Efficient total synthesis of (+)-curcuphenol via asymmetric organocatalysis

Article abstract of DOI:10.1016/j.tetlet.2005.02.047

The catalytic enantioselective synthesis of (+)-curcuphenol is described herein. This approach involves the use of an organocatalytic alkylation of m-anisidine, a diazotation/Sandmeyer reaction of the amine and a Negishi-type coupling with dimethylzinc. T

Full text of DOI:10.1016/j.tetlet.2005.02.047

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 2437–2439
Efficient total synthesis of (+)-curcuphenol via
asymmetric organocatalysis
Sung-Gon Kim,* Jaehak Kim and Heejung Jung
Medicinal Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu,
Daejeon 305-600, Republic of Korea
Received 18 January 2005; revised 4 February 2005; accepted 9 February 2005
Abstract—The catalytic enantioselective synthesis of (+)-curcuphenol is described herein. This approach involves the use of an
organocatalytic alkylation of m-anisidine, a diazotation/Sandmeyer reaction of the amine and a Negishi-type coupling with dimeth-
ylzinc. This versatile strategy allows for the rapid synthesis of other members of this class of natural products.
Ó 2005 Elsevier Ltd. All rights reserved.
Curcuphenol is a bioactive sesquiterpene phenol whose
different enantiomersexhibit tsrikingly different activi-
ties. (S)-(+)-Curcuphenol (1), isolated from the marine
sponge Didiscus flavus and Epipolasis species, display
antifungal activity against Candida albicans, antitumor
activity against several human cancer cell lines and anti-
malarial activity against Plasmodium falciparium.1 (S)-
(+)-Curcuphenol has also been shown to inhibit pro-
ton–potassium ATPase.2 (R)-(ꢀ)-Curcuphenol, isolated
from the gorgonian coral Pseudopterogorgia rigida,
tion using an imidazolidinone as catalyst.5 We employed
their organocatalytic Friedel–Craftsreaction in the syn-
thesis of curcuphenol.
The synthesis of (+)-curcuphenol 1 beginswith commer-
cially available m-anisidine as illustrated in Scheme 1.
The amino protection of m-anisidine with benzyl bro-
mide in the presence of K2CO3 gave 2 in 92% yield.
Aldehyde 5 wasobtained by the reaction of N,N-dibenz-
yl-3-anisidine 2 and crotonaldehyde 3 using imidazolid-
inone catalyst 4. Optimal enantiocontrol wasachieved
with catalyst 4 (10 mol%) in CH2Cl2 at ꢀ40 °C to afford
aldehyde (S)-5 in 90% yield with an enantiomeric excess
of 90%.6 This reaction establishes the benzylic stereoge-
nicity of curcuphenol. Catalyst 4 and crotonaldehyde 3
combine to generate a,b-unsaturated iminium ion that
isanticipated to eslectively populate the ( E)-isomer to
avoid nonbonding interactions between the substrate
olefin and the tert-butyl group. Since the benzyl group
on the catalyst framework effectively shields the si-face
of the activated olefin, N,N-dibenzyl-3-anisidine 2 ispre-
dominantly added to the re-face exposed.5c Aldehyde 5
wasreduced with osdium borohydride, thiswasfol-
lowed by in situ deprotection of the benzyl groups to
afford 6 in 90% yield.7
exhibitsantibacterial activitiesagaints
Staphylococcus
aureus and Vibrio anguillarum.3 Accordingly, a versatile
and efficient synthetic route to this sesquiterpene that
can be utilized to explore structure–activity relationships
is of significance. Though several enantioselective and
racemic syntheses of curcuphenol have been reported,4
to the best of our knowledge, the enantioselective syn-
thesis of curcuphenol through asymmetric catalysis to
introduce a stereogenic center in the benzylic position
have not yet been reported. Herein we report a short,
efficient asymmetric synthesis of (S)-(+)-curcuphenol,
based on asymmetric organocatalysis.
Our synthetic approach toward the target molecule was
based on the organocatalytic asymmetric Friedel–Crafts
alkylation of aniline which produced a stereogenic benz-
ylic center. Recently, MacMillan and co-workershave
developed catalytic enantioselective Friedel–Crafts reac-
OH
Keywords: Curcuphenol; Total synthesis; Organocatalysis.
*
1
Corresponding author. Tel.: +82 42 860 7115; fax: +82 42 861
1291; e-mail: sgkim@krict.re.kr
(S)-(+)-Curcumene
(S)-(+)-Curcuphenol
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.047

2438
S.-G. Kim et al. / Tetrahedron Letters 46 (2005) 2437–2439
O
N
N
O
OMe
OMe
H
HCl
OMe
Ph
4
H
1. NaBH4, EtOH
BnBr, K2CO3
92% yield
O
,
10 mol%
3
Bn
Bn
N
Bn
N
Bn
2. 10% Pd/C, H2, HCl
90% yield
H2N
H2N
90% yield, 90% ee
5
2
OMe
OMe
OMe
PPh3, imida zole, 2I
Me2Zn, cat. Pd(PPh3)2Cl2
85% yield
NaNO2, CuBr
55% yield
OH
OH
OH
84% yield
6
Br
7
8
OMe
OH
OMe
C2H5SNa
92% yield
cat. Li2CuCl4
I
MgBr,
80% yield
1
9
10
(+)-Curcuphenol
Scheme 1.
The conversion of 6 to known precursor 8 wasachieved
by a Sandmeyer-type bromination of aminobenzene 6,8
followed by a palladium-catalyzed methylation of a
bromobenzene 7 under Negishi-type coupling.9 Bromin-
ation of a aminobenzene 6 wasfound to be unexpectedly
difficult. Experimentation with t-BuONO and CuBr2
methodsprovided ( S)-3-(4,5-dibromo-2-methoxy-phen-
yl)-butan-1-ol. After much experimentation, a 55% yield
wasobtained in the reaction of 6 with NaNO2, HBr,
and CuBr.10 Compound 7 underwent methylation with
route represents potential route to other members of the
bisabolane family, which is now in progress and will be
presented in due course.
Acknowledgements
We thank Korea Research Institute of Chemical Tech-
nology (KRICT) for financial support of this work.
dimethylzinc in the presence of Pd(PPh3)2Cl2
23
D
(5.0 mol%) to give 8 in 85% yield (½aŠ +19.5 (c 1.0,
References and notes
CHCl3)).11
1. (a) Wright, A. E.; Pomponi, S. A.; McConnell, O. J.;
Kohmoto, S.; McCarthy, P. J. J. Nat. Prod. 1987, 50, 976–
978; (b) Fusetini, N.; Sugano, M.; Matsunaga, S.;
Hashimoto, K. Experientia 1987, 43, 1234–1235.
2. (a) Hashimoto, T.; Fuseya, N.; Shikama, H. Jpn. Kokai
Tokkyo Koho, Jpn. Pat. Appl. JP 85-201254 19850910.
CAN 107: 28375, 1987; (b) Nanba, R.; Isozaki, M.; Endo,
I.; Yomo, Y. Jpn. Kokai Tokkyo Koho, Jpn. Pat. Appl.
JP 89-60236 19890313. CAN 114: 121718, 1990; (c) Sayed,
K. A. E.; Yousaf, M.; Hamann, M. T.; Avery, M. A.;
Kelly, M.; Wipf, P. J. Nat. Prod. 2002, 65, 1547–1553.
3. McEnroe, F. J.; Fenical, W. Tetrahedron 1978, 34, 1661–
1664.
4. For asymmetric synthesis of curcuphenol, see; (a) Har-
mata, M.; Hong, X.; Barnes, C. L. Tetrahedron Lett. 2003,
44, 7261–7264; (b) Kimachi, T.; Takemoto, Y. J. Org.
Chem. 2001, 66, 2700–2704; (c) Ono, M.; Ogura, Y.;
Hatogai, K.; Akita, H. Chem. Pharm. Bull. 2001, 49, 1581–
1585; (d) Fuganti, C.; Serra, S. J. Chem. Soc., Perkin
Trans. 1 2000, 3758–3764; (e) Sugahara, T.; Ogasawara,
K. Tetrahedron: Asymmetry 1998, 9, 2215–2217; (f)
Fuganti, C.; Serra, S. Synlett 1998, 1252–1254; (g) Ono,
M.; Ogura, Y.; Hatogai, K.; Akita, H. Tetrahedron:
Asymmetry 1995, 6, 1829–1832.
5. (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc.
2001, 123, 4370–4371; (b) Austin, J. F.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2002, 124, 1172–1173; (c) Paras, N.
A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123,
7894–7895; (d) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao,
Compound 8 wasconverted into iodide 9 via the reac-
tion with PPh3, imidazole, I2 in 84% yield. The coupling
of iodide 9 with 2-methyl-1-propenylmagnesium bro-
mide catalyzed by copper(I) iodide wasattempted, in ac-
cord with an early reported procedure.4d Unfortunately
this Cu-catalyzed reaction did not provide a consistent
yield of the desired product.12 After several catalyst
screening, we found that Li2CuCl4 wasthe effective cat-
alyst for this cross-coupling reaction. Using 5 mol% of
Li2CuCl4, good yield (80%) of cross-coupling product
23
D
tion at rt for 6 h. Finally, the methyl ether functionality
10 (½aŠ +6.6 (c 1.0, CHCl3))13 wasobtained after reac-
of compound 10 was cleaved using sodium ethanethio-
late in DMF to give (S)-(+)-curcuphenol (1) in 90% yield
23
(½aŠ +23.8 (c 1.0, CHCl3)).14 The physical and spectro-
D
scopic data of 1 are in full agreement with literature
data.
In conclusion, we have completed the total synthesis of
(S)-(+)-curcuphenol, based on the organocatalytic alkyl-
ation of m-anisidine, and a diazotation/Sandmeyer reac-
tion of amine followed by a Negishi-type coupling with
dimethylzinc, as key steps. This versatile synthetic se-
quence could be employed for structure activity studies
on curcuphenol to determine the biologically relevant
components of the architecture. The present asymmetric

S.-G. Kim et al. / Tetrahedron Letters 46 (2005) 2437–2439
2439
W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. 2004,
101, 5482–5487.
6. Synthesis of (S)-3-(4-dibenzylamino-2-methoxy-phenyl)-
butyraldehyde (5): To a solution of compound 2 (4.56 g,
15.0 mmol), catalyst 4 (370 mg, 1.50 mmol), and HCl (asa
4 N solution in 1,4-dioxane, 380 lL, 1.50 mmol) in
106.1, 97.0, 59.5, 53.7, 39.2, 25.6, 19.7; HRMS calcd for
23
D
C11H17NOþ2 : 195.1259, found: 195.1264; ½aŠ +23.7 (c 1.0,
CHCl3).
8. (a) Atwal, K. S.; Ferrare, F. N.; Ding, C. Z.; Grover, G. J.;
Sleph, P. G.; Dzwonczyk, S.; Baird, A. J.; Normandin, D.
E. J. Med. Chem. 1996, 39, 304–313; (b) Nguyen, P.;
Corpuz, E.; Heidelbaugh, T. M.; Chow, K.; Garst, M. E.
J. Org. Chem. 2003, 68, 10195–10198.
CH2Cl2 (15 mL) at ꢀ40 °C wasadded crotonaldehyde
3
(597 mg, 5.22 mmol). After stirring for 48 h at this
temperature, the reaction mixture waspurified by column
chromatography (silica, 5% EtOAc in hexanes) to afford
product 5 (5.05 g, 90%) as a colorless, viscous oil; 90%
ee; 1H NMR (200 MHz, CDCl3) d 9.70 (t, J = 2.4 Hz, 1H),
7.21–7.40 (m, 10H), 6.96 (d, J = 8.6 Hz, 1H), 6.34 (dd,
J = 8.6, 2.0 Hz, 1H), 6.29 (d, J = 2.0 Hz, 1H), 4.67 (s, 4H),
3.64 (s, 3H), 3.52–3.68 (m, 1H), 2.48–2.75 (m, 2H), 1.28 (d,
J = 6.8 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 201.7,
155.9, 147.5, 137.2, 127.0, 125.7, 125.3, 125.1, 119.9, 103.1,
9. Herbert, J. M. Tetrahedron Lett. 2004, 45, 817–
819.
10. Compound 7: H NMR (200 MHz, CDCl3) 7.08 (s, 1H),
1
7.07 (d, J = 1.4 Hz, 1H), 7.01 (d, J = 1.4 Hz, 1H), 3.84 (s,
3H), 3.24–3.62 (m, 3H), 1.65–1.96 (m, 3H), 1.23 (d,
J = 7.0 Hz, 3H); 13C NMR (50 MHz, CDCl3) 157.6, 133.9,
128.3, 124.1, 120.0, 114.2, 61.1, 55.9, 40.4, 27.9, 20.9;
HRMS calcd for C11H15BrO2þ: 259.0255, found: 259.0247;
23
D
½aŠ +15.2 (c 1.0, CHCl3).
20
D
4.5, CHCl3); Ref. 4f.
94.8, 53.4, 53.1, 49.3, 25.6, 18.9; HRMS calcd for
11. Reported rotation valuesfor 8: ½aŠ25 +22.4 (c 1.25, CHCl3);
D
23
D
20
D
C25H27NO2þ: 373.2042, found: 373.2051; ½aŠ +5.5 (c
Ref. 4a: ½aŠ +22.8 (c 4, CHCl3); Ref. 4d: ½aŠ +17.8 (c
1.0, CHCl3). The enantiomeric ratio of the product was
determined by HPLC analysis of the corresponding
alcohol (obtained by NaBH4 reduction) using a Chiralcel
OD and OD guard column (2.0% isopropanol/hexanes,
1 mL/min); S-isomer tr = 21.9 min, R isomer tr = 24.5 min.
7. Compound 6: 1H NMR (200 MHz, CDCl3) d 6.92 (d,
J = 8.2 Hz, 1H), 6.26 (dd, J = 8.2, 2.0 Hz, 1H), 6.21 (d,
J = 2.0 Hz, 1H), 3.74 (s, 3H), 3.37–3.55 (m, 3H), 3.06–3.35
(m, 3H), 1.56–1.87 (m, 2H), 1.19 (d, J = 7.0 Hz, 1H); 13C
NMR (50 MHz, CDCl3) d 155.9, 143.9, 125.8, 122.9,
12. Zhang, A.; RajanBabu, T. V. Org. Lett. 2004, 6, 3159–
3161.
25
D
13. Reported rotation valuesfor 10: ½aŠ +7.8 (c 1.0, CHCl3);
20
Ref. 4d: ½aŠ +1.5 (c 4.5, CHCl3); Ref. 4f.
D
14. Reported rotation valuesfor 1: [a]D = +24.6 (natural
curcuphenol); Ref. 1a: ½aŠ25 +26.6 (c 0.35, CHCl3), (natural
D
20
D
curcuphenol); Ref. 2b: ½aŠ +24.8 (c 1, CHCl3); Ref. 4d:
27
D
CHCl3); Ref. 4f.
20
D
½aŠ +26.0 (c 0.3, CHCl3); Ref. 4e: ½aŠ +23.1 (c 4.5,