Total synthesis of (+)-machaeriol D with a key regio- and stereoselective SN2′ reaction

Article abstract of DOI:10.1002/anie.200600006

(Chemical Equation Presented) A general strategy for the synthesis of hexahydrodibenzopyrans (HHDBPs) is illustrated in the enantioselective total synthesis of (+)-machaeriol D. In the key step, an S_N2′ reaction of an aryl cyanocuprate with a s

Full text of DOI:10.1002/anie.200600006

Angewandte
Chemie
Natural Product Synthesis
products,[3] the stereocontrolled construction of the three or
four stereocenters located on the cyclohexane ring still
represents a significant synthetic challenge. Herein, a general
strategy is described for the first enantioselective total
synthesis of (+)-machaeriol D (1), one of the most complex
HHDBPs, via a 5,6-seco-HHDBP and with an SN2’ reaction[4]
as a key step.
DOI: 10.1002/anie.200600006
Total Synthesis of (+)-Machaeriol D with a Key
Regio- and Stereoselective SN2’ Reaction**
The highly regio- and stereoselective SN2’ reaction of aryl
or alkyl cyanocuprates with silyl enol ether epoxides has
Qiaoling Wang, Qinggang Huang, Bo Chen,
Jiangping Lu, Hui Wang, Xuegong She,* and
Xinfu Pan*
À
become an important method for C C bond formation
(Scheme 2).[5] The anti adduct can be subjected to mild
Since its discovery in 1964, tetrahydrocannabinol (THC) and
related derivatives (cannabidiol (CBD), non-natural hexahy-
drocannabinol (HHC)) have captured the imagination of
research groups all over the world.[1] The structurally related
5,6-secohexahydrodibenzopyrans
(5,6-seco-HHDBPs)
machaeridiol A–C and trans-HHDBPs machaeriol A–D
were recently isolated from the stem bark of Machaerium
multiflorum spruce (Fabaceae) (Scheme 1).[2] Although much
effort has been devoted to the synthesis of this class of natural
Scheme 2. Key SN2’ reaction. TMS=trimethylsilyl.
hydrolysis to afford a b-hydroxy ketone, which is a partic-
ularly versatile building block in organic synthesis.[5d,e] The
distinct advantage of the SN2’ reaction prompted us to
investigate its scope and its potential in the enantioselective
synthesis of natural products. We present herein the total
synthesis of (+)-machaeriol D as an example of our new
synthetic strategy, in which a tandem SN2’–hydrolysis reaction
sequence is used to establish four stereocenters of the 5,6-
seco-HHDBPs and HHDBPs enantioselectively.
Our retrosynthetic analysis is depicted in Scheme 3. We
envisaged that the target molecule 1 could be accessed from
the 5,6-seco-HHDBP benzofuran 2 by an acid-catalyzed
cyclization. In turn, 2 might be prepared from ketone 3 by
several transformations, including Barton deoxygenation,[6]
a
Corey–Fuchs reaction,[7] Sonogashira coupling,[8] and cycliza-
Scheme 1. Representative 5,6-seco-HHDBPs and trans-HHDBPs.
[*] Q. Wang, Q. Huang, B. Chen, J. Lu, H. Wang, Prof. X. She,
Prof. X. Pan
State Key Laboratory of Applied Organic Chemistry and
Department of Chemistry
Lanzhou University
Fax: (+86)931-891-2582
E-mail: shexg@lzu.edu.cn
panxf@lzu.edu.cn
Prof. X. She
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
Lanzhou 730000 (P.R. China)
[**] We are grateful for the financial support of the NSFC (No. 20572036,
QT program), the Special Doctorial Program Funds of the Ministry
of Education of China (20040730008), GanSu Science Foundation
(No. 3ZS051A25-004), and the Key Grant Project of the Ministry of
Education of China (No.105169).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 3. Retrosynthetic analysis of (+)-machaeriol D. R=MOM=
methoxymethyl, TBS=tert-butyldimethylsilyl.
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Communications
tion. As the key strategy-level step, a highly regio- and
stereoselective SN2’ reaction of the aryl cyanocuprate 6 with
the optically active silyl enol ether 5 would provide the
desired adduct 4, which can be converted readily into 3 with
the requisite stereoselectivity by mild hydrolysis.
Our synthetic journey began with the preparation of
substrates 5 and 6. As shown in Scheme 4, the (+)-cis-epoxy
Scheme 4. Preparation of the silyl enol ether 5 and the aryl cyanocup-
rate reagent 6. HDMS=hexamethyldisilazide.
alcohol 7[9] was readily oxidized[10] to the corresponding epoxy
ketone 8, which was converted into its trimethylsilyl enol
ether 5 in high overall yield. The reaction between the freshly
prepared aryl magnesium bromide derived from compound
10 (see the Supporting Information) and copper cyanide led
to the aryl cyanocuprate reagent 6.[11]
With the necessary components in hand, we carried out
the anti SN2’ reaction (Scheme 5). Following the slow addition
of 5 (1 equiv) to freshly prepared 6 (2 equiv) at À788C, the
Scheme 6. Total synthesis of (+)-machaeriol D (1). a) TBSCl, imida-
zole, DMF, 89%; b) LiAlH4, THF, À308C; c) NaH, CS2, MeI, 508C;
d) AIBN (cat.), nBu3SnH, toluene, 908C, 56% (three steps); e) NH4F,
MeOH, reflux, 95%; f) PDC, CH2Cl2, 94%; g) CBr4, PPh3, Zn dust,
CH2Cl2, 68%; h) nBuLi, THF, À788C, 95%; i) [Pd(PPh3)4], CuI, Et3N,
then 15, reflux, 89%; j) K2CO3, MeOH, reflux, 92%; k) TsOH, MeOH,
reflux, 90%. AIBN=azobisisobutyronitrile, DMF=N,N-dimethylform-
amide, PDC=pyridinium dichromate, Ts=para-toluenesulfonyl;
R=MOM.
thioketal or tosylhydrazone for deoxygenation were unsuc-
cessful.[12] Finally, compound 12 was accessed through the
reduction of 3 and elaboration of the product[13] to give the
methyl xanthate derivative in 85% yield, followed by
reduction by Barton radical deoxygenation.[6]
To construct the benzofuran moiety, 12 was first desilyl-
ated regioselectively to afford the corresponding primary
alcohol, which was oxidized to 13 with PDC. Installation of
the requisite alkyne was initiated by the treatment of 13 with
CBr4/PPh3/Zn according to the Corey–Fuchs protocol[7] to
provide the homologated dibromoalkene in 68% yield.
Treatment of this material with nBuLi then furnished
alkyne 14 (95%). Sonogashira coupling[8] of 14 with the
commercially available compound 15 (2-iodophenyl acetate)
gave the intermediate 16. Subsequent saponification of the
phenolic acetate with concomitant cyclization afforded the
desired benzofuran 2 in high yield.
To reach the HHDBP 1 from the 5,6-seco-HHDBP 2,
MOM deprotection and formation of the benzopyran moiety
was required. Compound 2 was heated in MeOH at reflux in
the presence of TsOH for 12 h to afford the desired product
(+)-machaeriol D (1) in 90% yield. The spectral properties of
the synthetic material were in agreement with those of the
natural product.[2]
Scheme 5. SN2’ reaction of 6 with 5. R=MOM.
reaction mixture was warmed to À108C over 45 min and
stirred for an additional 3 h at À10 to 08C. The silyl enol ether
4 was formed in 80% yield as a single diastereoisomer, as
determined by 1H NMR spectroscopy. This unstable adduct 4
was immediately subjected to mild hydrolysis to afford the
5,6-seco-HHDBP 11[5c] with the desired four stereocenters
(C8, C9, C6a, C10a) present in the final target. The relative
configuration of 11 was determined by 1D NOE spectroscopic
analysis (see Scheme 5).
The secondary hydroxy groupof 11 was readily protected
as its TBS ether 3 (Scheme 6). Efforts to convert the
superfluous carbonyl group (C10) into the corresponding
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Angewandte
Chemie
1981, 103, 2114; c) J. P. Marino, J. C. JaØn, J. Am. Chem. Soc.
In summary, we have developed a new and general
strategy for the synthesis of HHDBPs via 5,6-seco-HHDBPs
with a highly regio- and stereoselective SN2’ reaction of an
aryl cyanocuprate with a silyl enol ether of an optically active
a,b-epoxycyclohexanone as the key step. In this way, we have
completed the first total synthesis of (+)-machaeriol D. The
application of this method to more complex important
molecules is currently under investigation by our research
group.
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Received: January 2, 2006
Published online: April 28, 2006
Keywords: allylic substitution · asymmetric synthesis ·
.
benzopyrans · cyanocuprate reagents · natural products
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[11] The freshly prepared aryl magnesium bromide was added to an
equivalent amount of reagent-grade cuprous cyanide (Aldrich)
in anhydrous THF at À408C under a nitrogen atmosphere. The
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upon warming from À40 to 08C.
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