Application of the tandem Stryker reduction-aldol cyclization strategy to the asymmetric synthesis of lucinone

Article abstract of DOI:10.1016/S0040-4039(01)00638-4

The tandem conjugate reduction-aldol cyclization using Stryker's reagent has been employed as the key-step in an asymmetric total synthesis of lucinone.

Full text of DOI:10.1016/S0040-4039(01)00638-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4091–4093
Application of the tandem Stryker reduction–aldol cyclization
strategy to the asymmetric synthesis of lucinone
Pauline Chiu,* Chun Pong Szeto, Zhe Geng and Kin Fai Cheng
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, SAR PR China
Received 31 January 2001; accepted 12 April 2001
Abstract—The tandem conjugate reduction–aldol cyclization using Stryker’s reagent has been employed as the key-step in an
asymmetric total synthesis of lucinone. © 2001 Elsevier Science Ltd. All rights reserved.
Iberian Peninsula traditionally used as an antispas-
modic drug.5 The relatively simple structure of this
iphionane nevertheless bears five stereocenters in its
small sesquiterpenoid framework. In the paper docu-
menting its isolation and characterization, the configu-
ration at C11 was not assigned.5 However, lucinone is
likely to be biogenetically related to the other eudes-
mane alcohols isolated from the same species; therefore,
the stereochemistry at C11 is presumably the same as
that in the fully characterized eudesmanoids, which is
(R) as shown.6
Tandem reactions add tremendous efficiency to the
total syntheses of natural products by inducing multiple
transformations of substrates in one operation.1 We
reported on the first example of a tandem conjugate
reduction intramolecular aldol cyclization employing
Stryker’s reagent [Ph3PCuH]6,2,3 and subsequently, we
have undertaken a study of the scope of this cascade
reaction.4 In general, it has proven to be highly
efficient, and has afforded superior yields of the aldol
product. The use of this reductive aldol strategy allows
the unambiguous site-selective formation of enolates in
polycarbonyl substrates, which is the context of
intramolecular aldol reactions. To highlight the
efficiency and stereoselectivity of this reaction, we have
undertaken the total synthesis of an iphionane
sesquiterpenoid, lucinone.
The enantioselective synthesis of lucinone employed
(+)-dihydrocarvone as the starting material. The base-
induced alkylation of dihydrocarvone is known to
occur syn to the propenyl substituent;7 therefore it was
necessary to redirect the facial selectivity of the alkyla-
tion. The enantioselective alkylation of the (+)-methyl-
benzylamine enamine of cyclohexanones with Michael
acceptors such as a,b-unsaturated esters or ketones is
known.8 Our synthesis, however, requires alkylation
using a homologated a,b-unsaturated ketone such as 1
in order to build a tethered a,b-unsaturated ketone that
produces the requisite five-membered ring upon reduc-
tion. We decided to achieve this in two stages, via the
1
10
5
7
11
O
OMOM
I
3
OH
OH
X
H
O
OH
Lucinone
1
4
Lucinone was isolated in 1995 from the aerial parts of
Jasonia glutinosa, an annual medicinal plant in the
PhSO2
O
O
O
O
OH
OH
H
OH
O
OH
O
lucinone
Scheme 1. Retrosynthetic analysis of lucinone.
* Corresponding author. Fax: +852 2857 1586; e-mail: pchiu@hkucc.hku.hk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00638-4

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P. Chiu et al. / Tetrahedron Letters 42 (2001) 4091–4093
alkylation of the chiral enamine with a vinyl sulfone,
then further homologation of the sulfone to afford the
a,b-unsaturated ketone (Scheme 1).
ketone 8 under high dilution. In addition, a long-range
1H–1H coupling between the hydroxylic proton and the
angular methyl group observable in the COSY spec-
trum established the syn stereochemistry of the ring
junction in intermediate 8.
Thus, dihydrocarvone was converted to the enamine 2
using (+)-methylbenzylamine and treated with phenyl
vinyl sulfone (Scheme 2). A 9:1 mixture of epimers at
The asymmetric dihydroxylation of the olefin was the
final step leading to lucinone.12 However, treatment of
substrate 8 with either ADmix-a or ADmix-b gave
essentially the same 2:3 ratio of diastereomeric triols in
good combined yields.13 After careful chromatographic
separation of the closely related triols, it was found that
NMR data of the minor isomer in both AD reactions
corresponded to that of lucinone in the literature.14
Dihydroxylation of olefin 8 in the absence of chiral
ligands also yielded lucinone as the minor diastereomer
(2:3, 95% combined yield).
1
the a-position was generated as judged by the H NMR
of the crude product, with the desired diastereomer 3a
being the major product. The diastereomers were too
similar in polarity for effective separation by column
chromatography at this stage, so the synthesis was
continued using the mixture of 3a and 3b. Protection of
the ketone as the acetal prepared the substrate for chain
extension exclusively at the sulfone terminus. Deproto-
nation using n-BuLi, alkylation with the acetonyl
equivalent 4,9 followed by an acidic workup, produced
5 in 63% yield over two steps.
Thus, the asymmetric total synthesis of lucinone has
been achieved in seven steps. This synthesis serves to
highlight the efficiency and the stereoselectivity of the
tandem Stryker reduction–aldol cyclization to assemble
the iphionane skeleton. This overall reductive–aldol
methodology should be a useful general strategy for
organic synthesis.
Treatment of the b-sulfonyl ketone 5 with triethylamine
induced the elimination of the sulfone and resulted in
exclusively the trans-a,b-unsaturated methyl ketone. At
this stage, the epimers were separated by flash chro-
matography, and an 81% yield of enantiomerically pure
ketone 6 was thus obtained. Deprotection of the ketal
proceeded smoothly to yield enedione 7, the substrate
for the key copper hydride induced reductive aldol
cyclization.10
Acknowledgements
The treatment of substrate 7 with two hydride equiva-
lents of Stryker’s reagent in toluene at 0°C to room
temperature proceeded as anticipated to afford
stereoselectively a quantitative yield of aldol 8, in which
four of the five stereocenters in the target molecule have
been installed.11 The syn relationship between the
hydroxyl group and the acyl moiety was evidenced by
intramolecular hydrogen bonding of the carbonyl func-
tionality (1699 cm−1) in the IR spectrum of hydroxy-
The work described in this paper was supported by the
University of Hong Kong (CRCG 1999–2000) and by a
grant from the Research Grants Council of Hong Kong
Special Administrative Region, China (Project No.
HKU 7132/99P). C.P.S. thanks the University of Hong
Kong for a postgraduate studentship and a Swire schol-
arship. Mr. Chun Man Lee (summer student) is
thanked for his technical assistance.
PhSO2
PhSO2
+
a
b
O
HN
O
O
75%
Ph
2
3a
3b
9 : 1 mixture of epimers
PhSO2
PhSO2
c, d
e
O
O
O
O
63%
81%
O
O
O
3a + 3b
5
6
f
g
h
O
91%
99%
38%
O
OH
OH
H
OH
OH
O
O
7
8
lucinone
Scheme 2. Reagents and conditions. (a) (+)-Methylbenzylamine, PhMe, reflux; (b) i. phenyl vinyl sulfone, 35°C, ii. AcOH/H2O; (c)
ethylene glycol, PhH, reflux; (d) i. n-BuLi, THF, HMPA, −78°C, ii. 4, iii. 1% H2SO4, rt; (e) Et3N, CH2Cl2, separation of
diastereomers; (f) dilute H2SO4, SiO2, CH2Cl2; (g) Stryker’s reagent, PhMe; (h) cat. OsO4, K3Fe(CN)6.

P. Chiu et al. / Tetrahedron Letters 42 (2001) 4091–4093
4093
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+31.9 (c, 0.5 in CHCl3); H NMR (300 MHz, CDCl3) l
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1
+35.8 (c, 1.3 in CHCl3); H NMR (300 MHz, CDCl3) l
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Hz), 4.77 (1H, t, J=1.3 Hz), 4.72 (1H, s), 2.26–2.53 (4H,
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.