of DOI:10.1021/ol702530b

The synthesis of (+)-Sch 642305 is an example of chiral auxiliary multiuse methodology, which shows a new perspective for the synthesis of compounds with multiple asymmetric centers. Thus, (+)-Sch 642305 was concisely synthesized from the known compound.

Full text of DOI:10.1021/ol702530b

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5605-5608
New Perspective for Natural Products
Synthesis: Concise Synthesis of
(+)-Sch 642305 by Chiral Auxiliary
Multiuse Methodology
Hiromichi Fujioka,* Yusuke Ohba,† Kenji Nakahara, Mayuko Takatsuji,
Kenichi Murai,† Motoki Ito, and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6 Yamada-oka,
Suita, Osaka 565-0871, Japan
fujioka@phs.osaka-u.ac.jp; kita@phs.osaka-u.ac.jp
Received October 20, 2007
ABSTRACT
The synthesis of (+)-Sch 642305 is an example of chiral auxiliary multiuse methodology, which shows a new perspective for the synthesis
of compounds with multiple asymmetric centers. Thus, (
+
)-Sch 642305 was concisely synthesized from the known compound. Every reaction
is stereoselective, and the chiral nonracemic hydrobenzoin worked as chiral auxiliary for desymmetrization of diene, as a template for attaining
regio- and stereoselective reactions, as an oxygen source at the C4-position, and as a protecting group of hydroxyl functions. Namely, the
chiral auxiliary played a role in every step throughout the synthesis. Furthermore, the synthesis contains a new protocol for obtaining r′
-
alkylated enone compounds.
It is widely recognized that an enantioselective asymmetric
synthesis with asymmetric catalysts is more efficient than
the diastereoselective asymmetric synthesis with chiral
auxiliaries, in which at least an equivalent amount of a chiral
auxiliary is necessary. However, in the synthesis of complex
molecules such as natural products, other factors such as
regio-, stereo-, and chemoselectivity and protection and
deprotection of functional groups must also be considered.
Then, when we can use a single chiral auxiliary in controlling
the reactions several times during the synthesis, even
diastereoselective asymmetric synthesis becomes very ef-
ficient. The synthesis here is such an example and shows
new perspective for the synthesis of the compounds with
multiple asymmetric centers.
DNA primase, DnaG, which is crucial for the replication of
bacterial chromosomal DNA (an EC50 value of 70 µM).1 In
2005, 1 was isolated from the fungus Septfusidum sp. by
Merck scientists, Jayasuriya et al., and was shown to be a
potent inhibitor of HIV-1 Tat transactivation (an IC50 value
of 1 µM).2 Since HIV-1 Tat is a regulatory protein required
for viral replication, compounds inhibiting HIV-1 Tat show
potential as a treatment of HIV infections. In addition to their
unique structure, these promising biological profiles made
(+)-Sch 642305 an attractive synthetic target for synthetic
organic chemists. Four total syntheses3-6 have been reported
so far. The first three (refs 3-5) use long reaction schemes
(1) Chu, M.; Mierzwa, R.; Xu, L.; He, L.; Terracciano, J.; Patel, M.;
Gullo, V.; Black, T.; Zhao, W.; Chan, T.-M.; McPhail, A. T. J. Nat. Prod.
2003, 66, 1527-1530.
(+)-Sch 642305 (1) was first isolated from Penicillium
Verrucosum in 2003 by Schering-Plough scientists, Chu et
al. It has been shown to be a potent inhibitor of bacterial
(2) Jayasuriya, H.; Zink, D. L.; Polishook, J. D.; Bills, G. F.; Dom-
browski, A. W.; Genilloud, O.; Pelacz, F. F.; Herranz, L.; Quamina, D.;
Lingham, R. B.; Danzeizem, R.; Graham, P. L.; Tomassini, J. E.; Singh, S.
B. Chem. BiodiVers. 2005, 2, 112-122.
† JSPS Research Fellow.
(3) Mehta, G.; Shinde, H. M. Chem. Commun. 2005, 3703-3705.
10.1021/ol702530b CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/23/2007

(17-19 steps). Although a quite recent report (ref 6) presents
the very concise asymmetric synthesis of 1 in 12 steps, the
starting material is the natural product, quinic acid. Then,
an efficient and convergent approach to 1 remains highly
desirable. We present here a concise asymmetric synthesis
of 1 by chiral auxiliary multiuse methodology, in which the
auxiliary works not only for asymmetric induction but also
for regio- and stereoselective transformations and as a
protecting group of hydroxyl functions.
5, since its upper side is shielded by the 8-membered acetal
ring. The olefinic part (X-Y) in 5 would be olefin itself or
synthetic equivalent of olefin. Then 5 would be converted
to the macrolactone 6 by the selective transformations. Final
removal of 1,2-diphenylethylene unit would give (+)-Sch
642305 (1).
Conversion of the ene bromide 3 to the enone 4 was
achieved by hydroboration-oxidation10 (Scheme 2). Hy-
The synthetic plan for (+)-Sch 642305 (1) is shown in
Scheme 1. Our synthesis starts from the bromo acetal 3,
Scheme 2. Conversion of 3 to the Enone Acetal 4
Scheme 1. Synthetic Plan for (+)-Sch 642305
droboration of 3 followed by PDC oxidation gave the
â-bromo ketone, from which spontaneous elimination of HBr
occurred, giving the enone 4. The use of BH3‚SMe2 afforded
the desired enone 4 in 35% yield (entry 1). The more bulky
borane reagent, thexylborane, increased the yield (53%) of
4 (entry 2). However, the use of more bulky borane reagent,
thexylborane cyclohexane complex, did not react at all (entry
3). The use of PCC in place of PDC decreased the yield of
4 (entry 4). The three-dimensional structure of 4 from its
Dreiding model showed that the upper side of the cyclohex-
ene ring is shielded by the axial C-C bond and the
methylene group of the 8-membered acetal ring, which fixes
the conformation.
Since direct alkylation at the R′-position of the enone 4
using a 6C-unit aliphatic trifluoromethane sulfonate or iodide
failed, we attempted to introduce the 6C-unit by aldol
reaction of aldehyde 7.11 Aldol reaction of 4 with 7 proceeded
smoothly. As expected, it occurred from the sterically less
hindered R-face of the cyclohexenone ring, and 8 was
obtained as the diastereomerically pure form. The stereo-
chemistry at the C6-position of 8 was deduced from
mechanistic considerations and finally determined by an NOE
experiment of xanthate 9.12 Although the stereochemistry of
the secondary alcohol at the C7-position was not determined,
it was tentatively deduced to be S by consideration of the
6-membered transition state.13 Several trials for reducing the
which was previously synthesized by intramolecular bro-
moetherification of cyclohexadiene acetal 27 and has con-
vertible olefin and bromine moieties in the molecule.
Furthermore, the 8-membered acetal moiety derived from
the chiral auxiliary, (R,R)-hydrobenzoin, fixes the conforma-
tion of the cyclohexene ring promising high regio- and
stereoselective transformations. Since several methods to
remove the hydrobenzoin unit are available,8 we planned to
remove it at the final stage of the synthesis and hoped that
the auxiliary would work not only as a protecting group of
the alcohol part but also as a template for controlling the
regio- and stereochemistry during the synthesis. We supposed
the conversion of 3 to the enone 4 by regioselective
hydroboration-oxidation at C1-position in the influence of
the acetal ring. Introduction of a 6C unit at the R′-position
(C6-position) of the enone 49 was postulated to occur from
R-side of the cyclohexane ring to give R-alkylated compound
(4) Ishigami, K.; Katsuta, R.; Watanabe, H. Tetrahedron 2006, 62, 2224-
2230.
(5) Snider, B.; Zhou, J. Org. Lett. 2006, 8, 1283-1286.
(6) Wilson, E. M.; Trauner, D. Org. Lett. 2007, 9, 1327-1329.
(7) (a) Fujioka, H.; Kotoku, N.; Sawama, Y.; Nagatomi, Y.; Kita, Y.
Tetrahedron Lett. 2002, 43, 4825-4828. (b) Fujioka, H.; Kotoku, N.;
Sawama, Y.; Kitagawa, H.; Ohba, Y.; Wang, T.-L.; Nagatomi, Y.; Kita, Y.
Chem. Pharm. Bull. 2005, 53, 952-957. We obtained 3 in 63% yield from
2 in ref 7a. In ref 7b, a similar compound, in which the MeO group of 3 is
replaced by a MeOCH2 group, was obtained in 57% yield. For the procedure
to obtain 3, see the Supporting Information.
(8) Oxidation of alcohol followed by reductive elimination: (a) Alexakis,
A.; Trevitt, G. P.; Bermardinelli, G. J. Am. Chem. Soc. 2001, 123, 4358-
4359. Oxidation of alcohol followed by Baeyer-Villigar reaction and
methanolysis: (b) McNamara, J. M.; Kishi, Y. J. Am. Chem. Soc. 1982,
104, 7371-7372. Birch reduction or hydrogenolysis: (c) Fujioka, H.;
Kitagawa, H, Nagatomi, Y.; Kita, Y. J. Org. Chem. 2002, 67, 411-416.
Using CAN: (e) Fujioka, H.; Hirose, H.; Ohba, Y.; Murai, K.; Nakahara,
K.; Kita, Y. Tetrahedron 2007, 63, 638-643.
(10) Surendra U. K.; Herbert C. B. J. Organomet. Chem. 1979, 172,
c20-c22.
(11) Yu, M.; Alonso-Galicia, M.; Sun, C-W.; Roman, R. J.; Ono, N.;
Hirano, H.; Ishimoto, T.; Reddy, Y. K.; Katipally, K. R.; Reddy, K. M.;
Gopal, V. R.; Yu, J.; Yakhi, M.; Frank, J. R. Bioorg. Med. Chem. 2003,
11, 2803-2821.
(12) NOE was observed between the C4-R-proton and the C7-proton in
9.
(9) The numbering is the same as that for (+)-Sch 642305 (1).
5606
Org. Lett., Vol. 9, No. 26, 2007

secondary alcohol including radical reduction of the xanthate
9 in the presence of the enone unit were unsuccessful. This
undesirable result might be due to the successive system of
the enone unit and the γ-ether oxygen atom. The protocol,
(1) conversion of the enone unit to the saturated one (masked
enone), (2) radical reduction of the secondary alcohol, and
(3) regeneration of the enone, was next examined. The
masked enone method was accomplished by the use of the
Michael addition of PhSH to the enone 9. Thus, treatment
of 9 with PhSH afforded â-sulfinyl ketone 10, which was
reduced with 2,2′-azobis[2-(2-imidazolin-2-yl)propane] di-
hydrochloride (VA-044), the water-soluble radical initiator,
and (TMS)3SiH in the presence of PhSH to afford the desired
ketone 11.14 The configuration of the sulfinyl group was
tentatively deduced to be R from the conformation of 9
(Scheme 3).
radical initiators to search for a more efficient method.15 The
use of VA-044 as an initiator and (TMS)3SiH as a chain
carrier in wet EtOH gave a much better result, 75% (entry
3).
Addition of 20 mol % of PhSH improved the yield of 11
to 94% (entry 4). The use of PhS-SPh also showed the same
reactivity (entry 5). The method here has several advan-
tages: the use of nontoxic (TMS)3SiH, a mild, efficient, and
high yield reaction, and the use of wet EtOH.
Conversion of 11 to (+)-Sch 642305 (1) is shown in
Scheme 4. Hydrolysis of the 8-membered acetal ring with
Scheme 4. Completion of the Synthesis of (+)-Sch 642305
Scheme 3. Introduction of the 6C Unit
p-TsOH followed by PDC oxidation and deprotection of
TBDPS-ether with HF-pyridine afforded diketo carboxylic
acid 12. Macrolactonization using a modified Corey-
Nicolaou method16 gave the 10-membered lactone 13. During
the macrolactonization process, â-elimination of PhSH
occurred together to regenerate the enone unit. Finally,
m-CPBA oxidation of 13 caused the removal of the chiral
source via the ester intermediate, which was labile and not
isolated, to give (+)-Sch 642305 (1).
Radical reduction of 10 was a crucial step and studied in
detail. The representative results are shown in Table 1. The
In conclusion, we have succeeded in a concise asymmetric
synthesis of (+)-Sch 642305 (1) from the known compound
3.17 Every reaction is stereoselective, and the chiral nonra-
cemic hydrobenzoin worked as chiral auxiliary for desym-
metrization of diene, as template for attaining regio- and
stereoselective reactions, as an oxygen source at C4-position,
and as a protecting group of hydroxyl functions. Furthermore,
our synthesis, the method for constructing the 10-membered
lactone and 4-hydroxycyclohexenone of 1, is completely
different from the previously reported syntheses (refs 3-6).
Therefore, the method described here would be useful for
preparing new derivatives which cannot be synthesized by
other methods. Furthermore, new radical reduction using
nontoxic (TMS)3SiH in wet EtOH is a very valuable
transformation to obtain the R′-alkylated enone compound.
Table 1. Radical Reduction of 10 to 11
chain
solvent,
entry initiator
carrierc
additived
temp (°C)
yield (%)
1
2
AIBNa
Bu3SnH
Bu3SnH
dry benzene,
reflux
dry benzene,
complex
mixture
60
AIBNa
PhSH
reflux
3
4
5
VA-044b (TMS)3SiH
VA-044b (TMS)3SiH PhSH
wet EtOH,e 70 75
wet EtOH,e 70 94
VA-044b (TMS)3SiH PhS-SPh wet EtOH,e 70 90
a 0.2 equiv of AIBN was used. b 1.0 equiv of VA-044 was used. c 2.0
equiv of chain carriers was used. d 20 mol % of additive was used.
e Contains ca. 0.5 vol % of water.
most popular conditions for radical reduction of xanthates,
AIBN-Bu3SnH in dry benzene under reflux, afforded a
complex mixture (entry 1). On the other hand, the use of
PhSH as an additive gave the desired product 11 in a fairly
good yield (entry 2). We next tried to use the water-soluble
(15) For the effect of thiol in radical reduction, see: Cole, S. J.; Kirwan,
J. N.; Roberts, B. P.; Willis, C. R. J. Chem. Soc., Perkin Trans. 1 1991,
103-112.
(16) Corey E. J.; Nicolaou K. C. J. Am. Chem. Soc. 1974, 96, 5614-
5616.
(17) Although compound 2 was prepared from benzoic acid in four steps
in our previous reports (ref 7), we improved its synthetic method and
succeeded in getting 2 from commercially available cyclohexa-1,4-diene
in two steps (see the Supporting Information).
(13) The formation of single isomer depends on the substrate 4. The
reaction of cyclohexenone with 7 afforded a 3:1 mixture of the aldol
products.
(14) Cf. Kita, Y.; Matsugi, M. In Radicals in Organic Synthesis; Renaud,
P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 1-10.
Org. Lett., Vol. 9, No. 26, 2007
5607

Thus, the protocol for getting R′-alkylated enone compounds
from enone compounds has generality (see ref 18). This
transformation has two interesting aspects: a method for
providing R′-alkylated enone compounds in good yields and
a new method for radical reactions.
Acknowledgment. This paper is dedicated to the heartfelt
memory of the late Professor Yoshihiko Ito of Kyoto and
Doshisha Universities. This work was supported by Grant-
in-Aid for Scientific Research on Priority Areas (17035047)
from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan, by a Grant-in-Aid for Scientific
Research (A) and Exploratory Research from the Japan
Society for the Promotion of Science, and by the Shorai
Foundaation for Science and Technology.
(18) Although the direct R′-alkylation of cyclohexenone with alkyl iodide
or alkyl triflate under various conditions gave unsuccessful results, the
protocol here [(a) aldol reaction, (b) xanthate formation, (c) conversion to
the masked enone, (d) radical reduction, and (e) rebirth of the enone unit]
gave the R′-alkylkated cyclohexenone in 55% overall yield.
Supporting Information Available: Full experimental
details and detailed spectroscopic data of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a) LHMDS, decanal (93%); b) NHMDS, CS2 then Mel (84%); c) PhSH,
Et3N (99%); d) VA-044, (TMS)3SiH, PhSH, wet. EtOH (90%); e) m-CPBA,
CH2Cl2 then in benzene, 80 °C (79%)
OL702530B
5608
Org. Lett., Vol. 9, No. 26, 2007