Rapid construction of the ABC ring system in the Daphniphyllum alkaloid daphniyunnine C

Article abstract of DOI:10.1021/ol3026395

An efficient and scalable synthesis of the ABC ring system common to the calyciphylline A-type alkaloids has been developed. The tricyclic core of the alkaloids features a bowl-shaped [6-6-5] skeleton with five stereogenic centers including an all-carbon

Full text of DOI:10.1021/ol3026395

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5499–5501
Rapid Construction of the ABC Ring
System in the Daphniphyllum Alkaloid
Daphniyunnine C
Yanmin Yao and Guangxin Liang*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University,
Tianjin, China, 300071
lianggx@nankai.edu.cn
Received September 25, 2012
ABSTRACT
An efficient and scalable synthesis of the ABC ring system common to the calyciphylline A-type alkaloids has been developed. The tricyclic core
of the alkaloids features a bowl-shaped [6À6À5] skeleton with five stereogenic centers including an all-carbon quaternary center. It was
constructed rapidly from a readily available carvone derivative through a seven-step sequence involving an aza-Michael addition and
Pd-catalyzed enolate R-vinylation as key steps.
The Daphniphyllum alkaloids are a group of highly
complex polycyclic alkaloids with remarkable structural
diversity (Figure 1). More than 200 family members have
been isolated over the past 50 years, and they exhibit a vast
collection of novel skeletons with unusual ring systems.1
Historically, the unique structural features and intriguing
biosynthesis of these alkaloids have inspired a variety of
innovative and elegant studies in total synthesis.2 One
milestone that is well-recognized among organic chemists
is Heathcock’s biomimetic synthesis of dihydro-proto-
daphniphylline (1, Figure 1) and other structurally related
members based on his biogenetic proposal.2bÀd In recent
years, discoveries of unprecedented structures in this alka-
loid family have continuously prompted synthetic investi-
gations in this field.3
Among the >20 subgroups of the Daphniphyllum alka-
loids, we are particularly interested in calyciphylline
A-type alkaloids (Figure 2).4 Intrigued by the synthetic
challenge posed by these structures, we started a program
to study the total synthesis of calyciphylline A-type alka-
loids and to explore the possible formation of the core
structuresinothersubgroupmembersthrough elaboration
oftheir tricyclic ABC ring system. Toachievethese goals, it
was necessary to develop an efficient and scalable synthesis
for the rapid construction of the tricyclic bowl-shaped
[6À6À5] skeleton.
(1) For a review on the Daphniphyllum alkaloids, see: Kobayashi, J.;
Kubota, T. Nat. Prod. Rep. 2009, 26, 936–962.
(2) For the first total synthesis of a Daphniphyllum alkaloid, see:
(a) Heathcock, C. H.; Davidsen, S. K.; Mills, S.; Sanner, M. A. J. Am.
Chem. Soc. 1986, 108, 5650–5651. For selected biomimetic syntheses,
see: (b) Ruggeri, R. B.; Hansen, M. M.; Heathcock, C. H. J. Am. Chem.
Soc. 1988, 110, 8734–8736. (c) Piettre, S.; Heathcock, C. H. Science 1990,
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J. A.; Kath, J. C. J. Org. Chem. 1992, 57, 2554–2566.
(4) For recent synthetic approaches to calyciphylline A-type alka-
ꢀ
loids, see: (a) Sole, D.; Urbaneja, X.; Bonjoch, J. Org. Lett. 2005, 7,
(3) For selected recent synthetic approaches on Daphniphyllum alka-
loids, see: (a) Denmark, S. E.; Baiazitov, R. Y. J. Org. Chem. 2006, 71,
593–605. (b) Ikeda, S.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y. Org. Lett.
2009, 11, 1833–1836. (c) Dunn, T. B.; Ellis, J. M.; Kofink, C. C.; Manning,
J. R.; Overman, L. E. Org. Lett. 2009, 11, 5658–5661. (d) Coldham, I.;
Burrell, A. J. M.; Guerrand, H. D. S.; Oram, N. Org. Lett. 2011, 13, 1267–
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Chem. 2011, 76, 2360–2366. (g) Weiss, M. E.; Carreira, E. M. Angew.
Chem., Int. Ed. 2011, 50, 11501–11505.
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Wang, D. Z. Org. Lett. 2011, 13, 1812–1815. (c) Sladojevich, F.;
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10.1021/ol3026395
2012 American Chemical Society
Published on Web 10/24/2012

Figure 2. Representative calyciphylline A-type alkaloids.
Scheme 1. Retrosynthetic Analysis of Daphniyunnine C
Figure 1. Structural diversities of the Daphniphyllum alkaloids.
Our synthetic plan is illustrated in Scheme 1, with
daphniyunnine C (4, Figure 1) as an exemplary target.5
We envisioned that bond disconnections involving an
intramolecular PausonÀKhand reaction6 could greatly
simplify the hexacyclic molecule into the less complicated
tetracyclic structure 16. This key spiro intermediate could
be formed from 17 using a ring-closing metathesis (RCM)
strategy,7 which in turn could be procured through a
kinetic alkylation of the unsaturated ketone in 18. We
reasoned that the stereochemistry of this step could be
tightly controlled by the bowl-shaped architecture of the
substrate 18. A short sequence from (S)-carvone (23) was
(5) (a) Zhang, H.; Yang, S.-P.; Fan, C.-Q.; Ding, J.; Yue, J.-M.
J. Nat. Prod. 2006, 69, 553–557. (b) Di, Y.-T.; He, H.-P.; Lu, Y.; Yi, P.;
Li, L.; Wu, L.; Hao, X.-J. J. Nat. Prod. 2006, 69, 1074–1076.
(6) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.;
Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977–981. For recent
reviews, see: (b) Lee, H.-W.; Kwong, F.-Y. Eur. J. Org. Chem. 2010, 789–
811. (c) Moulton, B. E. Organomet. Chem. 2010, 36, 93–120. (d) For a
model study on applying the PausonÀKhand reaction in the synthesis of
daphniyunnine D (15, Figure 2), see ref 4d.
(7) (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 3800–
3801. (b) For a review on the application of metathesis reactions in total
synthesis, see: Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4490–4527.
expected to readily establish all the stereogenic centers in
18. An intramolecular aza-Michael addition of carvone
derivative 22 followed by alkylation and subsequent Pd-
catalyzed enolate R-vinylation reaction8 could generate 20.
Hydrogenation from the convex side of 20 would trans-
form this substrate to the tricyclic product 19 with five
stereogenic centers in place.
Herein, we report our success in the facile construction
of the common bowl-shaped [6À6À5] skeleton 32 in
calyciphylline A-type alkaloids with fivestereogenic centers
(Scheme 2) from the cost-effective (R)-carvone.
(8) For applications of Pd-catalyzed enolate R-vinylation reactions,
see: (a) Piers, E.; Oballa, R. M. Tetrahedron Lett. 1995, 36, 5857–5860.
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(b) Wang, T.; Cook, J. M. Org. Lett. 2000, 2, 2057–2059. (c) Sole, D.;
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Peidro, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225–2228. (d) Zhao, S.; Liao,
Our synthesis took advantage of a known transforma-
tion from (S)-carvone (23) to ent-24 reported by Overman
and co-workers.9 This four-step sequence is very robust
and can be readily scaled up to produce over 10 g of 24 in
one batch. This transformation neatly controlled the re-
quired stereochemistry of the methyl substituent on the B
ring. With a sufficient supply of 24 in hand, we started to
X.; Cook, J. M. Org. Lett. 2002, 4, 687–690. (e) Cao, H.; Yu, J.; Wearing,
X. Z.; Zhang, C.; Liu, X.; Deschamps, J.; Cook, J. M. Tetrahedron Lett.
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2003, 44, 8013–8017. (f) Sole, D.; Diaba, F.; Bonjoch, J. J. Org. Chem.
2003, 68, 5746–5749. (g) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.;
Flippin-Anderson, J.; Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68,
7565–7581. (h) Zhao, S.; Liao, X.; Cook, J. M. Org. Lett. 2004, 6, 249–
252. (i) Yu, J.; Wearing, X.; Cook, J. M. J. Org. Chem. 2005, 70, 3963–
3979. (j) Zhou, H.; Liao, X. B.-W.; Yin, Y.; Ma, J.; Cook, J. M. J. Org.
Chem. 2006, 71, 251–259. (k) Dounay, A. B.;Humphreys, P. G.; Overman,
L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368–5377.
(l) Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem., Int. Ed. 2008,
47, 3618–3621. (m) For amodel study ofapplying the Pd-catalyzed enolate
R-vinylation reaction in the construction of the B ring in calyciphylline A,
see ref 4a.
(9) (a) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am.
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Scheme 2. Synthesis of [6À6À5] Tricyclic Skeleton 32
Figure 3. ORTEP depiction of the oxalate salt of 32 (thermal
ellipsoids drawn at the 50% probability level).
Given that this synthetic sequence employed straightfor-
ward transformations and cost-effective chemicals and
reagents in each step, it could be readily scaled up to supply
sufficient material for further studies. To date, nearly 15 g
of 32 have been prepared in our laboratory.
In summary, we have developed an efficient and scalable
synthetic approach for the rapid construction of the ABC
ring system commonly found in the Daphniphyllum sub-
class calyciphylline A-type alkaloids. By harnessing the
intrinsic structural features of individual intermediates,
a high degree of stereochemical control was achieved
throughout the sequence. A seven-step sequence allowed
ustobuild the rather complex tricyclic core skeleton from a
readily available carvone derivative (24) in an overall yield
of 48%. Notably, this core skeleton contains five stereo-
genic centers including an all-carbon quaternary center,
making it a nontrivial synthetic target. Further studies
toward the total synthesis of daphniyunnine C and other
members of the Daphniphyllum alkaloids are currently
underway in our laboratory.
explore our synthetic strategy by substitution of the hydro-
xyl group with an amino group. The primary hydroxyl
group in 24 was selectively activated as a tosylate, which
underwent nucleophilic substitution with sodium azide to
afford 26 in excellent yield. Oxidation of the allylic alcohol
with PCC10 and a subsequent Staudinger reaction11 pro-
duced a mixture of ent-22 and the aza-Michael addition
product 28. With no need for purification, the mixture was
directly treated with allyl bromide 298f under typical
alkylation conditions to generate a pair of diastereomers
30. In this step, owing to the intrinsic structural feature of
the substrate, the aza-Michael addition could only occur
from one face of the Michael acceptor and neatly install the
CÀN bond in a stereoselective manner on the A ring.
Because the diastereomeric center in 30 would be lost in the
next step, the mixture was used without separation. When
30 was treated under typical conditions for Pd-catalyzed
enolate R-vinylation, it was smoothly converted to the
tricyclic product 31 with a newly formed all-carbon qua-
ternary center in 84% yield. Again, the intrinsic concavity
of the substrate facilitated the stereoselective formation of
the challenging all-carbon quaternary center. As we antici-
pated, hydrogenation of the double bond in 31 with Pd/C
afforded 32 in almost quantitative yield with absolute
stereochemical control. The stereochemistry of 32 was
unambiguously confirmed through single crystal X-ray cry-
stallographic analysis of the oxalate salt of 32 (Figure 3).
Acknowledgment. We thank the State Key Laboratory
of Elemento-organic Chemistry in China, the National
Natural Science Foundation of China (Grant Nos.
20902049, 21172117, 21032003, 21121002), Tianjin Natur-
al Science Foundation (Grant No. 12JCYBJC26400), and
the ‘111’ project (B06005) of the Ministry of Education of
China for financial support. We also thank Prof. Haibin
Song of the Institute of Elemento-organic Chemistry,
Nankai University for X-ray analysis.
Supporting Information Available. Experimental de-
tails and procedures, compound characterization data,
copies of 1H and 13C NMR spectra for new compounds,
and X-ray crystallographic data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(10) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647–2650.
(11) (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635–646.
(b) For a review on Staudinger reactions, see: Gololobov, Y. G.;
Kasukhin, L. F. Tetrahedron 1992, 48, 1353–1406.
The authors declare no competing financial interest.
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