The first asymmetric total syntheses of both enantiomers of cryptocaryone

Article abstract of DOI:10.1016/j.tetlet.2010.01.101

The first asymmetric total syntheses of the (+)- and (-)-cryptocaryones are described. Removal of the acetal unit of the enone acetal 5, which was obtained in our previous study from the cyclohexadiene acetal 3, afforded the enone acetal 8 in a one-pot procedure. The acylation of 8 with cinnamoyl chloride and subsequent hydrolysis of the resulting acetal gave the lactol 11. Its oxidation with NIS and tetra-n-butylammonium iodide (TBAI) finally furnished the natural (+)-cryptocaryone 2. The same procedure from ent-3 afforded the unnatural one 1.

Full text of DOI:10.1016/j.tetlet.2010.01.101

Tetrahedron Letters 51 (2010) 1945–1946
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Tetrahedron Letters
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The first asymmetric total syntheses of both enantiomers of cryptocaryone
*
Hiromichi Fujioka , Kenji Nakahara, Tomohiro Oki, Kie Hirano, Tatsuya Hayashi, Yasuyuki Kita
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first asymmetric total syntheses of the (+)- and (ꢀ)-cryptocaryones are described. Removal of the
acetal unit of the enone acetal 5, which was obtained in our previous study from the cyclohexadiene ace-
tal 3, afforded the enone acetal 8 in a one-pot procedure. The acylation of 8 with cinnamoyl chloride and
subsequent hydrolysis of the resulting acetal gave the lactol 11. Its oxidation with NIS and tetra-n-butyl-
ammonium iodide (TBAI) finally furnished the natural (+)-cryptocaryone 2. The same procedure from ent-
3 afforded the unnatural one 1.
Received 28 December 2009
Revised 26 January 2010
Accepted 28 January 2010
Available online 10 February 2010
Keywords:
Cryptocaryone
Ó 2010 Elsevier Ltd. All rights reserved.
Chiral auxiliary
Intramolecular bromoetherification
CAN
Cryptocaryone was first isolated from the root of Cryptocarya
bourdilloni Gamb in 1972 and its structure was reported as a chal-
cone.1 Its structure was revised in 1985 and its relative structure
was determined as 1 by X-ray analysis.2 In 2001, cryptocaryone
having the same optical rotation was also obtained from the trunk
bark of Cryptocarya infectoria (Bl.) Miq. and its absolute configura-
tion was determined as 2 from an X-ray analysis of its analogue.3
However, its absolute configuration is still confusing. For example,
cryptocaryone was also isolated from Cryptocarya rugulosa in 2009
by Cardellina II and co-workers, and its structure was shown as 1,
although they did not mention its absolute configuration.4 From a
biological aspect, cryptocaryone was reported to show a cytotoxic-
ity against the multi-drug resistant K562-DOX cells in 2001,3 and
quite recently, it was shown to be an inhibitor of the nuclear fac-
Ph
Ph
O
O
O
O
HO
HO
O
O
1 ref. 2, 4
2 ref. 3
Figure 1. Structure of cryptocaryone.
ford the optically active cyclohexene acetal 4 with multiple chiral
centers. One of its application to asymmetric syntheses of natural
products was conducted via the cyclohexenone acetal 5 obtained
from 4 by hydroboration–oxidation procedure (Scheme 1).6
The cyclohexenone structure and its two asymmetric centers of
5 seemed to be a good precursor of those in structure 2. Since the
structures 1 and 2 are enantiomers of each other, we then studied
the asymmetric syntheses of both enantiomers of cryptocaryone.
The introduction of the side chain at the a0-position of the enone
5 was achieved using LHMDS and cinnamoyl chloride in good yield.
However, the removal of the chiral auxiliary, the diphenylethyl
unit, was unsuccessful. We then first removed the chiral auxiliary
tor-jB (NF-j jB signaling pathway is active
B) activity.4 The NF-
in many cancers and is a potent therapeutic target. Therefore, cryp-
tocaryone is an important synthetic target in view of its biological
properties.
In this Letter, we present the first asymmetric syntheses of com-
pounds 1 and 2, the enantiomers of each other (Fig. 1), in a concise
manner with unambiguous determination of their absolute config-
urations by chemical synthesis.
During the course of our continuous efforts regarding natural
product syntheses, we have recently succeeded in the intramolec-
ular haloetherification of the cyclohexadiene acetal 3,5 easily ob-
tained from the commercially available 1,4-cyclohexadiene and
chiral (R,R)-hydrobenzoin in two steps and 75% overall yield, to af-
Ph
MeO
MeO
NBS
MeOH
O
Ph
Ph
thexylborane
then PDC
Ph
Ph
O
*
O
*
Ph
O
*
O
O
63%
53%
*
Br
O
* Corresponding author. Tel.: +81 6 6879 8225; fax: +81 6 6879 8229.
E-mail address: fujioka@phs.osaka-u.ac.jp (H. Fujioka).
3
4
5
Present address: College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-
1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan.
Scheme 1. Synthesis of the enone acetal 5 from the diene acetal 3.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.101

1946
H. Fujioka et al. / Tetrahedron Letters 51 (2010) 1945–1946
structure 1 of cryptocaryone via ent-5. The optical rotation of 1
O
OH
O
showed the opposite sign from the natural one (½a D24:9
ꢀ727.7
ꢁ
CAN
MeOH
5
(c 1.00, CHCl3)). From these facts, the structure of 1 was confirmed
to be an enantiomer of the natural one.
OH
CH3CN-H2O
(2/1)
O
In conclusion, we accomplished the first asymmetric syntheses
of the natural and unnatural cryptocaryones from the commer-
cially available 1,4-cyclohexadiene in a total of seven steps with
a 7.9% overall yield. Furthermore, the information about the abso-
lute structure of the natural one was presented by chemical
synthesis.
O
60 ºC
6
Ph
O
7
LHMDS
COCl
Ph
OMe
O
OMe
O
OMe
Ph
THF, -78 ºC
O
HO
Acknowledgments
O
O
O
8
9
10
This work was financially supported by Grant-in-Aid for Scien-
tific Research (A) and (B) and Grant-in-Aid for Scientific Research
for Exploratory Research from Japan Society for the Promotion of
Science.
67% from 5
Ph
Ph
O
O
OH
O
NIS
TBAI
4N HCl aq.
HO
References and notes
HO
CH2Cl2
74%
O
O
1. (a) Govindachari, T. R.; Parthasarathy, P. C. Tetrahedron Lett. 1972, 13, 3419–
3420; (b) Govindachari, T. R.; Parthasarathy, P. C.; Desai, H. K.; Shanbhag, M. N.
Tetrahedron 1973, 29, 3091–3094.
2. Maddry, J. A.; Joshi, B. S.; Newton, M. G.; Pelletier, S. W.; Parthasarathy, P. C.
Tetrahedron Lett. 1985, 26, 5491–5492.
(+)-cryptocaryone (2)
11
64% from 8
Scheme 2. Asymmetric synthesis of (+)-cryptocaryone (2).
3. Dumontet, V.; Gaspard, C.; Hung, N. V.; Fahy, J.; Tchertanov, L.; Sévenet, T.;
Guéritte, F. Tetrahedron 2001, 57, 6189–6196.
4. Meragelman, T. L.; Scudiero, D. A.; Davis, R. E.; Staudt, L. M.; McCloud, T. G.;
Cardellina, J. H., II; Shoemaker, R. H. J. Nat. Prod. 2009, 72, 336–339.
5. (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; (c) Fujioka, H.; Sawama, Y.; Kotoku, N.; Ohnaka, T.; Okitasu, T.; Murata, N.;
Kubo, O.; Li, R.; Kita, Y. Chem. Eur. J. 2007, 13, 10225–10238.
Ph
Ph
MeO
Ph
Ph
O
O
O
O
Ph
O
O
HO
6. Fujioka, H.; Ohba, Y.; Nakahara, K.; Takatsuji, M.; Murai, K.; Ito, M.; Kita, Y. Org.
Lett. 2007, 9, 5605–5608.
O
O
7. For deprotection of acetals by CAN, see: (a) Ates, A.; Gautier, A.; Leroy, B.;
Plancher, J.-M.; Quesnel, Y.; Markó, I. E. Tetrahedron Lett. 1999, 40, 1799–1802;
(b) Markó, I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.;
Vanherck, J.-C. Angew. Chem., Int. Ed. 1999, 38, 3207–3209; (c) Ates, A.; Gautier,
A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.; Vanherck, J.-C.; Markó, I. E.
Tetrahedron 2003, 59, 8989–8999.
(-)-cryptocaryone (1)
ent-3
ent-5
Scheme 3. Asymmetric synthesis of (ꢀ)-cryptocaryone (1).
8. For the method using CAN, see: (a) Fujioka, H.; Ohba, Y.; Hirose, H.; Murai, K.;
Kita, Y. Org. Lett. 2005, 7, 3303–3306; (b) Fujioka, H.; Hirose, H.; Ohba, Y.;
Murai, K.; Nakahara, K.; Kita, Y. Tetrahedron 2007, 63, 625–637.
9. Pachamuthu, K.; Vankar, Y. D. J. Org. Chem. 2001, 66, 7511–7513.
10. Spectral data of compound 8 (ca. 2:1 diastereomeric mixture): colorless oil; IR
and successively introduced the side chain as shown in Scheme 2.
The treatment of 5 with CAN in CH3CN–H2O (2/1) at 60 °C allowed
hydrolysis of an acetal unit7 and subsequent removal of the
diphenylethanol unit8 to give the hydroxyl aldehyde 6, which
spontaneously cyclized to afford the lactol 7 as a diastereomeric
mixture in a single operation. The lactol 7 was unstable and easily
decomposed during evaporation and SiO2 column chromatogra-
phy. The treatment of the reaction mixture with MeOH then affor-
ded the Me-ether 8 in 67% yield from 5 in a one-pot operation via
the lactol 7. It is proposed that the lactol 7 converted to the corre-
sponding acetal 810 by the Brønsted acid generated from CAN and
MeOH.9 Acylation at the a0-position of the enone unit of 8 with
LHMDS and cynnamoyl chloride produced the diketone 9, which
was spontaneously converted to the enol form 10. Acidic work-
up then afforded the lactol 1110 (64% yield from 8 in a one-pot
operation). Although usual oxidants such as PCC and PDC gave
poor results, the oxidation of the lactol unit with NIS and
tetra-n-butylammonium iodide (TBAI)11 finally furnished the
structure 210 in 74% yield. In addition to the physical data (1H NMR,
13C NMR, IR, HRMS), the agreement of its optical rotation with
(KBr): 1682, 1101, 1024 cmꢀ1
;
1H NMR (CDCl3, 400 MHz): d 1.55–1.85 (1H, m),
2.01–2.06 (1H, m), 2.47–2.66 (2H, m), 2.84–2.91 (1/3H, m), 2.97–3.05 (2/3H,
m), 3.35 (1H, s), 3.35 (2H, s), 4.73–4.76 (1H, m), 5.01 (2/3H, d, J = 5.0 Hz), 5.07
(1/3H, dd, J = 5.9, 4.1 Hz), 5.98 (1/3H, d, J = 10.1 Hz), 6.00 (2/3H, d, J = 10.5 Hz),
6.70 (2/3H, dd, J = 10.1, 3.2 Hz), 6.78 (1/3H, dd, J = 10.1, 2.7 Hz); 13C NMR
(CDCl3, 100 MHz): d 34.9, 36.6, 37.8, 37.9, 38.0, 38.1, 54.9, 55.7, 73.0, 74.1,
104.6, 106.2, 128.9, 129.3, 145.8, 148.1, 197.5, 197.7; LRMS (EI): m/z 168 (M+);
HRMS (EI): calcd for C9H12O3: 168.0786; found 168.0788. Spectral data of
compound 11 (ca. 4:1 diastereomeric mixture): yellow amorphous; IR (KBr):
3376, 1630, 1557 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 1.89–1.96 (1H, m), 2.28
;
(4/5H, dd, J = 12.8, 7.3 Hz), 2.63–2.70 (1/5H, m), 3.49 (1H, br s), 3.55–3.62 (1/
5H, m), 3.86–3.94 (4/5H, m), 4.93 (1/5H, d, J = 8.2 Hz), 5.12 (4/5H, d, J = 8.7 Hz),
5.56 (4/5H, d, J = 4.6 Hz), 5.66 (1/5H, t, J = 5.0 Hz), 6.04 (4/5H, d, J = 10.1 Hz),
6.06 (1/5H, d, J = 9.6 Hz), 6.45 (4/5H, dd, J = 10.1, 2.3 Hz), 6.67 (1/5H, d,
J = 10.1 Hz), 6.84 (1/5H, d, J = 15.6 Hz), 6.98 (4/5H, d, J = 15.6 Hz), 7.32–7.58
(5H, m), 7.71 (1/5H, d, J = 15.6 Hz), 7.73 (4/5H, d, J = 15.6 Hz); 13C NMR (CDCl3,
100 MHz): d 33.6, 37.0, 41.4, 42.1, 75.0, 75.3, 96.3, 98.2, 104.7, 105.4, 117.7,
117.8, 127.3, 128.0, 128.1, 128.9, 129.0, 130.0, 130.1, 135.1, 135.2, 140.8, 141.0,
143.7, 146.7, 173.0, 174.1, 186.5, 187.1; LRMS (FAB): m/z 285 (MH+); HRMS
(FAB): calcd for C17H17O4: 285.1127; found 285.1122. Spectral data of
compound 2 ((+)-cryptocaryone): yellow solid; ½a D25:0
ꢁ
+761.8 (c 0.69, CHCl3);
IR (KBr): 1778, 1630, 1556 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 2.62 (1H, dd,
;
the natural cryptocaryone (½a D25:0
ꢁ
+761.8 (c 0.69, CHCl3), (lit. [a]
D
J = 17.4, 12.3 Hz), 2.79 (1H, dd, J = 17.4, 8.6 Hz), 3.94–4.04 (1H, m), 5.48 (1H, dd,
J = 8.8, 2.0 Hz), 6.26 (1H, dd, J = 10.3, 1.8 Hz), 6.60 (1H, d, J = 10.1 Hz), 6.77 (1H,
d, J = 15.4 Hz), 7.41–7.58 (5H, m), 7.77 (1H, d, J = 15.4 Hz); 13C NMR (CDCl3,
100 MHz): d 33.9, 35.3, 76.1, 103.3, 116.7, 128.2, 129.1, 130.1, 130.6, 134.8,
140.0, 142.4, 174.1, 174.4, 185.8; LRMS (FAB): m/z 283 (MH+); HRMS (FAB):
calcd for C17H15O4: 283.0971; found 283.0958.
+776.6 (c 2, CHCl3),1a
½
a 2D5 +770.7 (c 0.99, CHCl3)3) indicated that
ꢁ
the absolute configuration of the natural one is structure 2.
For confirmation, the structure of 1 was also synthesized
(Scheme 3). Thus, the same procedure from the ent-3,5c prepared
from 1,4-cyclohexadiene and (S,S)-hydrobenzoin, afforded the
11. Hanessian, S.; Wong, D. H.; Therien, M. Synthesis 1981, 394–396.