First enantioselective total synthesis of the reported structure of (R)-(+)-Orizaterpenyl benzoate using an asymmetric allylation of a prochiral ketone in a domino process

Article abstract of DOI:10.1055/s-0030-1258537

An efficient synthesis of (R)-orizaterpenyl benzoate using a multicomponent domino allylation reaction of a prochiral ketone with allyltrimethyl silane and the enantiopure silyl ether of benzyl phenyl carbinol in the presence of catalytic amounts of TfOH is described. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258537

2130
LETTER
First Enantioselective Total Synthesis of the Reported Structure of (R)-(+)-
Orizaterpenyl Benzoate Using an Asymmetric Allylation of a Prochiral Ketone
in a Domino Process
First
E
nantiosel
u
ective Tota
l
t
Synthes
z
is of
(
R
)-(+)-Oriz
F
aterpenyl
B
en
.
z
oate Tietze,* Simon Biller, Thomas Wolfram
Institute of Organic and Biomolecular Chemistry of the Georg-August-University Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Fax +49(551)399476; E-mail: ltietze@gwdg.de
Received 29 May 2010
Thus, allylation of the commercially available ketone 2
Abstract: An efficient synthesis of (R)-orizaterpenyl benzoate
with allyltrimethyl silane (3) in the presence of the trime-
using a multicomponent domino allylation reaction of a prochiral
thylsilyl ether of (R)-benzyl phenyl carbinol 4 (>99%ee)3
ketone with allyltrimethyl silane and the enantiopure silyl ether of
and catalytic amounts of triflic acid at –78 °C in dichlo-
romethane gave the tertiary homoallylic ether 5 in 85%
yield as a diastereomeric mixture of 5a and 5b with a ratio
of 90:10 (13C NMR data) in favour of the desired R,R-
diastereomer 5a (Scheme 1). The high diastereoselectivi-
ty of this reaction is based on the si-face attack of the allyl
silane 3 to an intermediately formed carbocation at the
carbonylic position of the prochiral ketone 2.4 The config-
uration of the newly formed stereogenic center in the ma-
jor product 5a was determined as R based on the well-
established inducing effect of 4.3 The new auxiliary 4 has
a great advantage over the norpseudoephedrine deriva-
tive,5 which was used by us beforehand, since it can be ob-
tained in a two-step synthesis from benzyl phenyl ketone
by an enantioselective reduction followed by silylation.
Moreover, the benzylphenyloxy moiety can act as a good
protecting group like a benzyl group and also be removed
in a similar way.
benzyl phenyl carbinol in the presence of catalytic amounts of
TfOH is described.
Key words: allylsilane, asymmetric allylation, domino reactions,
natural products, ozonolysis, tertiary homoallylic alcohols
Orizaterpenyl benzoate was first isolated from the rice
hulls of Oriza sativa by I. M. Chung in 2005 and charac-
terized as 1 (Figure 1), however, without determining the
absolute configuration of the stereogenic center.1 It exhib-
its a minor cytotoxic effect against P388 murine leukemia
cells.
O
OH
Ph
O
1
Figure 1 (R)-(+)-Orizaterpenyl benzoate
As the next step in the synthesis of 1, the C–C double bond
in the homoallylic ether 5 and its diastereomer (90:10)
was cleaved by ozonolysis in dichloromethane at –78 °C
(Scheme 2). It followed a reduction of the intermediately
formed aldehyde with sodium borohydride in methanol at
0 °C to afford the alcohol 6 in 94% yield as a 90:10 dias-
tereomeric mixture, which again could not be separated
by chromatography.
Based on the auxiliary-mediated asymmetric multicom-
ponent domino allylation reaction of alkyl methyl ketones
developed in our group2 we have performed an efficient
stereoselective synthesis of enantiopure (R)-orizaterpenyl
benzoate (1).
Ph
Ph
O
5a
Ph
O
a)
TMS
+
+
+
Ph
5a/5b = 90:10
TMSO
Ph
2
3
4
Ph
O
5b
Scheme 1 Domino allylation reaction of ketone 2 with allyltrimethyl silane 3 and (R)-trimethylsilyl ether 4. Reagents and conditions: (a)
TfOH (20 mol%), CH2Cl2, –78 °C, 15 h, 85%.
SYNLETT 2010, No. 14, pp 2130–2132
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.07.2010
DOI: 10.1055/s-0030-1258537; Art ID: G16610ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
First Enantioselective Total Synthesis of (R)-(+)-Orizaterpenyl Benzoate
2131
Ph
Ph
Acknowledgment
Ph
Ph
a)
The authors would like to thank the Fonds of the Chemical Industry
for generous support.
O
O
RO
5
6
7
6
R = H dr = 90:10
R = 3,5-dinitrobenzoyl
R = H dr >99:1
b)
c)
References and Notes
dr = 90:10
(1) Chung, I. M.; Ali, M.; Hahn, S. J.; Siddiqui, N. A.; Lim,
Y. H.; Ahmad, A. Chem. Nat. Comp. 2005, 41, 182.
(2) Tietze, L. F.; Kinzel, T.; Brazel, C. Acc. Chem. Res. 2009,
42, 367.
(3) Tietze, L. F.; Kinzel, T.; Wolfram, T. Chem. Eur. J. 2009,
15, 6199.
d)
Ph
Ph
O
O
O
OH
e)
(4) (a) Tietze, L. F.; Kinzel, T.; Schmatz, S. J. Am. Chem. Soc.
2008, 130, 4386. (b) Tietze, L. F.; Schmatz, S.; Kinzel, T.
J. Am. Chem. Soc. 2006, 128, 11483.
Ph
O
Ph
O
1
8
(5) (a) Tietze, L. F.; Dölle, A.; Schiemann, K. Angew. Chem.
Int. Ed. 1992, 31, 1372; Angew. Chem. 1992, 104, 1366.
(b) Tietze, L. F.; Schiemann, K.; Wegner, C. J. Am. Chem.
Soc. 1995, 117, 5851. (c) Tietze, L. F.; Wegner, C.; Wulff,
C. Synlett 1996, 471. (d) Tietze, L. F.; Wegner, C.; Wulff,
C. Eur. J. Org. Chem. 1998, 1639. (e) Tietze, L. F.;
Weigand, B.; Völkel, L.; Wulff, C.; Bittner, C. Chem. Eur.
J. 2001, 7, 161. (f) Tietze, L. F.; Völkel, L.; Wulff, C.;
Weigand, B.; Bittner, C.; McGrath, P.; Johnson, K.; Schäfer,
M. Chem. Eur. J. 2001, 7, 1304. (g) Tietze, L. F.; Hölsken,
S.; Adrio, J.; Kinzel, T.; Wegner, C. Synthesis 2004, 2236.
(6) Chung et al. reported a value of [a]D20 +1.6 (CHCl3) and
proposed the S configuration at the stereogenic center
without giving an explanation. Moreover, the spectroscopic
data of the synthesised material do not match the data of the
isolated compound. Unfortunately, neither a sample nor
copies of the original spectra could be provided by Chung et
al. on our request for comparison.
Scheme 2 Reagents and conditions: (a) O3, Ph3P, CH2Cl2, –78 °C to
r.t., 12 h, then NaBH4, MeOH, 0 °C, 1 h, 94%; (b) 3,5-dinitrobenzoyl
chloride, Et3N, cat. DMAP, CH2Cl2, r.t., 2 h, then recrystallisation
(EtOAc–n-heptane), 65%; (c) LiOH·H2O, MeOH, r.t., 30 min, 74%;
(d) PhC(O)Cl, Et3N, cat. DMAP, CH2Cl2, r.t., 4 h, 99%; (e) H2 (80
bar), Pd/C, H-Cube®, MeOH, r.t., 0.3 mL/min, 90%.
For the purification of the required (R,R)-alcohol 6 the
mixture was therefore transformed into the 3,5-dini-
trobenzoates by treatment with 3,5-dinitrobenzoyl chlo-
ride in the presence of triethylamine and catalytic amounts
of N,N-dimethyl-4-aminopyridine (DMAP) in dichlo-
romethane at 0 °C. Recrystallisation from ethyl acetate–
n-heptane yielded the pure (R,R)-dinitrobenzoate 7 in
65% yield. Hydrolysis of 7 using lithium hydroxide
monohydrate in methanol at room temperature gave back
the alcohol 6 in 74% yield with a diastereomeric purity of
>99:1 (HPLC). For the esterification of alcohol 6 with
benzoyl chloride to give compound 8 in almost quantita-
tive yield the same conditions were used as described for
the formation of 7. Finally, compound 8 was deprotected
by hydrogenolysis in the flow reactor H-Cube® using a
cartridge of 10% palladium on charcoal and methanol as
solvent. The reaction was carried out at room temperature
and with a hydrogen pressure of 80 bar. (R)-Orizaterpenyl
benzoate (1) was obtained in 90% yield and with an enan-
tiomeric purity of >99% ee as determined by HPLC on
chiral support. The physical and spectroscopic data of the
synthesised compound were not in full agreement with
those reported in the literature for the isolated (R)-oriza-
terpenyl benzoate (1).1,6 Thus, at this stage a decision
whether the compound is indeed a natural product can not
be made.
(7) (4R,1¢R)-4,8-Dimethyl-4-(1,2-diphenylethoxy)nonene
(5): To a stirred solution of the (R)-trimethylsilyl ether 4
(404 mg, 1.50 mmol, 1.0 equiv), ketone 2 (192 mg, 1.50
mmol, 1.0 equiv) and allyltrimethyl silane (171 mg, 1.50 mmol,
1.0 equiv) in anhyd CH2Cl2 (10 mL) was slowly added
precooled TfOH (30 mL, 0.30 mmol, 0.2 equiv) at –78 °C.
After stirring for 15 h at this temperature the reaction was
quenched by adding Et3N (0.2 mL, 1.43 mmol, 0.8 equiv),
the solvent was evaporated and the residue was resolved in
THF (10 mL). To this solution TBAF (200 mg, 0.75 mmol,
0.5 equiv) was added at r.t. and the mixture was stirred for
another 2 h. Then the solution was filtered through a short
pad of Celite, which was washed with MTBE. After
evaporation of the solvents, the crude product was purified
by column chromatography on silica gel (n-pentane–MTBE,
50:1) to obtain a mixture of the diastereomeric homoallylic
ethers 5a and 5b (446 mg, 1.30 mmol) in 85% yield with a
ratio of 90:10 as a colourless oil; [a]D20 +19.0 (c = 0.67,
CHCl3). Major diastereomer 5a: 1H NMR (300 MHz,
CDCl3): d = 0.82 (d, J = 6.6 Hz, 3 H), 0.83 (d, J = 6.6 Hz, 3
H), 0.83 (s, 3 H), 0.89–1.08 (m, 2 H), 1.10–1.32 (m, 4 H),
1.43 (non, J = 6.6 Hz, 1 H), 2.06 (dd, J = 14.9, 7.2 Hz, 1 H),
2.13 (dd, J = 14.9, 7.2 Hz, 1 H), 2.85 (dd, J = 13.2, 5.8 Hz, 1
H), 2.99 (dd, J = 13.2, 7.6 Hz, 1 H), 4.63 (dd, J = 7.6, 5.8 Hz,
1 H), 4.89–5.00 (m, 2 H), 5.68 (ddt, J = 15.9, 11.2, 7.2 Hz, 1
In summary, we have developed an efficient synthesis of
enantiomerically pure (R)-orizaterpenyl benzoate (1) us-
ing a multicomponent domino allylation reaction as key
step.7 Moreover, by this way it has been shown that the
asymmetric allylation reaction using the trimethylsilyl
ether of benzyl phenyl carbinol as auxiliary has great po-
tential.
H), 7.09 (dd, J = 7.8, 1.6 Hz, 2 H), 7.17–7.31 (m, 8 H). 13
C
NMR (150 MHz, CDCl3): d = 21.3, 22.6, 22.7, 23.7, 27.9,
39.4, 39.6, 43.5, 47.0, 75.5, 78.1, 116.7, 125.9, 126.4 (2 × C),
126.7, 127.8 (2 × C), 127.8 (2 × C), 130.0 (2 × C), 135.0,
138.8, 145.6. Minor diastereomer 5b (showing
distinguishable signals): 1H NMR (300 MHz, CDCl3): d =
0.87 (d, J = 6.6 Hz, 3 H), 0.88 (d, J = 6.6 Hz, 3 H). 13C NMR
(150 MHz, CDCl3): d = 21.3, 22.7, 22.7, 23.6, 27.9, 38.9,
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 14, 2130–2132 © Thieme Stuttgart · New York

2132
L. F. Tietze et al.
LETTER
39.5, 44.3, 47.1, 75.4. IR (film): 3064, 3028, 2952, 1639,
1603, 1495, 1454, 1377, 1309, 1148, 1059, 912, 757, 699
cm–1. UV (MeCN): lmax (log e) = 258.5 (2.6408), 253.0
(2.5649), 264.0 (2.5235) nm. HRMS (ESI): m/z [M + Na]+
calcd for C25H34O: 373.2502; found: 373.2500.
H), 1.25 (s, 3 H), 1.28–1.40 (m, 2 H), 1.44–1.52 (m, 2 H),
1.51 (non, J = 6.6 Hz, 1 H), 1.77 (br s, 1 H, OH), 1.92 (dt,
J = 14.3, 6.9 Hz, 1 H), 1.96 (dt, J = 14.3, 6.9 Hz, 1 H), 4.47
(t, J = 6.9 Hz, 2 H), 7.40 (t, J = 7.4 Hz, 2 H), 7.52 (tt, J = 7.4,
1.3 Hz, 1 H), 8.00 (dt, J = 7.4, 1.3 Hz, 2 H). 13C NMR (125
MHz, CDCl3): d = 21.7, 22.6, 22.6, 27.2, 28.0, 39.4, 39.8,
42.9, 61.8, 71.9, 128.2 (2 × C), 129.4 (2 × C), 130.2, 132.8,
166.5. IR (film): 2955, 2931, 1717, 1495, 1460, 1438, 1274,
1246, 1115, 1026, 755 cm–1. UV (MeCN): lmax (log e) =
259.0 (2.5696), 268.0 (2.5640) nm. HPLC (Chiralcel® OD,
eluent: n-hexane, flow rate: 0.8 mL/min, c = 1 mg/mL,
injection volume: 10 mL): tR = 18 min. For comparison also
the racemic mixture of 1 was prepared using a racemic
mixture of 4 in the synthesis. HRMS (ESI): m/z [M + Na]+
calcd for C17H26O3: 301.1780; found: 301.1775.
(R)-3-Hydroxy-3,7-dimethyloctyl Benzoate (1):
Compound 8 (30 mg, 65 mmol, 1.0 equiv) was hydrogenated
in MeOH (5 mL) using a flow reactor (H-CUBE®) loaded
with a 10% Pd/C cartridge and H2 (80 bar) with a flow rate
of 0.3 mL/min. Evaporation of the solvent and purification
of the residue by column chromatography on silica gel
(n-pentane–MTBE, 5:1) afforded (R)-orizaterpenyl
benzoate (1) (16.2 mg, 58.6 mmol) in 89% yield as a
colourless oil; [a]D20 +1.3 (c = 1, CHCl3). 1H NMR (300
MHz, CDCl3): d = 0.84 (d, J = 6.6 Hz, 6 H), 1.08–1.20 (m, 2
Synlett 2010, No. 14, 2130–2132 © Thieme Stuttgart · New York