Total synthesis of (+)-cryptocaryanone A

Article abstract of DOI:10.1055/s-0032-1316580

The first total synthesis of (+)-cryptocaryanone A is described. The synthesis features a Mukaiyama aldol reaction, one-pot saponification/ lactonization sequences, and TsOH-assisted dihydropyrone formation as key steps.

Full text of DOI:10.1055/s-0032-1316580

LETTER
▌2129
letter
Total Synthesis of (+)-Cryptocaryanone A
Total Synthesis of (+)-Cryptocaryanone A
Bingbin Zhang,a Zhen Yang,a Juan Yang,a Gaoyuan Zhao,a Bin Ma,a Xingang Xie,*a Xuegong She*a,b
a
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: shexg@lzu.edu.cn; E-mail: xiexg@lzu.edu.cn
b
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, P. R. of China
Received: 07.05.2012; Accepted after revision: 27.05.2012
5, which would be easily prepared from known chiral
enone 6 and epoxide 7 respectively.
Abstract: The first total synthesis of (+)-cryptocaryanone A is de-
scribed. The synthesis features a Mukaiyama aldol reaction, one-pot
saponification/lactonization sequences, and TsOH-assisted dihy-
dropyrone formation as key steps.
3'
4'
5'
2'
Key words: total synthesis, natural products, aldol reaction, sapon-
ification, lactonization
O
OH
OTBS
O
8
1'
9
2
3
7
6
6'
10
4
5
O
12
O
11
Flavonoids are a large class of natural products with di-
verse structures and good bioactivities that have been used
to treat diseases for centuries.1 In 2001, Guéritte and co-
workers reported the isolation of two new dihydroflava-
nones, cryptocaryanones A (1) and B (2), from the trunk
bark of Cryptocarya infectoria (Figure 1).2 Both com-
pounds exhibit modest cytotoxicity against KB cell lines,
with IC50 values of 2.5 μM for 1 and 2.1 μM for 2. In ad-
dition, cryptocaryanone A also shows cytotoxicities
against MCF-7, NCI-H460, and SF-268 cell lines.3 Struc-
turally, these dihydroflavanones contain a tricyclic [6,6,5]
skeleton comprising a γ-lactone and a dihydropyrone sub-
unit. To date, to the best of our knowledge, no synthetic
efforts towards these natural products have been reported.
Attracted by its biological activity and unique chemical
structure, we sought to develop a flexible synthetic route
to these dihydroflavanones. Herein, we reported a concise
synthesis of (+)-cryptocaryanone A.
OBz
CO2Et
O
cryptocaryanone A (1)
3
O
O
O
O
OEt
O
OBz
4
6
+
O
OTBS
O
H
7
5
Scheme 1 Retrosynthetic analysis of cryptocaryanone A
3'
The synthesis of cyclohexenone 4 commenced from the
known chiral enone 6 as shown in Scheme 2.4 Conjugate
addition of TBS-enol ether 8 to enone 6 smoothly afford-
4'
5'
2'
O
O
O
8
1'
9
2
3
7
6
6'
10
4
5
O
O
O
O
OTBS
OTBS
OEt
12
O
11
O
O
NaOH (0.5 M)
8
OEt
O
O
cat. HgI2, Et2O,
–78 °C to r.t., 90%
TBAF, THF,
0 °C, 85%
cryptocaryanone A (1)
cryptocaryanone B (2)
O
O
Figure 1 Structures of cryptocaryanone A and B
6
9
Retrosynthetically, cryptocaryanone A (1) could be ob-
tained from enone 3 via lactonization and dihydropyrone
formation (Scheme 1). Enone 3 was convergently discon-
nected into two segments, cyclohexenone 4 and aldehyde
O
O
Ph3P, PhCO2H,
DIAD, THF, 0 °C to r.t,
O
O
6
6
OEt
OEt
82%
OH
OBz
SYNLETT 2012, 23, 2129–2131
Advanced online publication: 04.07.2012
10
4
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316580; Art ID: ST-2012-W0399-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthesis of cyclohexenone (4)

2130
B. Zhang et al.
LETTER
O
OH
S
2,6-lutidine, TBSOTf
1,3-dithiane (11), n-BuLi
S
CH2Cl2, 0 °C to r.t.
91%
DMPU, THF, –15 °C to r.t.
93%
7
12
O
OTBS
OTBS
S
CaCO3, MeI
H
S
MeCN–H2O (9:1)
40 °C, 65%
13
5
Scheme 3 Synthesis of aldehyde 5
ed 9 as a single isomer.5 Treatment of 9 with sodium hy- agent) were all unsuccessful. Gratifyingly, the use of
droxide and tetrabutylammonium fluoride (TBAF) gave TFAA-assisted Swern condition was effective and fur-
10 in 85% yield.4,6 Compound 10 was subjected to a Mit- nished ketone 3 in 87% yield.9 Treatment of 3 with TfOH
sunobu reaction with benzoic acid and the stereochemis- in dichloromethane at –15 °C for five hours led to cleav-
try of the C6 secondary hydroxy group was inverted to age of the TBS ether and cyclization in one pot to provide
give the desired cyclohexenone 4 in 82% yield.
hydropyranone 15 in excellent yield.10 At this time, we an-
ticipated that cryptocaryanone A (1) could be obtained
from ester 15 by a lactonization reaction.11 Surprisingly,
when ester 15 was treated with potassium carbonate in
methanol at –15 °C, 7-epi-cryptochinone F (16)12 was ob-
tained, the structure of which was assigned by means of
The synthesis of aldehyde 5 is depicted in Scheme 3: lithi-
ation of 1,3-dithiane 11, followed by addition of epoxide
7, afforded alcohol 12 in 93% yield.7 Protection of the free
alcohol as the TBS ether and removal of the 1,3-dithiane
group gave aldehyde 5 in 59% overall yield for two steps.
1
comprehensive spectroscopic analysis, including H, 13C
With cyclohexenone 4 and aldehyde 5 in hand, we turned
our attention to the completion of the total synthesis of
cryptocaryanone A (Scheme 4). Ketone 4 was first con-
verted into the corresponding silyl enol ether, which was
treated with aldehyde 5 in the presence of BF3·OEt2 to af-
ford alcohol 14 in 72% overall yield for two steps.8 Sub-
sequent oxidation of 14 was more problematic; attempted
oxidations (PCC, 2-iodoxybenzoic acid, Dess–Martin re-
NMR, H–H COSY, HMBC and NOE experiments.3,13
The synthetic route was adjusted slightly to construct the
γ-lactone subunit first. Lactone 17 was readily obtained in
61% yield by treating ketone 3 with potassium carbonate
in methanol. Subjecting 17 to the TsOH-promoted dihy-
dropyrone formation reaction smoothly furnished crypto-
caryanone A (1) in 49% isolated yield (Scheme 5). The
optical rotation and spectroscopic data of synthetic cryp-
O
O
OH OTBS
1) TBSOTf, Et3N,
0 °C, CH2Cl2, r.t.
O
TFAA, DMSO, Et3N,
CH2Cl2, –78 °C, 87%
2) BF3⋅OEt2, then 5,
–78 °C, CH2Cl2
OEt
OBz
OBz
CO2Et
72% (2 steps)
4
14
O
OH OTBS
O
O
K2CO3, MeOH,
–15 °C, 30%
TfOH, CH2Cl2,
–30 °C, 91%
BzO
EtO2C
OBz
CO2Et
3
15
MeO
O
MeO
O
O
7
7
O
O
O
O
O
7-epi-cryptochinone F (16)
cryptochinone F (18)
Scheme 4 Synthesis of 7-epi-cryptochinone F (16)
Synlett 2012, 23, 2129–2131
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of (+)-Cryptocaryanone A
2131
O
OH OTBS
O
OH OTBS
O
K2CO3, MeOH,
r.t., 61%
TsOH, CH2Cl2,
r.t., 49%
O
O
O
OBz
CO2Et
O
O
17
3
cryptocaryanone A (1)
Scheme 5 Synthesis of cryptocaryanone A
Lett. 2004, 14, 4855. (c) Danishefsky, S. J.; Selnick, H. G.;
Zelle, R. E.; DeNinno, M. P. J. Am. Chem. Soc. 1988, 110,
4368.
tocaryanone A (1) were in agreement with those of the
isolated natural product.14
In summary, an enantioselective total synthesis of crypto-
caryanone A (1) has been accomplished that involved a
Mukaiyama aldol reaction and a one-pot saponifica-
tion/lactonizaton sequence as key steps. The 7-epi-crypto-
chinone F (16) was also achieved accidently and the
developed strategy can be used to access other cryptochi-
none analogues.
(9) Cuthbertson, J. D.; Godfrey, A. A.; Taylor, R. J. K. Org.
Lett. 2011, 13, 3976.
(10) (a) Jin, M.; Taylor, R. E. Org. Lett. 2005, 7, 1303.
(b) Crossman, J. S.; Perkins, M. V. J. Org. Chem. 2006, 71,
117.
(11) (a) Hayashi, Y.; Urushima, T.; Shin, M.; Shoji, M.
Tetrahedron 2005, 61, 11393. (b) Hon, Y.-S.; Liu, Y.-W.;
Hsieh, C.-H. Tetrahedron 2004, 60, 4837.
(12) 7-epi-Cryptochinone F (16): [α]D20 +40 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3): δ = 2.35 (dd, J = 18.0, 5.2 Hz,
1 H), 2.50 (dd, J = 18.4, 5.6 Hz, 1 H), 2.71 (dd, J = 17.0,
3.4 Hz, 1 H), 2.76 (dd, J = 19.8, 3.8 Hz, 1 H), 2.92 (dd,
J = 16.8, 13.6 Hz, 1 H), 3.03 (dd, J = 18.2, 8.6 Hz, 1 H),
3.47 (s, 3 H), 3.61 (br dd, J = 14.4, 6.4 Hz, 1 H), 3.83 (br dd,
J = 10.6, 5.4 Hz, 1 H), 4.67 (t, J = 6.6 Hz, 1 H), 5.48 (dd,
J = 13.2, 3.6 Hz, 1 H), 7.37–7.43 (m, 5 H). 13C NMR (100
MHz, CDCl3): δ = 30.24, 32.05, 34.89, 43.01, 58.18, 74.75,
78.26, 80.94, 110.75, 126.27, 129.11, 129.24, 137.88,
167.88, 176.16, 190.80. IR (KBr): 2985, 2547, 2256, 1739,
1374, 1245, 915, 734 cm–1; HRMS (ESI): m/z [M + H]+ calcd
Acknowledgment
We are grateful for generous financial support from the MOST
(2010CB833200), the NSFC (21125207, 21072086, 21102062) and
program 111.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
+
References and Notes
for C18H19O5 : 315.1227; found: 315.1223.
(13) Cryptochinone F was isolated from the evergreen tree
Cryptocarya chinensis by Chou et al. (see ref. 3).
(1) (a) Spencer, J. P. E. Br. J. Nutr. 2008, 99 ,01 ES60.
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2008, 10, 1939.
(7) (a) Davey, A. E.; Parsons, A. F.; Taylor, R. J. K. J. Chem.
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(8) (a) Dunn, T. B.; Ellis, J. M.; Kofink, C. C.; Manning, J. R.;
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(14) Cryptocaryanone A (1): To a solution of diketone 17 (9 mg,
0.022 mmol) in CH2Cl2 (5 mL) at r.t., was added TsOH·H2O
(41 mg, 0.22 mmol). The reaction mixture was stirred for 3
days, then quenched with sat. aq NaHCO3 (2 mL). The layers
were separated and the aqueous phase was extracted with
CH2Cl2 (3 × 5 mL), dried over anhydrous Na2SO4, filtered,
and concentrated. Flash chromatography (hexanes–EtOAc,
3:1) afforded cryptocaryanone A (1; 3 mg, 49%) as a white
powder. [α]D20 +217 (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3): δ = 2.41 (dd, J = 17.9, 10.5 Hz, 1 H), 2.73 (dd,
J = 16.8, 3.6 Hz, 1 H), 2.94 (dd, J = 17.2, 14.0 Hz, 1 H),
2.99 (dd, J = 18.0, 9.2 Hz, 1 H), 3.88 (dd, J = 19.8, 10.4 Hz,
1 H), 5.46–5.50 (m, 2 H), 6.10 (dd, J = 10.1, 1.8 Hz, 1 H),
6.29 (dd, J = 10.1, 2.7 Hz, 1 H), 7.41–7.45 (m, 5 H); 13
C
NMR (100 MHz, CDCl3): δ = 30.75, 33.34, 42.94, 76.70,
81.08, 109.00, 124.30, 126.36, 129.13, 129.34, 134.87,
137.71, 162.77, 175.58, 190.47. IR (KBr): 2923, 2253, 1782,
1652, 1589, 1428, 910 cm–1; HRMS (ESI): m/z [M + H]+
+
calcd for C18H19O5 : 283.0965; found: 283.0959.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2129–2131

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