Catalytic enantioselective total syntheses of bisorbicillinolide, bisorbicillinol, and bisorbibutenolide

Article abstract of DOI:10.1002/anie.200500480

(Chemical Equation Presented) A modified cinchona alkaloid catalyzed ketone cyanosilylation reaction is used as the stereochemistry-defining step in the total synthesis of sorbicillinol derivatives (a protected derivative is shown (PMB = para-methoxybenzy

Full text of DOI:10.1002/anie.200500480

Communications
Natural Product Synthesis
successful biomimetic total syntheses of bisorbicillinol (2) and
trichodimerol (3) through a [4+2] dimerization and a Michael
reaction/ketalization dimerization, respectively.[1,2] Further-
more, the Corey and Nicolaou groups showed that dimeriza-
tion of optically active sorbicillinol (1a), prepared by
hydrolysis of the optically active 6-acetylsorbicillinol (1b;
obtained through preparative HPLC resolution of its racemic
counterpart), led to the formation of 2 and 3 in the optically
active form.[2a,d] Nicolaou et al. also demonstrated that
bisorbicillinol (2) could be converted into bisorbibutenolide
(4),[2c,d] thus supporting the proposal of Abe et al. that
bisorbicillinol (2) is a biosynthetic precursor to other more
structurally complex bisorbicillinoids.[3] Although Abe et al.
postulated that intermediate 5, which is formed during the
conversion of 2 into 4, could also give rise to bisorbicillinolide
(6),[3b] the total synthesis of 6, in either its racemic or optically
active form, has not yet been reported.
Catalytic Enantioselective Total Syntheses of
Bisorbicillinolide, Bisorbicillinol, and
Bisorbibutenolide**
Ran Hong, Yonggang Chen, and Li Deng*
Dedicated to Professor Eric N. Jacobsen
The remarkable structural complexity and broad range of
interesting biological activitiesis of bisorbicillinoids have
made them attractive synthetic targets. Although structurally
diverse, it was postulated that bisorbicillinoids were biosyn-
thetically generated from a common intermediate, sorbicilli-
nol (1a), through several fascinating and chemically distinct
dimerizations of 1a (Scheme 1).[1,2] This notion was confirmed
in pioneering synthetic studies of bisorbicillinoids by the
research groups of Corey and Nicolaou that culminated in the
These inspiring synthetic studies underscored the impor-
tance of developing a highly enantioselective synthesis of
sorbicillinol derivatives (1). The presence of a single heter-
Scheme 1. Selected bisorbicillinoids and the biosynthesis hypothesis.
oatom-substituted quaternary stereocenter and densely
packed sensitive functionalities apparently render this task
highly challenging, as no enantioselective total synthesis of
any member of the bisorbicillinoids has been reported.[4]
Herein, we describe a catalytic, enantioselective, and flexible
synthesis of sorbicillinol derivatives 1 and the enantioselec-
tive total syntheses of bisorbicillinolide (6), bisorbicillinol (2),
and bisorbibutenolide (4).
[*] Dr. R. Hong, Y. Chen, Prof. L. Deng
Department of Chemistry
Brandeis University
Waltham, MA 02454-9110 (USA)
Fax: (+1)781-736-2516
E-mail: deng@brandeis.edu
[**] This work was financially supported by the National Institutes of
Health (GM-61591).
Our synthetic plan, outlined in Scheme 2 featured a
catalyst-controlled enantioselective construction of the het-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500480
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Scheme 2. Retrosynthetic analysis of bisorbicillinol (2). TMS=trimethylsilyl.
eroatom-substituted quaternary stereocenter in sorbicillinol
derivative 1c. Considering the sensitive nature of the dienone
side chain,[5] we planned to introduce it at a later stage in our
synthesis of 1c. We envisaged that quinol 7 could be derived
from aldehyde 8 through a Knoevenagel condensation and a
subsequent Claisen–Vorlꢀnder condensation.[6] Aldehyde 8
could be prepared from cyanohydrin (R)-9, which was
prepared in 92% ee and quantitative yield on a multigram
scale by a modified cinchona alkaloid catalyzed enantiose-
lective cyanosilylation of acetal ketone 10 (Scheme 3).[7]
The addition of Grignard reagent EtMgBr to the optically
active cyanohydrin 9 in THF/Et2O proceeded smoothly to
form a-hydroxy ketone 11 in nearly quantitative yield
(Scheme 3).[8] After masking the ketone as a methylene
group through a Wittig olefination,[9] the tertiary alcohol was
protected as a para-methoxybenzyl (PMB) ether to furnish
12.[10] The acetal group of 12 was readily hydrolyzed in
excellent yield with aqueous HCl to provide aldehyde 8,
which was required for the critical Knoevenagel condensa-
tion. A modification of the procedure developed by Leh-
nert[11] was used for the TiCl4-promoted Knoevenagel con-
densation of aldehyde 8 with ethyl acetoacetate, which
proceeded to generate 13 as a 7:1 mixture of isomers (Z/E).
The desired Z isomer was isolated in 85% yield. Ozonolysis in
the presence of pyridine at À728C provided diketone ester 14
in 80% yield.[12] Gratifyingly, the Claisen–Vorlꢀnder conden-
sation with NaOH in dry dimethyl sulfoxide (DMSO)
furnished the PMB-protected chiral quinol 7 in 67% yield.
Having secured an eight-step enantioselective route for
the construction of the chiral quinol ring, we turned our
attention to the installation of the dienone side chain to form
the PMB-protected sorbicillinol 1c. Unfortunately, all
attempts to accomplish this task through either an aldol
condensation or a two-step sequence[5b] of allylation followed
by dehydrogenation were unsuccessful because of the pro-
pensity of 7 to undergo decomposition under basic conditions.
We then began to explore an alternative strategy involving the
introduction of all the carbon atoms required for the
construction of sorbicillinol derivatives 1 before the forma-
tion of the quinol ring. We envisaged using the readily
accessible ynone ester 15[13] instead of ethyl acetoacetate for
the Knoevenagel condensation (Scheme 4) with subsequent
isomerization of the alkynone to a dienone.
The Knoevenagel condensation of 15 with aldehyde 8
proceeded in the presence of N-methylmorpholine
(NMM)[11b] with exceedingly high Z selectivity (Z/E > 50:1)
to afford 16 in 93% yield. Following the ozonolysis of 16, the
isomerization of ynone 17 to dienone 18 was accomplished in
92% yield with a modified Trost–Lu protocol[14] utilizing
palladium acetate and tri-p-tolylphosphine. The outcome of
the Claisen–Vorlꢀnder cyclization of 18 depended critically
on the base used for the generation of the enolate, as 18
readily underwent decomposition with either lithium diiso-
propylamide (LDA) or NaH, whereas no reaction occurred
with lithium bis(trimethylsilyl)amide (LiHMDS) or sodium
bis(trimethylsilyl)amide (NaHMDS). After numerous experi-
Scheme 3. Conditions: a) TMSCN, (DHQ)2AQN (2 mol%), CHCl3, 100%, 92% ee; b) EtMgBr, Et2O/THF (4:1), 98%; c) Ph3PCH3Br, Et(Me)2COK,
=
benzene, 82%; d) PMBOC( NH)CCl3, TfOH (cat.), Et2O, 92% (based on the recovered starting material); e) 3n HCl (aq), acetone, 90%; f) ethyl
acetoacetate, TiCl4, pyridine, THF, 85%; g) ozone, pyridine, CH2Cl2, 80%; h) NaOH, DMSO, 67%. (DHQ)2AQN=1,4-bis(dihydroquinyl)anthraqui-
none, TfO=trifluoromethanesulfonate; PMB=para-methoxybenzyl.
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Scheme 4. Conditions: a) 15, TiCl4, NMM, THF, 93%; b) ozone, pyridine, CH2Cl2, 99%; c) Pd(OAc)2 (cat.), p-tol3P, benzene, 92%; d) Ph3COH,
KH, THF, 90%; e) TFA, CH2Cl2, 54%. tol=tolyl.
ments, we found that the cyclization proceeded cleanly with
Ph3COK to afford PMB-protected sorbicillinol 1c in 90%
yield. Treatment of 1c with trifluoroacetic acid (TFA) at room
temperature[15] accomplished the removal of the PMB group
and the [4+2] dimerization of the resulting sorbicillinol 1a in
one pot to afford (+)-bisorbicillinol (2) in 54% yield after
isolation. The conversion of (+)-2 into (+)-4 following the
procedure reported by Nicolaou et al.[2c,d] allowed us to
complete an 11-step enantioselective synthesis of 4 in 15%
overall yield.[16,17]
In light of the proposal by Abe et al. that bisorbicillinol
(2) is the possible biosynthetic precursor for bisorbicillinolide
(6),[3b] we attempted the conversion of synthetic (+)-2
into (+)-6. We were pleased to observe that (+)-2, on
standing in methanol for 48 hours, rearranged to give (+)-6
and (+)-4 as a 4:1 mixture, which after isolation gave these
compounds in 64% and 10% yield, respectively (Scheme 5).
Thus, the first total synthesis of bisorbicillinolide (6) was
completed.[16,17]
In conclusion, the first enantioselective total syntheses of
bisorbicillinolide (6), bisorbicillinol (2), and bisorbibuteno-
lide (4) have been accomplished in 10/11 steps and 12–19%
overall yields by using a modified cinchona alkaloid catalyzed
cyanosilylation as the stereochemistry-defining step.[18] More-
over, the rearrangement of 2 into 6 sheds light on the
biosynthesis of 6. Further exploration of the potential for
modified cinchona alkaloid catalyzed enantioselective ketone
cyanosilylations in target-oriented synthesis are now under-
way. These investigations are being carried out in the context
of asymmetric total syntheses of other complex natural
products and biosynthetically related analogues of chiral
quinols 7 or sorbicillinol derivatives 1.
Received: February 8, 2005
Published online: April 28, 2005
Keywords: bisorbicillinoids · natural products · rearrangement ·
.
sorbicillinol · total synthesis
Scheme 5. Total synthesis of bisorbicillinolide (6).
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[1] K. C. Nicolaou, S. A. Snyder, Classics in Total Synthesis II,
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[13] Alkynonyl ester 15 is prepared in quantitative yield from the
reaction of commercially available ethyl malonyl chloride with
1-pentynylmagnesium chloride (see the Supporting Informa-
tion).
[14] a) D. Ma, Y. Lin, X. Lu, Y. Yu, Tetrahedron Lett. 1988, 29, 1045;
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[15] L. Yan, D. Kahne, Synlett 1995, 523.
[16] Synthetic (+)-2, (+)-4, and (+)-6 were spectroscopically iden-
tical to reported natural products (see the Supporting Informa-
tion for details). (+)-2: [a]D = + 1818 (c = 0.23, MeOH)
(Ref. [17a]: + 195.28 (c = 0.5, MeOH)); (+)-6: [a]D = + 3108 (c =
0.05, MeOH) (Ref. [17b]: + 3188 (c = 0.1, MeOH)); (+)-4: [a]D =
+ 128.68 (c = 0.14, MeOH) (Ref. [17b]: + 124.48 (c = 0.5, MeOH)).
[17] a) N. Abe, T. Murata, A. Hirota, Biosci. Biotechnol. Biochem.
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[18] The absolute configuration of cyanohydrin 9 has been deter-
mined to be R;[7] consequently, the current asymmetric syntheses
with (R)-9 as an intermediate provide direct experimental
evidence confirming the previous assignment of the absolute
configurations for (+)-2, (+)-4, and (+)-6 based on their
biosynthesis hypothesis (see the Supporting Information).
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