Enantioselective total synthesis of heliespirone B

Article abstract of DOI:10.1016/j.tetlet.2011.12.115

The first enantiocontrolled total synthesis of heliespirone B has been accomplished employing a biomimetic intramolecular oxy-Michael reaction followed by the regio- and diastereoselective reduction of the carbonyl function as key steps.

Full text of DOI:10.1016/j.tetlet.2011.12.115

Tetrahedron Letters 53 (2012) 1236–1239
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective total synthesis of heliespirone B
⇑
Akari Miyawaki, Yuki Manabe, Masahiro Yoshida, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first enantiocontrolled total synthesis of heliespirone B has been accomplished employing a biomi-
metic intramolecular oxy-Michael reaction followed by the regio- and diastereoselective reduction of
the carbonyl function as key steps.
Received 25 November 2011
Revised 22 December 2011
Accepted 26 December 2011
Available online 10 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Heliespirone B
Intramolecular oxy-Michael reaction
Regioselective reduction
Diastereoselective reduction
Heliespirone B (1)1 was isolated by Macías and co-workers from
the polar bioactive fractions of the leaf aqueous extracts of Helian-
thus annuus L. along with heliespirone C (3), a C1 diastereoisomer of
the previously isolated heliespirone A (2),2 also from the same
sources. The heliespirones have been shown to exhibit allelopathic
activity, with potential for becoming lead compounds for new types
of agrochemicals. The structure of heliespirone B (1), established by
X-ray crystallographic analysis, possesses the characteristic, syn-
thetically challenging 1-oxaspiro[5.5]undecenone skeleton with
four stereogenic centers, including a quaternary spiro center (C1).
To date, no successful total synthesis has been reported. Herein,
we present the first total synthesis of (+)-heliespirone B (1),
employing a biomimetic,1 diastereoselective intramolecular oxy-
Michael (IMOM) reaction for the construction of the six-membered
oxaspirocyclic core structure and a highly regio- and diastereose-
lective reduction of the carbonyl group at C2 as the key steps
(Fig. 1).
Our retrosynthetic strategy is shown in Scheme 1. We envis-
aged the regio- and diastereoselective reduction of the carbonyl
function at C2 of 4 via a C11-hydroxy-directed hydride reduction
to give heliespirone B (1). The six-membered oxaspirocyclic skele-
ton would be constructed via a biomimetic IMOM reaction of the
dihydroxy quinone 5. The key substrate for the spirocyclization
would be prepared by a selective oxidation of the aryl ring of the
optically active diol 6, which has already been synthesized in our
laboratories (Scheme 1).3
with the oxazolidinone 8, via a diastereoselective conjugate addi-
tion,4 asymmetric dihydroxylation, and CAN-mediated chemose-
lective oxidation of the aryl ring of 11 (93% de) in 19% overall
yield for the 9 steps (Scheme 2).3
Alternatively, to obtain a more efficient synthesis of 5, another
approach was examined. Thus, silylation and catalytic hydrogena-
tion of 15, which has already been synthesized through the Mits-
unobu coupling of 12 with 13 and subsequent Me3Al-mediated
Claisen rearrangement of the resulting allyl ether 14,5 provided
the alcohol 16. Swern oxidation followed by the Kocienski–Julia
olefination of the resulting aldehyde 17 with the sulfone 18 yielded
19,4 which was exposed to dihydroxylation conditions using AD-
mix-a to give the diol 20 quantitatively with 86% de. Oxidation
with CAN produced 5 in 57% overall yield from 12 for the 8 steps
(Scheme 3).
With the requisite substrate 5 in hand, we then examined the
key intramolecular oxy-Michael reaction. When the reaction was
t
conducted with BuOK6 (0.3 equiv) or Triton BÒ7 (1 equiv) as the
base, the expected cyclized products were not obtained (entries 1
and 2). A combination of LiCl (10 equiv) and DBU8 (10 equiv) was
The optically active dihydroxy quinone 5 was prepared from 9,
which was derived from the Heck coupling of the aryl bromide 7
⇑
Corresponding author. Tel.: +81 88 6337287; fax: +81 88 6339575.
E-mail address: shishido@ph.tokushima-u.ac.jp (K. Shishido).
Figure 1. Structures of heliespirons.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.115

A. Miyawaki et al. / Tetrahedron Letters 53 (2012) 1236–1239
1237
Scheme 1. Retrosynthetic analysis.
Figure 2. ORTEP drawings of 4 and 21.
Scheme 4. Equilibration of the spirocycles.
18-crown-6 (0.3 equiv) at 0 °C.
A
large rate acceleration8a
(6 h?10 min) was observed and 4 was produced in 34% yield along
with 21 and 5 in 13% and 32% yields, respectively (entry 5). When
the reaction was conducted at ꢀ20 °C (entry 6), 4 was obtained in a
higher yield (42%), with the same diastereomeric ratio as for entry
5 (2.6:1). At lower temperatures (ꢀ30 and ꢀ40 °C), the results
were disappointing (entries 7 and 8). The best result, the formation
of 4 in a 46% yield, was achieved by conducting the reaction in the
presence of 21-crown-7 (0.3 equiv) as an additive (entry 9)
(Table 1).
The diastereoselection obtained in the cyclization step can be
rationalized as a consequence of the difference in the steric repul-
sion of the two chair-like transition states (T1 <T2), thereby favor-
ing 4 (Fig. 3).
Scheme 2. Synthesis of quinone 5.
used with the expectation that the lithium-chelated transition
state would provide the requisite diastereoisomer 4; however, that
resulted in decomposition (entry 3). Treatment of a solution of 5 in
CH2Cl2 with Cs2CO3 (3 equiv) at 0 °C for 6 h provided a chromato-
graphically separable mixture of the diastereoisomers 49 and 2110
in 22% and 3% yield, respectively, with the recovered starting 5
(38%) (entry 4). The structures of both diastereoisomers were
established by X-ray crystallographic analyses11 as shown in Figure
2, and the major diastereoisomer 4 proved to be the desired
product. Since the use of Cs2CO3 proved favorable, we therefore
performed the reaction with Cs2CO3 (3 equiv) in the presence of
To evaluate the thermodynamic equilibration of the spirocycles,
4 was exposed to Cs2CO3 (3 equiv)/18-crown-6 (0.3 equiv) in
CH2Cl2 at ꢀ25 °C for 7 h to give a 1.6:1.1:1 mixture of 21, 4, and
5 in 73% yields. This result indicated that the undesired isomer
21 is thermodynamically more stable than 4 (Scheme 4).
Completion of the total synthesis involved a regio- and stereo-
selective reduction of the carbonyl group at C2. The success of this
approach depends on whether the two carbonyl groups in 4 can be
differentiated. The results are shown in Table 2. Attempted reduc-
tion with diisobutylaluminum hydride (1 equiv)12 resulted in the
recovery of the starting 4 in 79% yield (entry 1). Treatment of 4
with Red-AlÒ (1 equiv) at 0 °C led to the exclusive formation of 1
in a 43% yield (entry 2). Encouraged by this result, we decided to
evaluate the reduction using an ate-complex type of reagent.
Reduction with LiAl(OtBu)3H (1 equiv)13 produced a chromato-
graphically separable 10:1 mixture of 1 and the regioisomer 2214
in 74% yields (entry 3). The best result was obtained by employing
Zn(BH4)2 (1 equiv),15 which provided a separable 13:1 mixture of 1
and 22 in 73% yields (entry 4). The spectral properties of 1, {½a D26
ꢁ
+58.5 (c 0.41, CHCl3); lit.1 ½a D25
ꢁ
+19.6 (c 0.1, CHCl3)}, were identical
with those for the natural heliespirone B (Table 2).
The selective formation of 1 through the reduction with
Zn(BH4)2 can be explained by considering the chelated transition
state15 shown in Figure 4.
In summary, we have completed the first enantiocontrolled to-
tal synthesis of heliespirone B (1) with a longest linear sequence of
10 steps and an overall yield of 23%. The unique features of this
work include the use of the biomimetic IMOM reaction of the dihy-
droxy quinone precursor 5, which was prepared efficiently by two
Scheme 3. Alternative synthesis of 5. Reagents and conditions: (a) 1,1-(azodicar-
bonyl)dipiperidine, nBu3P, benzene, 0 °Cꢂrt, 0.5 h, 81%; (b) Me3Al (3 equiv), hexane,
rt, 1 h, 88% (>99% ee); (c) TBSCl, imidazole, 4-DMAP, CH2CL2, rt, 0.5 h, 96%; (d) H2
(5 atm), Pd-C, THF, rt, 15 h, 98%; (e) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °Cꢂrt, 0.5 h;
(f) 18, LHDMS, THF, ꢀ78 °Cꢂrt, 0.7 h, 99% (2 steps); (g) AD-mix-
a, CH3SO2NH2,
tBuOH, H2O, rt, 15 h, quant. (86% de); (h) CAN, CH3CN, H2O, 0 °C, 1 min, 86%.

1238
A. Miyawaki et al. / Tetrahedron Letters 53 (2012) 1236–1239
Table 1
Intramolecular oxy-Michael reaction of 5
Entry
Conditions
4 (%)
21 (%)
Ratio 4:21
Recovered 5 (%)
1
2
3
4
5
6
7
8
9
tBuOK, THF, rt
Decomp.
Decomp.
Decomp.
22
34
42
32
1.5
46
Triton BÒ, MeOH, rt, 15 h
LiCl, DBU, CH3CN, 0ꢂ60 °C, 0.5 h
Cs2CO3, CH2Cl2, 0 °C, 6 h
3
7:3:1
2:6:1
2:6:1
4:6:1
38
32
27
31
80
23
Cs2CO3, 18-crown-6, CH2Cl2 0 °C, 10 min
Cs2CO3, 18-crown-6, CH2Cl2 ꢀ20 °C, 2 h
Cs2CO3, 18-crown-6, CH2Cl2, ꢀ30 °C, 2 h
Cs2CO3, 18-crown-6, CH2Cl2, ꢀ40 °C, 2 h
Cs2CO3, 21-crown-7, CH2Cl2, ꢀ20 °C, 1 h
13
16
7
Trace
12
3:8:1
References and notes
1. Macías, F. A.; Gallindo, J. L. G.; Valera, R. M.; Torres, A.; Mollinillo, J. M. G.;
Fronczek, R. Org. Lett. 2006, 8, 4513–4516.
2. Macías, F. A.; Valera, R. M.; Torres, A.; Mollinillo, J. M. G. Tetrahedron Lett. 1998,
39, 427–430.
3. Miyawaki, A.; Osaka, M.; Kanematsu, M.; Yoshida, M.; Shishido, K. Tetrahedron
2011, 67, 6753–6761.
4. Osaka, M.; Kanematsu, M.; Yoshida, M.; Shishido, K. Tetrahedron: Asymmetry
2010, 21, 2319–2320.
5. Kanematsu, M.; Soga, K.; Manabe, Y.; Morimoto, S.; Yoshida, M.; Shishido, K.
Tetrahedron 2011, 67, 4758–4766.
6. Nising, C. F.; Bräse, S. Chem. Soc. Rev. 2008, 37, 1218–1228.
7. Ko, S. S.; Klein, L. L.; Pfaff, K. P.; Kishi, Y. Tetrahedron Lett. 1982, 23, 4415–4418.
8. (a) Kanematsu, M.; Yoshida, M.; Shishido, K. Angew. Chem., Int. Ed. 2011, 50,
2618–2620; (b) Kobayashi, H.; Kanematsu, M.; Yoshida, M.; Shishido, K. Chem.
Commun. 2011, 47, 7440–7442.
Figure 3. Transition states of IMOM reaction.
9. Compound 4: mp 87.387.6 °C (Et2O/hexane); ½a D28
ꢁ
ꢀ63.5° (c 0.73 CHCl3); IR
(KBr) 3459, 2922, 1687, 1433, 1378, 1266, 1117, 1115, 1048 cmꢀ1
;
1H NMR
Table 2
(400 MHz, CDCl3) d 6.60 (1H, q, J = 1.2 Hz), 3.38 (1H, dd, J = 11.6 and 2.4 Hz),
3.25 (1H, d, J = 16.0 Hz), 2.87 (1H, d, J = 16.0 Hz), 2.312.21 (1H, m), 2.01 (3H, d,
J = 1.2 Hz), 1.811.74 (1H, m), 1.761.68 (OH, br, D2O exchangeable), 1.681.62
(1H, m), 1.511.44 (1H, m), 1.411.34 (1H, m), 1.05 (3H, s), 1.04 (3H, s), 0.80 (3H,
d, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) d 197.0 (C), 194.7 (C), 150.4 (CH),
135.9 (C), 82.1 (C), 77.4 (CH), 71.4 (C), 40.5 (CH2), 32.1 (CH), 26.8 (CH2), 26.3
(CH3), 24.8 (CH2), 24.4 (CH3), 17.3 (CH3), 16.0 (CH3); HRMS (ESI) calcd for
Reduction of 4 and completion of total synthesis of 1
C
15H23O4 267.1596 (M++H), found 267.1603.
10. Compound 21: mp 99.6100.7 °C (Et2O/hexane); ½a D26
ꢁ
+174.03° (c 0.22 CHCl3);
1H NMR (400 MHz,
Entry
Conditions
Yield (1 + 22, %)
Ratioa
IR (KBr) 3563, 2950, 1691, 1466, 1378, 1271, 1230 cmꢀ1
;
CDCl3) d 6.45 (1H, q, J = 1.6 Hz), 3.17 (1H, d, J = 16.4 Hz), 3.16 (1H, dd, J = 11.6
and 2.0 Hz), 2.77 (1H, d, J = 16.4 Hz), 2.13–2.01 (1H, m), 1.97 (3H, d, J = 1.6 Hz),
1.93–1.68 (OH, br, D2O exchangeable), 1.67–1.62 (2H, m), 1.55–1.41 (2H, m),
1.06 (3H, s), 1.05 (3H, s), 1.05 (3H, d, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) d
197.2 (C), 196.8 (C), 149.1 (CH), 136.3 (C), 81.2 (C), 79.8 (CH), 71.4 (C), 50.0
(CH2), 37.9 (CH), 27.4 (CH2), 26.0 (CH3), 25.3 (CH2), 24.1 (CH3), 16.6 (CH3), 15.6
(CH3); HRMS (ESI) calcd for C15H22O4Na 289.1416 (M++Na), found 289.1422.
11. The X-ray crystal data of 4 and 21 were obtained using a Rigaku RAXIS-PAPID
1
2
3
4
DIBAH, THF, ꢀ78 °Cꢂrt
Recovered of 4 (79%)
Red-AlÒ, THF, 0 °C
43
74
73
1:0
10:1
13:1
LiAl(OtBu)3H, THF, 0 °C15
Zn(BH4)2, Et2O, 0 °C
Determined by 1H NMR.
a
diffractometer, MoK radiation (k = 0.71075 Å), graphite monochromator. 4:
a
C
15H22O4, monoclinic, space group P212121, unit cell dimensions
a = 5.5917(3) Å, b = 9.5202(4) Å, c = 27.279(1) Å,
V = 11452.2(1) Å3,
Dcalcd = 1.218 g/cm3, Z = 4, F(000) = 576, = 0.0087 mmꢀ1
Data were
l
.
collected at 123 K. A total of 12831 reflections was collected, 6090 were
unique (Rint = 0.016). The structure was refined by full-matrix least-squares on
F. The final refinement [I >2r(I)] gave R1 = 0.035, wR2 = 0.064. 21: C15H22O4,
orthorhombic, space group P212121, unit cell dimensions a = 8.7360(5) Å,
b = 10.3233(6) Å, c = 15.7689(9) Å, V = 1422.1(1) Å3, Dcalcd = 1.244 g/cm3, Z = 4,
F(000) = 576,
reflections was collected, 3266 were unique (Rint = 0.018). The structure was
refined by full-matrix least-squares on F. The final refinement [I >2 (I)] gave
l
= 0.0089 mmꢀ1. Data were collected at 123 K. A total of 13578
Figure 4. Proposed mechanism with Zn(BH4)2 reduction.
r
R1 = 0.033, wR2 = 0.047. Crystallographic data (excluding structure factors) for
4 and 21 have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC 851889 and CCDC 851673,
respectively. Copies of these information may be obtained free of charge from
the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK (fax: +44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk or http://
www.ccdc.cam.ac.uk).
different routes, and a highly regio- and diastereoselective reduc-
tion of the carbonyl at C2. The synthetic route developed here is
general and efficient and could also be applied to the synthesis of
other related natural products.
Acknowledgments
12. Hu, Y.; Li, C.; Kulkarni, B. A.; Strobel, G.; Lobkovsky, E.; Torczynski, R. M.; Porco,
J. A., Jr. Org. Lett. 2001, 3, 1649–1652.
13. Liu, C.; Burnell, J. J. Org. Chem. 1997, 62, 3683–3687.
This work was supported financially by a Grant-in-Aid for the
Program for Promotion of Basic and Applied Research for Innova-
tions in the Bio-oriented Industry (BRAIN).
14. The isomer 22 was obtained as a single product and the stereochemistry at C5
remains to be established. ½a D27
ꢁ
+35.8° (c 0.05 CHCl3); IR (KBr) 3387, 2926,
1691, 1686, 1436, 1377, 1207, 1089 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 5.87

A. Miyawaki et al. / Tetrahedron Letters 53 (2012) 1236–1239
1239
(1H, d, J = 1.6 Hz), 4.10–4.07 (1H, m), 3.74 (1H, dd, J = 12.0 and 2.3 Hz), 2.74
(1H, dd, J = 15.6 and 1.0 Hz), 2.44–2.35 (1H, m), 2.08 (3H, d, J = 1.6 Hz), 1.87
(1H, dd, J = 15.6 and 4.4 Hz), 1.79–1.71 (1H, m), 1.64–1.50 (1H, m), 1.48–1.02
(2H, m), 1.17 (3H, s), 1.13 (3H, s), 0.71 (3H, d, J = 6.8 Hz); 13C NMR (125 MHz,
CDCl3) d 194.4 (C), 159.9 (C), 125.0 (CH), 78.2 (C), 77.6 (CH), 76.6 (CH), 72.7 (C),
67.4 (CH), 31.1 (CH), 28.4 (CH2), 27.1 (CH2), 26.8 (CH3), 26.5 (CH2), 23.0 (CH3),
21.8 (CH3), 17.2 (CH3); HRMS (ESI) calcd for C15H24O4Na 291.1572 (M++Na),
found 291.1580.
15. Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi, T. Chem. Pharm. Bull. 1984, 32, 1411–
1415.