Total synthesis of incarviditone and incarvilleatone

Article abstract of DOI:10.1021/ol302042u

The total synthesis of the racemic natural products (±)- incarviditone and (±)-incarvilleatone has been accomplished in three steps via biomimetic dimerization of (±)-rengyolone. Homochiral dimerization of (±)-rengyolone affords (±)-incarviditone through a domino oxa-Michael/Michael sequence. Heterochiral dimerization, involving a domino oxa-Michael/Michael/aldol reaction sequence, affords (±)- incarvilleatone. Single-crystal X-ray analysis of a derivative of (±)-incarviditone has resulted in revision of the originally proposed structure.

Full text of DOI:10.1021/ol302042u

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4537–4539
Total Synthesis of Incarviditone and
Incarvilleatone
Patrick D. Brown, Anthony C. Willis,† Michael S. Sherburn, and Andrew L. Lawrence*
Research School of Chemistry, Australian National University, Canberra, ACT 0200,
Australia
allawrence@rsc.anu.edu.au
Received July 24, 2012
ABSTRACT
The total synthesis of the racemic natural products (()-incarviditone and (()-incarvilleatone has been accomplished in three steps via biomimetic
dimerization of (()-rengyolone. Homochiral dimerization of (()-rengyolone affords (()-incarviditone through a domino oxa-Michael/Michael
sequence. Heterochiral dimerization, involving a domino oxa-Michael/Michael/aldol reaction sequence, affords (()-incarvilleatone. Single-crystal
X-ray analysis of a derivative of (()-incarviditone has resulted in revision of the originally proposed structure.
The racemic natural product (()-incarviditone (1) was
isolated in 2009 by Zhang and co-workers from Incarvillea
delevayi.1 In the isolation paper, Zhang noted that (()-
incarviditone (1) was a dimer of the coisolated natural
product (()-rengyolone (2; synonyms: halleridone, clero-
indicin F),2 although no mechanism for this dimerization
was presented. A plausible biosynthesis of (()-incarvidi-
tone (1) from the p-quinolethanoid glycoside natural
products, e.g., cornoside (3),3 is depicted in Scheme 1.
Thus, upon cleavage of the glycosidic bond, the puta-
tive aglycone undergoes an intramolecular oxa-Michael
reaction to afford (()-rengyolone (2).4 Dimerization of
(()-rengyolone (2) then occurs through a domino oxa-
Michael/Michael sequence to form (()-incarviditone (1).
This hypothesis involves two “like” enantiomers reacting
together (i.e., a homochiral dimerization) to afford a single
diastereomeric product as a racemate (Scheme 1). The
origin and magnitude of this apparent stereoselectivity,
which presumably is nonenzymatic, was immediately in-
triguing to us. Therefore, we embarked upon a biomimetic
synthesis of (()-incarviditone (1).
Scheme 1. Proposed Biogenesis of (()-Incarviditone (1)
† To whom correspondence regarding X-ray crystallography should be
addressed. E-mail: willis@rsc.anu.edu.au.
(1) Chen, Y. Q.; Shen, Y. H.; Su, Y. Q.; Kong, L. Y.; Zhang, W. D.
Chem. Biodiversity 2009, 6, 779–783.
(2) (a) Endo, K.; Hikino, H. Can. J. Chem. 1984, 62, 2011–2014. (b)
Messana, I.; Sperandei, M.; Multari, G.; Galeffi, C.; Marini Bettolo,
G. B. Phytochemistry 1984, 23, 2617–2619. (c) Tian, J.; Zhao, Q. S.;
Zhang, H. J.; Lin, Z. W.; Sun, H. D. J. Nat. Prod. 1997, 60, 766–769.
(3) Isolation of cornoside: (a) Rosendal, J. S.; Kjaer, A.; Juhl, N. B.
Acta Chem. Scand. 1973, 27, 367–369. For a review of C6C2 glycosides,
see: (b) Jimenez, C.; Riguera, R. Nat. Prod. Rep. 1994, 11, 591–606.
(4) It has been shown that enzymatic hydrolysis of cornoside affords
rengyolone directly.6b
5
As noted by Nising and Brase, the reversible nature of
oxa-Michael reactions has precluded their general applica-
tion in synthesis. Nevertheless, we were encouraged by the
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10.1021/ol302042u
2012 American Chemical Society
Published on Web 08/29/2012

likelihood that our oxa-Michael adduct would be trapped
through an essentially irreversible carbo-Michael reaction.5
Confident in our proposed domino Michael strategy, we
first required access to (()-rengyolone (2). The synthesis of
(()-rengyolone (2) from commercially available phenol 4
has been reported by several groups.6 Photosensitized
generation and addition of singlet oxygen has been ex-
plored in detail with only moderate yields of (()-rengyolone
catalysis were unsuccessful. The likely explanation is the
poor nucleophilicity of the tertiary alcohol. Following a
screen of basic reaction conditions, including Taylor’s stoi-
10
~
chiometric LiOH/THF and Carreno’s stoichiometric NaH/
CH2Cl2 conditions,11 we were delighted to find that catalytic
K2CO3 in(CH2Cl)2 was sufficient for the dimerization of (()-
rengyolone (2). Thus, 1gof(()-rengyolone(2) was treated to
10 mol % of K2CO3 in 0.4 mL of (CH2Cl)2 at 70 °C for 18 h.
Following flash chromatography, (()-incarviditone (1) was
isolated in 19% yield, and the remaining (()-rengyolone (2)
was recovered in 6% yield (Scheme 3).
(2) obtained.6a,b Carreno and Urbano have described the
~
same transformation using Oxone/NaHCO3 in water
and, following a same-pot Na2S2O3 reduction, obtained
a 50% yield of (()-rengyolone (2).6c In our hands, this
protocol invariably gave low yields (10ꢀ20%) and was
difficult to scale up (Scheme 2);7 work is ongoing in our
laboratorytooptimize this one-potprocedure. Witha need
for larger quantities of (()-rengyolone (2), we elected
to devise a new practical, reliable, and scalable synthetic
route (Scheme 2). The PIDA oxidation of phenol 5 is a
known transformation,6d and the resultant p-quinol 6 can
be viewed as a synthetic equivalent of cornoside (3).
Pleasingly, when treated with TBAF, p-quinol 6 afforded
(()-rengyolone (2) in high yield.8 This three-step sequence
was easily scaled up to afford multigram quantities of (()-
rengyolone (2).
Scheme 3. Biomimetic Synthesis of (()-Incarviditone (1) and
(()-Incarvilleatone (7) with the Proposed Intermediates
Scheme 2. Synthesis of (()-Rengyolone (2)6c,d,7
Our initial efforts at the biomimetic dimerization of
(()-rengyolone (2) using acid catalysis and iminium ion
The spectroscopic data for our synthetic (()-incarvidi-
tone (1) matched perfectly with that reported by Zhang
and co-workers,1,8 thus confirming that the total synthe-
sis had been achieved. The structure reported for the
natural product by Zhang and co-workers was based on
their analysis of NMR data. Upon re-evaluation of this
data we concluded that, although the connectivity of
(5) (a) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2008, 37, 1218–1228.
(b) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2012, 41, 988–999.
(6) (a) Breton, J. L.; Llera, L. D.; Navarro, E.; Trujillo, J. Tetrahe-
dron 1987, 43, 4447–4451. (b) Endo, K.; Seya, K.; Hikino, H. Tetra-
hedron 1989, 45, 3673–3682. (c) Carreno, M. C.; Gonzalez-Lopez, M.;
Urbano, A. Angew. Chem., Int. Ed. 2006, 45, 2737–2741. For asymmetric
syntheses of rengyolone, see: (d) You, Z.; Hoveyda, A. H.; Snapper,
M. L. Angew. Chem. Int. Ed 2009, 48, 547–550. (e) Gu, Q.; Rong, Z. Q.;
Zheng, C.; You, S. L. J. Am. Chem. Soc. 2010, 132, 4056–4057.
(7) The yields we have obtained for the Oxone/NaHCO3 reaction are
in agreement with the yield reported by Prof. You.6e
(9) Agarwal, K. L.; Khorana, H. G. J. Am. Chem. Soc. 1972, 94,
3578–3585.
(10) Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Tiekink, E. R. T.
J. Org. Chem. 2003, 68, 4239–4246.
(11) Cerrano, M. C.; Ribagorda, M. Org. Lett. 2003, 5, 2425–2428.
(8) The NMR spectra of (()-rengyolone (2), (()-incarviditone (1),
and (()-incarvilleatone (7) all show concentration dependency in chem-
ical shifts; see the Supporting Information for details.
4538
Org. Lett., Vol. 14, No. 17, 2012

of (()-incarvilleatone (7) was secured by Zhang and
co-workers using single-crystal X-ray analysis.12 Therefore,
we report the first total syntheses of both these complex
polycyclic natural products. The biosynthesis of (()-
incarvilleatone (7) involves the union of two “unlike”
enantiomers of rengyolone (2) (i.e., a heterochiral
dimerization). We propose a domino oxa-Michael/
Michael/aldol biosynthetic reaction sequence from rengyo-
lone (2) to (()-incarvilleatone (7) (Scheme 3).13 The differ-
ence in product outcome for the homochiral and heterochiral
dimerization pathways appears to stem from the ability of
the latter to adopt transition state 8 (Scheme 3).
Scheme 4. Formation and Crystal Structure of Compound 9
In summary, the synthetic work outlined in this com-
munication provides strong evidence that (()-rengyolone
(2) undergoes domino sequences of nucleophilic addition
reactions in nature to afford both (()-incarviditone (1) and
(()-incarvilleatone (7).14 It is well established that imitat-
ing nature in synthesis has many anticipated benefits,15
but this work also highlights an unexpected one. Our
synthesis of (()-incarvilleatone (7) is the more impres-
sive of the two, with seven new bonds, four new rings, and
nine new stereocenters formed in just three steps and yet was
neither planned nor even considered at the outset.16 This
serendipitous result is a direct result of following a biomi-
metic approach.
(()-incarviditone (1) was secure, the relative stereochemistry
could not be unequivocally established. After numerous
attempts to grow crystals of (()-incarviditone (1) and its
derivatives, we finally discovered that treatment of (()-
incarviditone (1) to excess phenyl isocyanate in pyridine at
100 °C afforded crystalline oxazolidinone 9 (Scheme 4).9
Single-crystal X-ray analysis of 9, which is presumably
formed through a sequence involving carbamate forma-
tion, retro-oxa-Michael addition, and aza-Michael addi-
tion, revealed a trans-configuration between C5 and C60 at
the central tetrahydrofuran ring. The structure originally
assigned to (()-incarviditone (1) (Scheme 1) with a cis-
configuration between these two stereocenters is incorrect
and must be revised to that shown in Schemes 3 and 4.
Compound 7, a further isomeric dimer of (()-rengyo-
lone (2), was also isolated in 23% yield (Scheme 3). During
the preparation of this manuscript, Zhang and co-workers
disclosed the isolation of (()-incarvilleatone (7) from
Incarvillea younghusbandii.12 The physical and spectroscopic
data reported for this natural product matched perfectly
with that of our synthetic dimer (Scheme 3).8 The structure
Acknowledgment. We thank Prof. Zhang (School of
Pharmacy, Second Military Medical University, Shanghai)
for kindly providing copies of the original NMR data. We
also thank Mr. Chris Blake (Australian National University)
and Dr. Thomas Fallon (Australian National University) for
NMR measurements. A.L.L. gratefully acknowledges finan-
cial support from the Australian Research Council in the
form of a Discovery Early Career Researcher Award (Project
ID: DE120102113).
Supporting Information Available. Experimental pro-
cedures and analytical data for all compounds and atomic
displacement ellipsoid plots for compound 9 (CCDC
897209). This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) The possibility that (()-incarviditone (1) and (()-incarvilleatone
(7) are formed during the isolation process can not be ruled out.
However, during our attempts to mimic the isolation conditions
(rengyolone (2) in EtOH, 78 °C, 24 h) no trace of either dimer was
observed via 1H NMR.
(15) For a recent perspective on biomimetic syntheses, see: Razzak,
M.; De Brabander, J. K. Nat. Chem. Biol. 2011, 7, 865–875.
(16) For a recent example of a biomimetic approach yielding a
natural product prior to isolation from natural sources, see: Lawrence,
A. L.; Adlington, R. M.; Baldwin, J. E.; Lee, V.; Kershaw, J. A.;
Thompson, A. L. Org. Lett. 2010, 12, 1676–1679.
(12) Gao, Y. P.; Shen, Y. H.; Zhang, S. D.; Tian, J. M.; Zeng, H. W.;
Ye, J.; Li, H. L.; Shan, L.; Zhang, W. D. Org. Lett. 2012, 14, 1954–1957.
(13) Prof. Zhang proposed a different biosynthetic hypothesis for
(()-incarvilleatone, involving an oxa-Michael/intramolecular-Dielsꢀ
Alder sequence:12
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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