Unexpected diels-Alder/carbonyl-ene cascade toward the biomimetic synthesis of chloropupukeananin

Article abstract of DOI:10.1021/ol400549q

The biomimetic synthesis of the advanced model compound of chloropupukeananin has been achieved. The present synthesis features an unexpected enantiomer-differentiating Diels-Alder/carbonyl-ene cascade under high-pressure conditions and a base-promoted migration of the salicyl group.

Full text of DOI:10.1021/ol400549q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Unexpected DielsꢀAlder/Carbonyl-ene
Cascade toward the Biomimetic Synthesis
of Chloropupukeananin
Takahiro Suzuki,*,† Yuria Miyajima,† Kaname Suzuki,† Kanako Iwakiri,† Masaki
Koshimizu,† Go Hirai,‡ Mikiko Sodeoka,‡ and Susumu Kobayashi*,†
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki,
Noda-shi, Chiba 278-8510, Japan, and RIKEN, 2-1, Hirosawa, Wako-shi,
Saitama 351-0198, Japan
suzuki-t@rs.noda.tus.ac.jp; kobayash@rs.noda.tus.ac.jp
Received February 27, 2013
ABSTRACT
The biomimetic synthesis of the advanced model compound of chloropupukeananin has been achieved. The present synthesis features an
unexpected enantiomer-differentiating DielsꢀAlder/carbonyl-ene cascade under high-pressure conditions and a base-promoted migration of the
salicyl group.
Chloropupukeananin (1), an inhibitor of HIV-1 replica-
tion, was originally isolated from the plant endophytic
fungus Pestalotiopsis fici by Che and colleagues as the
first chlorinated pupukeanane derivative, along with its
proposed biosynthetic precursors, iso-A82775C (2) and
pestheic acid (3) (Figure 1).1 They also reported the isola-
tion of the congeners of 1, such as chloropestolide A (4),
chloropupukeanolide C (5) and D (6), from the same
fermentation extract.2 Structurally, these natural products
possess a highly functionalized tricyclo[4.3.1.03,7]decane or
bicyclo[2.2.2]octane, comprised of 2and 3by a reverse electron-
demand DielsꢀAlder reaction (REDDA). Inspired by the
structural complexity and diversity of this class of com-
pounds, we investigated a synthetic study of chloropup-
ukeananine.3
In the previous paper,3 we proposed a biosynthetic path-
way to 1 and 4 from 2 and maldoxin 7 (Scheme 1a).4,5
Recent isolation of chloropupukeanolide C and D also
supports our proposed biosynthetic pathway. In addition,
we described the biomimetic synthesis of the core skeleton
of chloropupukeananin by a REDDA reaction and carbonyl-
ene reaction from masked o-benzoquinone (MOB)6 10
(3) Suzuki, T.; Kobayashi, S. Org. Lett. 2010, 12, 2920–2923.
(4) Although stereochemistry of the allene moiety of 2 and the acetal
moiety of 7 have not been determined, we postulated that those are S and
R, as shown in Scheme 1a, from the structure of 4-6.
(5) In this manuscript the stereochemical course of the REDDA is
classified as “endo” or “exo”. “Endo” and “exo” represent the syn and
anti-orientation of R-keto-acetal and allene moiety, respectively.
(6) For reviews on MOBs, see: (a) Liao, C.-C.; Peddinti, R. K. Acc.
Chem. Res. 2002, 35, 856–866. (b) Magdziak, D.; Meek, S. J.; Pettus,
T. R. R. Chem. Rev. 2004, 104, 1383–1429. (c) Liao, C.-C. Pure Appl.
Chem. 2005, 77, 1221–1234. (d) Roche, S. P.; Porco, J. A., Jr. Angew.
Chem., Int. Ed. 2011, 50, 4068–4093.
† Tokyo University of Science
‡ RIKEN
(1) Liu, L.; Liu, S. C.; Jiang, L. H.; Chen, X. L.; Guo, L. D.; Che,
Y. S. Org. Lett. 2008, 10, 1397–1400.
(2) (a) Liu, L.; Li, Y.; Liu, S. C.; Zheng, Z. H.; Chen, X. L.; Zhang,
H.; Guo, L. D.; Che, Y. S. Org. Lett. 2009, 11, 2836–2839. (b) Liu, L.;
Niu, S. B.; Lu, X. H.; Chen, X. L.; Zhang, H.; Guo, L. D.; Che, Y. S.
Chem. Commun. 2010, 46, 460–462. (c) Liu, L.; Bruhn, T.; Guo, L. D.;
Gotz, D. C. G.; Brun, R.; Stich, A.; Che, Y. S.; Bringmann, G. Chem.
ꢀEur. J. 2011, 17, 2604–2613.
r
10.1021/ol400549q
XXXX American Chemical Society

and vinylallene 9 (Scheme 1b).7 We report here the synthe-
sis of advanced model compound 18 from spirolactone-
type MOB 15 and vinylallene 14 (Scheme 2). Significant
features of the present study include; (i) a biomimetic
cascade reaction (REDDA and carbonyl-ene reaction) pro-
ceeded under high-pressure conditions, and (ii) the desired
REDDA occurs in a stereoselective and an enantiomer-
differentiating manners.
Scheme 2. Synthetic Strategy toward Advanced Model Com-
pound 18
(Scheme 3). Selective protection of the resulting catechol
gave phenol 20, which was subjected to SNAr reaction with
benzyl 2-fluoro-5-nitrobenzoate8 to give diaryl ether 21 in
high yield. Diaryl ether 21 was transformed to 22 by a
conventional three step sequence of reactions. The oxida-
tivedearomatizationof diarylether22withPIDAafforded
MOB 15 possessing a salicylic acid ketal. Vinylallene 14
was prepared in 2 steps from cis-1-ethynylcyclohexane-1,2-
diol 23.9 Treatment of diol 23 with triphosgene gave
carbonate 24. Cu-promoted anti-selective SN20 reaction10
with isopropenylmagnesium bromide in the presence of
(n-BuO)3P gave vinylallene 14 as a single diastereomer
albeit in low yield.11
Figure 1. Chloropupukeananin, 1, and its related compounds.
Scheme 3. Preparation of MOB 15 and Vinylallene 14
Scheme 1. Our Proposed Biosynthesis Involving (a) Maldoxin
and (b) Our Previous Results
(7) Yu and Snider have also reported the synthesis of (()-maldoxin
and its thermal DielsꢀAlder reaction with allene 9, see: (a) Yu, M.;
Snider, B. B. Org. Lett. 2011, 13, 4224–4227. (b) Yu, M.; Snider, B. B.
Tetrahedron 2011, 67, 9473–9478.
(8) South, M. S.; Case, B. L.; Dice, T. A.; Franklin, G. W.; Hayes,
M. J.; Jones, D. E.; Lindmark, R. J.; Zeng, Q. P.; Parlow, J. J. Comb.
Chem. High Throughput Screening 2000, 3, 139–151.
(9) Battistini, C.; Crotti, P.; Macchia, F. J. Org. Chem. 1981, 46, 434–
436.
The preparation of MOB precursor 15 was commenced
with the removal of the Me group of chlorophenol 193
(10) Tang, X. P.; Woodward, S.; Krause, N. Eur. J. Org. Chem. 2009,
2836–2844.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. High Pressure REDDA Reaction
yield (%)
25bb
entry
pressure (GPa)
time (h)
17a
25ab
25cc
25dþ25ec
1
2
3
4
5
6
0.5
0.8
1.0
1.0
1.0
1.0
24
24
24
3
12
32
37
17
47
48
7
24
18
16
21
24
16
10
11
9
12
18
21
14
19
15
35
14
13
39
3
48
96
9
9
0
a Isolated yield. b Calculated yield from the ratio of a mixture 25a and 25b. c Calculated yield from the ratio of a mixture of 25c, 25d, and 25e.
With (()-15 and (()-14 in hand, we conducted a high
pressure REDDA reaction. The REDDA reaction of
racemic pair was predicted to generate eight possible
isomers. Although the use of enantiomerically pure pre-
cursors will give only four isomers, REDDA reaction of a
pair of racemates was first conducted to obtain any
information on the reactivity of 15 and 14.
Using our previous conditions (0.8 GPa, 0.1 M, CH2Cl2,
rt, 24h, Table 1, entry 2), the REDDA reaction afforded at
least six products 17 and 25aꢀe. NMR studies showed that
these products possess both salicylic acid ketal and cyclo-
hexanol moieties. Surprisingly and to our delight, the
X-ray crystallographic analysis of the major product 17
showed it to be the desired tricyclo[4.3.1.03,7]decane with
the same stereochemistry as that of chloropupukeanolide
D (Figure 2).12 This result indicated that the REDDA
adduct 16 underwent a carbonyl-ene reaction under high-
pressure conditions. The yield of product 17 clearly de-
pended on the pressure (entries 1ꢀ3) and reaction time
(entries 3ꢀ6). The highest yield (48%) was obtained by
treatment of an equimolecular amount of MOB 15 and
allene 14 under 1.0 GPa for 96h (entry 6).
The structures of the other products have not been
fully established. Products 25aꢀc are assumed to be exo-
REDDA adducts (25a and 25c) and a normal-electron-
demand DielsꢀAlder adduct (25b) by NMR studies.13
Two other cycloadducts 25d and 25e could not be purified
in order to determine their structures. However, either 25d
or 25e is the initially expected DielsꢀAlder adduct 16
because ene product 17 was obtained by the treatment of
the mixture of 25c, 25d and 25e under high-pressure
conditions. This was supported by the fact that prolonged
reactiontime increased the yield of17with a decrease in the
combined yield of 25d and 25e.
Direct formation of the desired tricyclo[4.3.1.03,7]decane
17 in 48% yield under high-pressure conditions is interest-
ing for the following three reasons: (i) the REDDA reac-
tion of a racemic pair predominantly afforded the most
desired adduct 16 among eight possible isomers; (ii) the
REDDA reaction was almost complete after just 3 h, in
contrast to our previous results; and (iii) the carbonyl-ene
reaction of endo-cycloadduct 16 occurred in a biomimetic
manner. The unexpectedly predominant formation of
cycloadduct 16 might be the outcome of several factors
(Scheme 4). For the facial selectivity of the MOB 15,
dienophile 14 tends to approach from the same face as
the spirolactone carbonyl of MOB 15 by analogy to the
(11) Despite of our efforts to improve the yield, any condition was
failed.
(12) CCDC 919015 (for 17) and CCDC919016 (for (ꢀ)-(R)-15)
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(13) Further structural determination was impeded by the isolated
stereocenters on the cyclohexane ring and salicylic acid ketal. Use of
wavy bonds in 25aꢀc means unknown facial selectivity of 14 and 15, not
implying that a diastereomer mixture of 14 was used. Probable struc-
tures of 25a and 25c were illustrated in Supporting Information.
(14) Drutu, I.; Njardarson, J. T.; Wood, J. L. Org. Lett. 2002, 4, 493–
496. Similar facial selectivity was observed by Snider and Yu. See also ref
7b.
Figure 2. Ortep drawing of tricyclic compond 17.
Org. Lett., Vol. XX, No. XX, XXXX
C

pioneering work by Wood et al.14 In addition, the hydro-
gen bonding between the hydroxyl group of dienophile 14
and spirolactone carbonyl of 15 might also contribute to
the desired selectivity (TS1). With regard to the reaction
rate, the lower LUMO energy level of the diene of MOB 15
caused by the salicyclic acid ketal moiety might accelerate
the REDDA reaction (Table 1, entry 4; REDDA reaction
was almost complete within 3 h). This moiety may also
lower the LUMO energy level of the carbonyl group of
endo adduct 16. As a result, the cascade carbonyl-ene
reaction took place.15 Hydrogen bonding between cyclo-
hexanol and the spirolactone carbonyl moiety might also
result in the close proximity of the carbonyl and olefin
moiety (TS2).
Scheme 5. REDDA/Carbonyl-ene Cascade Reaction with En-
antiomerically Pure Precursors
Scheme 4. Proposed Transition State of REDDA Reaction and
Carbonyl-ene Reaction
Scheme 6. Migration of Salicyl Group
We next examined the cascade reaction with the enan-
tiomerically pure precursors. The resolution of racemic
MOB 15 was performed by chiral column HPLC
(CHIRALPAK IC, Hex/EtOH/CHCl3 = 2/1/1). The
(þ)-(1S,2S)-14 was prepared from enantiopure diol
(ꢀ)-23 obtained by the separation of mandelic acid deri-
vatives.16,17 Both enantiomers of MOB, (ꢀ)-(R)- and
(þ)-(S)-15,12,18 were subjected to the DielsꢀAlder/
carbonyl-ene cascade reaction with (þ)-(1S,2S)-14 under
the high-pressure conditions (Scheme 5). The reaction of
(ꢀ)-(R)-15 and (þ)-(1S,2S)-14 (natural combination)
afforded the desired product (ꢀ)-17 (70%) and (ꢀ)-25a
(20%), whereas the reaction of (þ)-(1S,2S)-14 and
(þ)-(S)-15 (unnatural combination) resulted in the for-
mation of a mixture of cycloadducts. The difference in the
selectivity between the natural and unnatural combina-
tion is interesting, although the degree of enantiomer-
differentiation is not high.19
of 17 with t-BuOK in DMF to afford salicylate 18 in 86%
yield. The 1H and 13C NMR spectral data of salicylate 18
are ingood accordancewiththose ofchloropupukeananin.
In conclusion, we were able to achieve the synthesis of an
advanced model of chloropupukeananin by employing a
biomimetic DielsꢀAlder/carbonyl-ene cascade reaction
under high pressure conditions. Further study toward the
asymmetric total synthesis of chloropupukeananin is cur-
rently underway.
Acknowledgment. This research was supported in part
by a Grant-in-Aid for Young Scientists (B, KAKENHI
no. 22790022and 24790025) from theJapan Societyfor the
Promotion of Science. We thank the Naito Foundation,
the Uehara Memorial Foundation, and the Research
Foundation for Pharmaceutical Sciences for financial
support. We also thank the Materials Characterization
Team (RIKEN, Japan) for management of the superhigh
pressure reaction apparatus and Prof. K. Miyamura and
Mr. K. Ueji (Department of Chemistry, Tokyo University
of Science) for assistance with X-ray analysis.
Finally, the migration of salicyl group in 17 was exam-
ined (Scheme 6). This was best carried out by the treatment
(15) To the best of our knowledge, only two examples of carbonyl-
ene reaction under high-pressure condition have been reported: (a)
Jurczak, J.; Kozluk, T.; Pikul, S.; Salanski, P. J. Chem. Soc. Chem.
Comm. 1983, 1447–1448. (b) Dauben, W. G.; Hendricks, R. T. Tetra-
hedron Lett. 1992, 33, 603–606.
(16) Whitesell, J. K.; Reynolds, D. J. Org. Chem. 1983, 48, 3548–
3551.
Supporting Information Available. Detail experimental
procedures and characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Absolute stereochemistry of (ꢀ)-23 was determined by modified
Mosher method. See Supporting Information.
(18) Absolute stereochemistry of (ꢀ)-15 was determined by X-ray
crystallographic analysis. See Supporting Information.
(19) See Supporting Information for HPLC analysis of these
reactions.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX