Influence of diene substituent position on the stereochemical outcome in IMDA reaction of decatrienones. An asymmetric synthesis of C10-epi- dihydro-epi-deoxy arteannuin B

Article abstract of DOI:10.1021/ol202562w

An asymmetric synthesis of C₁₀-epi-dihydro-epi-deoxy arteannuin B is reported employing an IMDA reaction of sugar embedded decatrienone. During this investigation it has been demonstrated that changing the position of the methyl group on the di

Full text of DOI:10.1021/ol202562w

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6078–6081
Influence of Diene Substituent Position on
the Stereochemical Outcome in IMDA
Reaction of Decatrienones. An
Asymmetric Synthesis of C10-epi-Dihydro-
epi-deoxy Arteannuin B
Sujit Mondal, Ram Naresh Yadav, and Subrata Ghosh*
Department of Organic Chemistry, Indian Association for the Cultivation of Science,
Jadavpur, Kolkata 700 032, India
ocsg@iacs.res.in
Received September 23, 2011
ABSTRACT
An asymmetric synthesis of C10-epi-dihydro-epi-deoxy arteannuin B is reported employing an IMDA reaction of sugar embedded decatrienone.
During this investigation it has been demonstrated that changing the position of the methyl group on the diene moiety changes the stereochemical
outcome leading to access to either cis- or trans-decalin derivatives exclusively.
Artemisinin or Qinghaosu 1,1 a sesquiterpene endoper-
oxide natural product isolated from Artemisia annua L.,2
has been the subject of synthetic, mechanistic, and phar-
macological studies due to its efficacy in the battle against
malaria (Figure 1). It is the active principle of the herbal
medicine known as Qinghao that has been in use in China
and other parts of South East Asia for thousands of years.
In addition to its antimalarial activity, artemisinin exhibits
selective cytotoxicity against iron-rich cancer cells and is
considered to be a lead compound in cancer research.3
Arteannuin B 44 and dihydro-epi-deoxy arteannuin B 65
are two other important compounds that have been iso-
lated from A. annua. Although both compounds lack anti-
malarial activity, Nowak and Lansbury6 have demon-
strated that arteannuin B 4 can chemically be transformed
to artemisinin through dihydro-epi-deoxy areteannuin B 6
manifesting 4 as the biosynthetic precursor of artemisinin.
The challenge associated with the synthesis of artemisi-
nin having an endoperoxide bridge combined with its
pharmacological activities has elicited considerable syn-
thetic interest. A number of syntheses of artemisinin7 and
its analogues8 have been developed. Synthesis of some
(1) (a) Klayman, D. L. Science 1985, 228, 1049–1055. (b) Haynes,
R. K.; Vonwiller, S. C. Acc. Chem. Res. 1997, 30, 73–79.
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(3) Lai, H.; Nakase, I.; Lacoste, E.; Singh, N. P.; Sasaki, T. Anticancer
Res. 2009, 29, 3807–3810 and the references cited therein.
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3042.
(6) Nowak, D. M.; Lansbury, P. T. Tetrahedron 1998, 54, 319–336.
(7) Hao, H.-D.; Li, Y.; Han, W.-B.; Wu, Y. Org. Lett. 2011, 13, 4212–
4215 and the references cited therein.
(8) (a) Zhou, W. S. Pure Appl. Chem. 1986, 58, 817–824. (b) Posner,
G. H.; Paik, I.-H.; Chang, W.; Borstnik, K.; Sinishtaj, S.; Rosenthal,
A. S.; Shapiro, T. A. J. Med. Chem. 2007, 50, 2516–2519. (c) Posner,
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r
10.1021/ol202562w
Published on Web 10/20/2011
2011 American Chemical Society

artemisinin analogues relies on the transformation of
arteannuin B analogues. For example, Avery et al.9 have
synthesized C10,11-didesmethyl artemisinin 2 which shows
significant antimalarial activity against strains of Plasmo-
dium falciparum. To synthesize the artimisinin analogue 3,
Schwaebe and Little10 have synthesized C10-desmethyl
arteannuin B 5. These investigations reveal that the pre-
sence or absence of a Me group on the B ring influences the
antimalarial activity of artemisinin significantly.
subjected to cross metathesis with methacrolein in the
presence of Grubbs’ second generation catalyst (G II) to
provide the aldehyde 13a in excellent yield. Wittig olefina-
tion of the aldehyde 13a with the ylide generated from
methyltriphenylphosphonium bromide provided, with
concomitant deacetylation, the trienol 14a in 62% yield.
In a similar fashion cross metathesis of 12 with acrolein
gave the aldehyde 13b in 86% yield. Wittig olefination of
13b using the above protocol gave the trienol 14b.
The synthesisof thetrienol20wasachieved asdelineated
in Scheme 3. Addition of the Grignard reagent prepared
Scheme 1. Retrosynthesis
Figure 1. (ꢀ)-Artemisinin (1), (ꢀ)-arteannuin B (4), etc.
The only route reported in the literature11 for the synthe-
sis of 6, the precursor of artemisinin, lacks generality for
incorporation of substituents on its nucleus. Thus the main
focus of the present investigation is to develop a general
methodology for the synthesis of dihydro-epi-deoxy ar-
teannuin B 6 and its analogues 7a and b. Compounds 7a
and b can then be converted to the corresponding artemi-
sinin analogues employing the method of Nowak and
Lansbury.
Scheme 2. Synthesis of IMDA Precursors 14a,b
Our synthetic protocol relies on an intramolecular
DielsꢀAlder (IMDA) reaction12 of the trienone 9 which
was anticipated to lead to a functionalized decalin 8, the
furanose ring of which could be employed to construct the
γ-butyrolactone unit present in 6 and 7 (Scheme 1). The
trienone 9 would be available from the aldehyde 10.13
The stereochemical outcome in a DielsꢀAlder reaction
to form decalins is dependent on a number of factors in-
cluding conformation, steric, and electronic effects of the
substituents in the transition state. We became interested
toseewhethersubstituentsatvarious locationson the diene
moiety could enable the cycloaddition to be stereoselective
to give exclusively either the cis- or trans-fused decalins.
This will then lead to access to the structures related to
arteannuin B as well as dihydro-epi-deoxy arteannuin B.
The synthesis of the IMDA precursors was achieved in
the following way. Addition of a Grignard reagent pre-
pared from 5-bromo-1-pentene to the aldehyde 10 gave the
hydroxy compound 11 as a single diastereoisomer in 84%
yield (Scheme 2). The acetate 12 derived from 11 was
from the bromide 1514 affordedthe hydroxycompound 16.
The acetate 17 obtained from 16 was desilylated, and the
resulting alcohol 18 was oxidized to give an aldehyde.
Wittig olefination of this aldehyde with the ylide generated
from methallyltriphenyl phosphonium bromide followed
by basic hydrolysis of the resulting acetate 19 provided in
excellent yield the trienol20alongwithits Z-isomer (2:1) as
evidenced by J-values of the olefinic protons in the central
alkene unit.
(10) Schwaebe, M.; Little, R. D. J. Org. Chem. 1996, 61, 3240–3244.
(11) Dudley, G. B.; Engel, D. A.; Ghiviriga, I.; Lam, H.; Poon,
K. W. C.; Singletary, J. A. Org. Lett. 2007, 9, 2839–2842.
(12) For reviews, see: (a) Fallis, A. G. Can. J. Chem. 1984, 62, 183–
234. (b) Singh, V.; Iyer, S. R.; Pal, S. Tetrahedron 2005, 61, 9197–9231.
(13) Sun, K. M.; Fraser-Reid, B. Synthesis 1982, 28–29.
€
(14) Furstner, A.; Albert, M.; Mlynarski, J.; Matheu, M.; DeClercq,
E. J. Am. Chem. Soc. 2003, 125, 13132–13142.
Org. Lett., Vol. 13, No. 22, 2011
6079

With the trienols ready in hand they were subjected to
oxidation with DessꢀMartin periodinane (DMP) and
subsequently to an IMDA reaction (Scheme 4). Treatment
of the trienol 14a with DMP at 0 °C to rt resulted in
oxidation with concomitant cycloaddition of the resulting
enone 9a to produce the trans-decalin derivative 21 exclu-
sively in 85% yield. The trans ring fusion in 21 followed
from the single-crystal X-ray structure of the compound 39
prepared from 21 (Scheme 6). The unstable trienone 9c
obtained by DMP oxidation of the trienol 20, without
purification and characterization, was subjected to IMDA
reaction by heating its toluene solution in a sealed tube at
Scheme 4. IMDA of 9aꢀc
Scheme 3. Synthesis of IMDA Precursor 20
160 °C for nearly 40 h to produce the cis-decalin derivative
22, mp 108ꢀ109 °C in 70% yield. The structure of this
adduct was established through X-ray (Figure 2).15 In
contrast to the above observation, IMDA reaction of the
unstable trienone 9b obtained from the trienol 14b was
achieved on heating its toluene solution in a sealed tube at
140 °C for 12 h to produce 23 and 24 in 64% and 16% yields
respectively. The stereochemical assignment to the adducts
23 and 24 were based on comparison of the chemical shifts
of the acetonide methyl protons of 21 and 22. It may be noted
that the difference in chemical shifts of the acetonide methyls
in 1H NMR spectrum for the trans-adduct 21 is 0.98 while
that for the cis-fused product is 0.17. In the major isomer
obtained from IMDA reaction of 9b the chemical shift dif-
ference between the two acetonide methyls was found to be
0.95, and accordingly this adduct was assigned the trans-
decalin structure 23 while the minor isomer for which this
value is 0.163 was assigned the cis-decalin structure 24.
It is interesting to note that the stereochemical outcome
in an IMDA reaction of the decatrienones 9aꢀc is strongly
Figure 2. X-ray structure of 22.
Scheme 5. TS for IMDA Reaction of 9a,c
(15) Crystallographic data for compounds 22 and 39 have been
deposited with the Cambridge Crystallographic Data Center as suppli-
mentary publication numbers CCDC 844476 and 844475, respectively.
Copies of the data can be obtained, free of charge, on application to the
CCDC, 12 Union Road, Cambridge CB2 IEZ, U.K. Fax: þ44-1233-
336033. Email: deposit@ccdc.cam.ac.uk.
6080
Org. Lett., Vol. 13, No. 22, 2011

Scheme 6. Synthesis C10-epi-Deoxy-epi Arteannuin B
dependent on the position of the Me substituent on the
diene moiety. The observed results may be attributedtothe
steric interaction in the transition states (Scheme 5). A
DielsꢀAlder reaction of the decatrienone 9a may proceed
through either the endo mode 25 or the exo mode 26. Endo
oriented structure 25 is strained due to steric interaction
between C6-methylene hydrogens and the C3-methyl sub-
stituent. This steric interaction is absent in exo mode 26.
Thus cycloaddition proceeds through the chair, chair tran-
sition state (TS) 27 to give rise to thermodynamically more
stable trans-decalin 21. In contrast, the endo orientation
28 of the trienone 9c is devoid of this sort of interaction.
Thus reaction proceeds through the boat, chair TS 29 to
produce the cis-decalin 22. IMDA reaction of the trienone
9b, devoid of any Me group on the diene moiety, proceeds
through a chair, chair TS to produce the thermodynamically
more stable trans-decalin as the major product. It is probably
the relief of steric strain that makes 9a more reactive than the
trienones 9b and c which are free of this strain.
After successfully finding methodology for synthesizing
exclusively the trans-orcis-decalin, we focused our attention
toward the synthesis of dihydro-epi-deoxy arteannuin B in
which a trans-decalin system is present. The tricyclic ketone
21 was methylated on treating its lithium enolate with
MeI, resulting exclusively in the ketone 30 in 90% yield
(Scheme 6). Catalytic hydrogenation of 30 gave exclusively
the saturated compound 31 in 94% yield. The stereochem-
istry of the C10-methyl in 31 was found to be epimeric with
that in the natural isomer 6. LAH reduction of the ketone 31
produced the alcohol 32, the hydroxyl group of which was
then protected to provide the benzyl ether 33 in an overall
excellent yield. The stereochemical assignment to these com-
pounds was based on an X-ray structure of the lactone 39.
Conversion of the furanose residue in 33 to the
γ-butyrolactone unit was initiated with acid catalyzed
opening of the acetonide moiety in methanol to produce
the acetal 34 in quantitative yield. Deoxygenation of the
hydroxyl group in 34 was effected through TBTH reduction
of its xanthate derivative 35 to afford the acetal 36 in high
overall yield. The cyclic acetal 36 when subjected to treat-
ment with Jones’ reagent furnished directly the lactone 37 in
85% yield. Hydrogenolysis of the benzyl ether in 38 was
carried out with Pd(OH)2 cat. to provide the hydroxy-
lactone 39 as a crystalline solid, mp 142ꢀ143 °C in quan-
titative yield. The structure of the hydroxy-lactone 39 was
unambiguously established through X-ray. With the estab-
lishment of the structure of the lactone 39, the structures
of the compounds 21 and 30ꢀ38 were also established.
Finally, a Martin sulfurane mediated dehydration16 of the
hydroxy compound 39 led to the formation of the olefin 40
in 80% yield. Kinetic protonation of the lithium enolate of
the lactone 40 led to complete epimerization to afford the
lactone 41, the C10-epimer of dihydro-epi-deoxy arteannuin
B in quantitative yield. The C10-epimer 41 should in
principle be converted to C10-epi-artemisinin by the pro-
cedure of Nowak and Lansbury.
In conclusion, we have demonstrated that an IMDA
reaction of decatrienones 9aꢀc may lead to either cis- or
trans-decalin exclusively by changing the position of the
substituent on the diene moiety, leading to the synthesis of
a C10-epimer of dihydro-epi- deoxy arteannuin B and
offering an opportunity to access its analogues with or
without a Me group on the B ring.
Acknowledgment. Financial support from DST, Govt.
of India is gratefully acknowledged. S.M. and R.N.Y.
thank CSIR, New Delhi for Senior Research Fellowships.
Supporting Information Available. Experimental pro-
cedure and spectroscopic data for all the new com-
pounds and crystallographic data for 22 and 39. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Spangler, J. E.; Carson, C. A.; Sorensen, E. J. Chem. Sci. 2010, 1,
202–205.
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