Total synthesis of (+)-arteanniun M using the tandem oxy-Cope/ene reaction.

Article abstract of DOI:10.1021/ol015970l

[see reaction]. The first total synthesis of (+)-arteannuin M was accomplished using the tandem oxy-Cope/transannular ene reaction as the key step to construct the bicyclic core of the natural product. The tandem reaction proceeded with high diastereo- an

Full text of DOI:10.1021/ol015970l

ORGANIC
LETTERS
2001
Vol. 3, No. 12
1925-1927
Total Synthesis of (+)-Arteanniun M
Using the Tandem Oxy-Cope/Ene
Reaction
Louis Barriault* and Daniel H. Deon
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada, K1N 6N5
lbarriau@science.uottawa.ca
Received April 10, 2001
ABSTRACT
The first total synthesis of (+)-arteannuin M was accomplished using the tandem oxy-Cope/transannular ene reaction as the key step to
construct the bicyclic core of the natural product. The tandem reaction proceeded with high diastereo- and enantiomeric excess.
Artemisia annua L. (compositae) is found in the mountains
of Sichuan province, Southern China and is the source of
the sesquiterpene endoperoxide artemisin (1), one of the most
important drugs for the treatment of malaria in South East
Asia (Figure 1).1 In 1998, Brown and co-workers isolated
2. To the best of our knowledge no synthesis of this molecule
has yet been reported. We have recently established that the
tandem oxy-Cope/transannular ene reaction of 1,2-divinyl-
cyclohexanols provides a powerful method to rapidly con-
struct polycyclic compounds possessing a bridgehead alcohol
at the ring junction.3,4 Our retrosynthetic analysis of artean-
nuin M (2) took cognizance of the cadinane framework
sesquiterpene 3, which can be directly obtained via the
tandem oxy-Cope/ene reaction.
(3) (a) Barriault, L.; Warrington, J. M.; Yap, G. P. A. Org. Lett. 2000,
2, 663. For other examples, see: (b) Paquette, L. A.; Nakatani, S.;
Zydowsky, T. M.; Edmondson, S. D.; Sun, Q.-L.; Skerlj, R. J. Org. Chem.
1999, 64, 3244. (c) Rajagopalan, K.; Srinivasan, R. Tetrahedron Lett. 1998,
39, 4133. (d) Shanmugan, P.; Devan, B.; Srinivasan, R.; Rajagopalan, K.
Tetrahedron 1997, 53, 12637. (e) Rajagopalan, K.; Shanmugam, P.
Tetrahedron 1996, 52, 7737. (f) Rajagopalan, K.; Janardhanam, S.; Devan,
B. Tetrahedron Lett. 1993, 34, 6761. (g) Rajagopalan, K.; Janardhanam,
S.; Balakumar, A. J. Org. Chem. 1993, 58, 5482. (h) Chorlton, A. P.; Morris,
G. A.; Sutherland, J. K. J. Chem. Soc., Perkin Trans. 1 1991, 1205.
(4) For other examples of transannular carbonyl ene reaction, see: (a)
Mihailovic, M. L.; Lorenc, L.; Forsek, H.; Nesovic, G.; Snatzke, G.; Traska,
P. Tetrahedron 1970, 26, 557. (b) Yamamra, S.; Iguchi, M.; Nishiyama,
M.; Niwa, M. Tetrahedron 1971, 27, 5419. (c) Yamamra, S.; Iguchi, M.;
Niwa, M. Bull. Chem. Soc. Jpn. 1976, 49, 3148. (d) Yamamra, S.; Tereda,
Y. Tetrahedron Lett. 1979, 1623. (e) Lange, G. L.; McCarthy, F. C.
Tetrahedron Lett. 1978, 4749. (f) Williams, J. R.; Callahan, J. F. J. Org.
Chem. 1980, 45, 4479. (g) Wender, P. A.; Hubbs, J. C. J. Org. Chem. 1980,
45, 365. (h) Williams, J. R.; Cleary, T. P. J. Chem. Soc., Chem. Commun.
1982, 626.
Figure 1.
from this plant a new sesquiterpene, arteannuin M (2).2 It is
important to point out that the stereochemistry at C4 has
not yet been defined, nor has the absolute configuration of
(1) Liu, J.-M.; Ni, M.-Y.; Fan, Y.-F.; Tu Y.-Y.; Wu, Z.-H.; Wu, Y.-L.;
Zhou, W. S. Acta Chim. Sin. 1979, 37, 129.
(2) Brown, G. D.; Sy, L.-K.; Haynes, R. Tetrahedron 1998, 54, 4345.
10.1021/ol015970l CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/17/2001

The synthesis started with a halogen-metal exchange of
3-iodo-3-butenol silyl ether5 using tert-butyllithium (1.7 M
in pentane) in ether at -90 °C followed by addition of the
ketone 46 (readily available from (+)-limonene). This
sequence afforded the desired 1,2-divinylcyclohexanol 5 in
91% yield (Scheme 1). This compound was heated in toluene
Scheme 1a
Figure 2. Transition state of the carbonyl ene reaction.
enantioselectivity control observed during the oxy-Cope
rearrangement can be explained on the basis of the energy
a (a) CH2dCH(Li)CH2CH2ODPS, Et2O, -90 °C. (b) DBU,
toluene, 220 °C. (c) TBAF, THF. (d) VO(acac)2, t-BuOOH, CH2Cl2.
(e) Ir[(COD)(PCy3)]PF6, H2, CH2Cl2.
Scheme 2
and DBU (5 equiv) for 5 h in a sealed tube to give 6 in
55-60% yield as the only detectable diastereoisomer.7
We have discovered that DBU is essential for the tandem
oxy-Cope/ene reaction to proceed in good yield.8 Indeed, in
the absence of DBU a complex mixture of products was
obtained from which it was impossible to isolate 6.
The high diastereoselectivity observed in the tandem oxy-
Cope/ene reaction can be explained by the proposed mech-
anism shown in Figure 2. Thermal rearrangement of 5
produces enol 10, which immediately tautomerizes to ketone
intermediate 11. The macrocyclic ketone 11 can exist in two
different conformations, which can each undergo an ene
reaction via two competing reactive conformers, A and B,
thus producing 12 and 6, respectively. A close examination
of A and B reveals that the alkyl chain in A is oriented
pseudoaxially, whereas in B the alkyl group is in a pseudo-
equatorial position, thus favoring the formation of 6 over
12.
barrier to invert 10 to ent-10 and stereofacial protonation
(Figure 3). The macrocycle 10 possesses a conjugated dienol
(E,Z) and another E double bond (ene donor), which create
a strained and rigid macrocyclic ring.
As a result, the conversion of 10 into ent-10 requires that
the enol moiety rotate inside the macrocycle, which is
energetically demanding. At the same time, protonation of
enol 10 can only occur from the â-face to yield ketone 11.
The preferential formation of ketone 11 over ent-11 is thus
readily explained.
Subsequent exposure of 6 to TBAF unmasked the primary
alcohol 7 in quantitative yield. At this stage, diastereoselec-
tive oxirane formation and exo-cyclic olefin reduction took
advantage of the C6 tertiary alcohol, which can be used as
a coordinating source. Allylic epoxidation of 7 using VO-
The chirality transfer of the tandem process was evaluated
1
by 500 MHz H NMR analysis of the Mosher ester 8a and
8b (diastereomeric ratio of 89%) (Scheme 2). The high
(5) Prepared by treatment of 3-butynol with HI followed by alcohol
protection with DPSCl, imidazole in THF.
(6) (+)-Limonene 98% ee was used. Dauben, W. B.; Lorber, M.;
Fullerton, D. S. J. Org. Chem. 1969, 34, 3587.
(7) No evidence of a second diastereoisomer was seen by 500 MHz 1H
NMR.
(8) For examples of solvent-induced oxy-Cope reactions, see: (a) Fujita,
Y.; Onishi, T.; Nishida, T. Synthesis 1978, 934. (b) Onishi, T.; Fujita, Y.;
Nishida, T. J. Chem. Soc., Chem. Commun. 1978, 651. (c) Utagawa, A.;
Hirota, H.; Ohno, S.; Takahashi, T. Bull. Chem. Soc. Jpn. 1988, 61, 1207.
1926
Org. Lett., Vol. 3, No. 12, 2001

72% yield. The methylation step reveals a high level of
stereocontrol in that only the â-isomer 14 is produced
(>98:2). Inversion of configuration at C11 by formation of
the lithium enolate and subsequent protonation with am-
monium chloride afforded the desired R-isomer 15 in
quantitative yield. NOESY experiments confirmed that 15
possess the 11S configuration (Scheme 3).
At this point in the synthesis, the remaining unsettled
question concerned the possible stereochemistry of the C4-
C5 diol. During the course of this synthesis, Brown et al.
revised their stereochemical assignments at C4 and C5. They
confirmed the presence of a C4-C5 cis diol in 2, but they
were unable to determine the relative configuration of C4
and C5. To assign these stereogenic centers correctly,
regeneration of the double bond in ring A was imperative.
Therefore, deoxygenation of 15 using Sharpless protocol
successfully removed the epoxide and generated 16 in 67%
yield.12 Catalytic hydroxylation on the less indered face of
16 produced 17 having a cis diol anti to the lactone.
The 500 MHz 1H and 125 MHz 13C NMR spectra (CDCl3)
of 17 were compared directly with those of the natural
substance and were identical. This confirms without ambigu-
ity the relative configuration of C4 and corrects the stereo-
chemistry at C5. Furthermore, the positive optical rotation of
17 ([R]D ) +34.1°, c 0.26 in CH2Cl2), which is the opposite
sign of the natural product, establishes its absolute config-
uration as shown in 18 ([R]D ) -31.1°, c 1.25 in CHCl3).
In summary, we have accomplished the total synthesis of
(+)-arteannuin M (17) in 10 steps starting from readily
available (+)-4 (overall yield 14.1%). Expeditious construc-
tion of the arteanniun M core 6 with high control of
diastereoselectivity demonstrated the power and versatility
of the tandem oxy-Cope/ene reaction of 1,2-divinylcyclo-
hexanols. In addition, we have established the correct relative
stereochemistry at C4 and C5, as well as the absolute
configuration of the natural (-)-arteannuin M (18) as
illustrated in Scheme 3.
Figure 3.
(acac)2 and TBHP in methylene chloride proceeded smoothly
and led to the desired epoxide 8 in 95% yield.9
A second hydroxy-oriented reaction was performed using
Crabtree’s catalyst under H2 atmosphere to reduce the double
bond to afford 9 with the required C10 stereochemistry in
99% yield (diastereomeric ratio of 11:1 at C10).10 The
absolute configuration of 9 was established by X-ray analysis.
Sequential oxidation of the diol 9 with TPAP and NMO in
methylene chloride provided the lactone 13 in 90% yield
(Scheme 3).11 Installation of the C11 methyl in 13 required
formation of the lithium enolate (LDA, THF -78 °C), which
was then treated with iodomethane at -78 °C to give 14 in
Scheme 3a
Acknowledgment. Financial support from the University
of Ottawa, NSERC, Canada Foundation for Innovation,
Ontario Innovation Trust, Bristol-Myers Squibb (Candiac,
Que´bec), Merck-Frosst Canada, and la Cite´ Colle´giale
d'Ottawa is gratefully acknowledged. The authors are
1
indebted to Professor G. Brown for providing H and 13C
NMR spectra of (-)-arteannuin M and Professor T. Durst
from this department for helpful discussions.
Supporting Information Available: Spectroscopic data
and experimental procedures for 5-9 and 13-17, ORTEP
view of 9, and copies of the 1H and 13C spectra of synthetic
and natural arteannuin M. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL015970L
(9) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136.
(10) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
(11) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(12) (a) Deslongchamps, P. et al. Can. J. Chem 1990, 68, 153. (b)
Sharpless, K. B.; Umbreit, M. A.; Nieh, M. T.; Flood, T. C. J. Am. Chem.
Soc. 1972, 94, 6538.
a (a) TPAP cat., NMO, molecular sieves 4 Å. (b) LDA, then
MeI, THF, -78 °C. (c) LDA, then NH4Cl, THF, -78 °C. (d) WCl6,
n-BuLi, LiI, THF, -78 to 25 °C. (e) OsO4, NMO, THF-H2O
(4:1).
Org. Lett., Vol. 3, No. 12, 2001
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