Total Synthesis of (±)-Waihoensene

Article abstract of DOI:10.1002/anie.201704492

The first total synthesis of waihoensene, a tetracyclic diterpene containing an angular triquinane and a six-membered ring, with four contiguous quaternary carbon atoms, was achieved through the tandem cycloaddition reaction of an allenyl diazo substrate containing a six-membered ring via trimethylenemethane (TMM) diyl intermediate.

Full text of DOI:10.1002/anie.201704492

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Accepted Article
Title: Total Synthesis of (±)-Waihoensene
Authors: Hee-Yoon Lee, Hongsoo Lee, and Taek Kang
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Total Synthesis of (±)-Waihoensene
Hongsoo Lee, Taek Kang, and Hee-Yoon Lee*[a]
Dedicated to Professor Paul A. Wender on the occasion of his 70th birthday.
Abstract: The first total synthesis of waihoensene, a tetracyclic
diterpene containing an angular triquinane and a six-membered ring,
with four contiguous quaternary carbon atoms, was achieved through
the tandem cycloaddition reaction of an allenyl diazo substrate
containing a six-membered ring via trimethylenemethane (TMM) diyl
intermediate.
1). If we place a six-membered ring at the proper location in the
starting material, we can set a test ground to construct tetracyclic
skeleton of waihoensene in one-pot. Herein, we report the first
total synthesis of waihoensene where TMM diyl mediated tandem
cycloaddition reaction constructs the tetracyclic ring skeleton of
waihoensene.
Tandem TMM
N2
strategy to
angular
diyl
triquinanes
a)
A tetracyclic diterpene, waihoensene (1) was isolated from the
New Zealand podocarp, Podocarpus totara var waihoensis by
Rex T. Weavers and co-workers in 1997 (Figure 1).[1a] It is closely
related to compounds 3, which are acid-induced rearrangement
products[1] of laurenene (2), the only natural product with C-C
fenestrane ring structure.[2] Waihoensene is presumed to be the
product derived from the extended biosynthetic pathway of
laurenene and has as challenging structure as laurenene with four
contiguous quaternary carbon centres of highly congested
tetracyclic structure. Thus, waihoensene was recognized in a
recent review[3] of structurally challenging natural products
against total synthesis as one of the natural products waiting for
creative synthetic strategies to conquer the total synthesis, and
has not been explored by the synthetic organic chemistry
community much.[4]
N
N
i
ii
TMM
strategy to tetracyclic
compound
of
Application
diyl
b)
N2
Scheme 1. Tandem cycloaddition strategy via TMM diyl to polycyclics.
Recently, we have successfully applied the synthetic strategy
to the first total synthesis of (-)-crinipellin A[5k], a tetraquinane
compound. In the case of the synthesis of crinipellin A, the
anticipated tetraquinane skeleton was obtained stereoselectively
owing to the fact that the cis-fused ring system was highly
favoured due to strain at the ring junctions. On the other hand, for
construction of the core skeleton of waihoensene, presence of the
six-membered ring does not guarantee the regiochemical and
stereochemical outcome of the tandem cycloaddition reaction as
it could form isomers including the [3.2.1]bicyclic containing
tetracyclic structure or the undesired trans-hydrindane structure.
wa oensene
aurenene
2
( )
1
3
ih
l
( )
Figure 1. Natural products and derivatives from podocarp
This challenging structural feature of waihoensene makes it
an excellent target for the tandem cycloaddition strategy via
trimethylenemethane (TMM) diyl intermediate, which we have
developed for synthesis of polyquinanes from linear substrates
and have applied to the total synthesis of various natural products
with complex and congested structural features.[5] In the tandem
synthetic methodology, the skeleton of angular triquinane is
assembled through [2+3] cycloaddition between olefin and TMM
diyl (ii) generated from nitrogen extrusion of tetrahydropyrazole (i)
formed by [2+3] cycloaddition of diazo group and allene (Scheme
O
1
4
5
6
v.s.
6'
6"
O
O
O
[a]
Dr. H. Lee, Dr. T. Kang, Prof. Dr. H.-Y. Lee
Department of Chemistry
N2
OEt
OEt
Korea Advanced Institute of Science and Technology (KAIST)
291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
E-mail: leehy@kaist.ac.kr
7
9
8
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 2. Retrosynthetic analysis for waihoensene.
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10.1002/anie.201704492
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COMMUNICATION
We envisioned that waihoensene 1 could be derived from
enone compound 4 that could be obtained through allylic
oxidation of the corresponding tetracyclic compound 5 The
tetracyclic compound 5 could be assembled from the allenyl diazo
compound 7 through the tandem cycloaddition reaction via TMM
diyl intermediate 6 (Scheme 2). Examination of the transition state
reduction of the conjugated double bond using magnesium in
methanol[9] followed by diisobutylaluminum hydride mediated
partial reduction at -78 °C. Preparation of the propargylic alcohol
13 was achieved through the Corey-Fuchs procedure,[10] 1,1-
dibromoolefination followed by the in situ hydroxymethylation of
the corresponding alkynyl anion. Tosylation of 13 with p-
model of the reaction intermediate 6’ between TMM diyl and olefin, toluenesulfonyl chloride and potassium hydroxide furnished the
hinted that the desired tetracyclic compound containing a cis-
hydrindane would be the major product as the transition state 6’
appeared to be more stable than 6” by avoiding 1,3-diaxial
interaction of two methyl groups. The substrate 7 would be readily
obtained from the α,β-unsaturated ester 8 that can be obtained
from the keto-ester 9.
activated propargylic alcohol 14. 14 was converted to the allenyl
alcohol 15 by copper(I) catalysed SN2’ reaction with the Grignard
reagent generated from 3-bromopropoxy-tert-butyldimethylsilane
followed by desilylation with TBAF and oxidized to the aldehyde
16 using Swern’s oxidation condition.
O
O
O
X
NaH, 0 oC to reflux
a)
b)
OH
H
OEt
OEt
e,f)
toluene
83% for 2 steps
=
=
16
17
O)
(X
(X
9
10
11
H2NNHTs
MeOH
=
5
:isomers 3.3:1)
(
NNHTs)
5
O
c,d)
OEt
O
N
N
8
12
14
N2
OH
OTs
i)
g,h)
7
18
6
13
Scheme 4. Synthesis of the tetracyclic compound 5.
l)
j,k)
O
OH
The hydrazone 17 which is the precursor for 7 that would
spontaneously undergo the tandem cycloaddition reaction, was
obtained by p-toluenesulfonyl hydrazide treatment, and used for
the tandem cycloaddition reaction immediately due to its
instability (Scheme 4). Heating the sodium salt of the hydrazone
initiated the formation of the tetracyclic products by converting 17
into diazo compound 7[11] (Scheme 4). Subsequent intramolecular
[2+3] cycloaddition reaction of the diazo group with the allene
moiety provided methylenepyrazole intermediate 18[12] that
immediately lost nitrogen molecule to generate the TMM diyl
15
16
Scheme 3. Reagents and conditions: a) Zn, TiCl4, CH2I2, THF, DCM, 0 °C to r.t.,
60%; b) LAH, Et2O, 0 °C to r.t., 91%; c) (COCl)2, DMSO, TEA, DCM, -78 °C to
r.t.; d) EtO2P(O)CH2CO2Et, NaH, THF, 0 °C, 93% for 2 steps; e) Mg, MeOH, r.t.,
99%; f) DIBAL, DCM, -78 °C to r.t., 97%; g) CBr4, PPh3, DCM, 0 °C, 93%; h) n-
BuLi, (CH2O)n, THF, -78 °C to r.t., 91%; i) TsCl, KOH, Et2O, 0 °C to r.t., 94%; j)
Mg, 1,2-dibromoethane, Br(CH2)3OTBS, CuCN, THF, 0 °C; k) TBAF, THF, 0 °C
to r.t., 95% for 2 steps; l) (COCl)2, DMSO, TEA, DCM, -78 °C to r.t., 94%. LAH
= lithium aluminium hydride, DMSO = dimethyl sulfoxide, TEA = triethylamine,
DIBAL = diisobutylaluminum hydride, TsCl = toluenesulfonyl chloride, TBAF =
tetrabutyl ammonium fluoride.
intermediate 6.[13] The highly reactive diyl intermediate
6
underwent final [2+3] cycloaddition reaction with the olefin despite
of high steric congestion during the cycloaddition reaction to yield
the tetracyclic compounds. Fortunately, the desired tetracyclic
product 5 was obtained as the major product as an inseparable
mixture with minor isomeric products. Based on the signature
peaks at the olefinic region in NMR spectrum, the minor products
were presumed to be stereoisomer 5’ along with regioisomers 5e
and/or 5’e (Scheme 5). Though the formation of 5 was not
exclusive as in the case of tetraquinane formation, the transition
state conformation 6’ for the formation of 5 was presumed to be
highly favoured over other transition states as anticipated in the
scheme 2. Structure of the major isomer was firmly confirmed
after purification at the enone (4) or tosylated dihydroxide (20)
stage.
The total synthesis started with the known racemic keto-ester
compound 9 that was readily prepared from commercially
available ethyl 2-cyclohexanonecarboxylate through a 2-step
literature sequence.[6] Conversion of the ketone in 9 into the exo-
olefin of 10 was achieved using Lombardo-Takai olefination[7] as
Wittig reaction was unsuccessful and it was known that the
titanium mediated olefination well tolerated steric hindrance
around carbonyl groups (Scheme 3). Another advantage of the
reaction was the neutral nature of the reaction condition that
prevented a possible isomerization of the methyl group of 9.[8]
Reduction of 10 with lithium aluminium hydride produced the
alcohol 11. Swern’s oxidation of 11 followed by Horner-
Wadsworth-Emmons olefination gave the α,β-unsaturated ester 8.
8 was converted to the aldehyde 12 through the selective
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10.1002/anie.201704492
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COMMUNICATION
With the enone 4 in hand, overcoming the rigidity and steric
congestion of 4 for introduction of two methyl groups and a
methylene group was crucial for the successful completion of the
total synthesis. The first step in the original plan, introduction of
the methyl group at the C-3 of 4 using standard enolate alkylation
procedures or Noyori’s protocol[15] for alkylation with dimethylzinc
as the catalyst did not yield any product, presumably due to the
rigidity of the ring skeleton and the steric hindrance between the
H-3 and the C-ring of 4. We decided to compromise the original
plan by reversing the sequence of methylations. The methyl group
at the ring junction (C-11a) was introduced first in a hope that
alteration of the carbonyl conformation would allow the enolate
alkylation reaction to proceed in the second step, even though
reversed methylation sequence could pose a regioselectivity
issue during the second methylation step at the C-3.
5-exo
6-endo
6'
5e
5
5-exo
6-endo
5'e
6"
5'
Scheme 5. Possible products from transition states of TMM diyls.
Successful construction of the tetracyclic structure for
waihoensene along with three contiguous quaternary centers set
up the final stage of the synthesis that required introduction of one
methyl group for the last quaternary center, stereoselective
introduction of a methyl group, and regioselective introduction of
a methylene group. For those reactions, conversion of 5 into the
enone 4, had to be preceded. First, we tried allylic oxidation of 5
with PDC and TBHP in benzene, the oxidation condition used in
the synthesis of crinipellin A.[5k] The oxidation reaction was quite
daunting as the desired product 4 was obtained along with other
oxidation products in low yield (<22%) and was separated only
after the formation of 22. We attempted several other allylic
oxidation conditions[14] but the outcome was not any better.
Alternatively, we were able to obtain 4 through 4-step sequence
(Scheme 5). Dihydroxylation using OsO4 followed by the selective
tosylation of the secondary alcohol of 19 produced 20 selectively.
Then, 20 was converted to the allylic alcohol 21 by elimination
reaction with DBU in DMF at 115 °C, and subsequent oxidative
rearrangement produced 4.
O
O
O
1
2
3
a)
c)
b)
11a
4
22
23
1
Scheme 7. Reagents and conditions: a) CuCN, MeLi, BF3•Et2O, THF, -78 °C to
-55 °C, 65%; b) LiHMDS, MeI, THF, -78 °C to r.t., 75%(81% brsm); c)
Cp2TiMe2(Petasis reagent), toluene, r.t. to 70 °C, 32%. LiHMDS = lithium
bis(trimethylsilyl)amide.
Methylation at C-11a of 4 with ordinary cuprate(LiCu(CH3)2)
again failed to yield the product because of the steric hindrance
imposed by the C-ring. Gratifyingly, treatment of the enone with
higher order cuprate in presence of boron trifluoride etherate
delivered the methyl group to produce the desired product 22
(Scheme 6).[16] Fortuitously, 22 was obtained as a solid form and
single-crystal X-ray diffraction of crystalized 22 established the
relative stereochemistry and the atom connectivity of the
congested tetracyclic structure (Figure 2). Careful analysis of the
crystal structure[17] indicated that bases and electrophiles couldn’t
approach from α-face of 22 due to steric hindrance by the C-15 of
22 and the concave feature of the structure, therefore methylation
from β-face should be preferable. Analysis of the dihedral angles
in the X-ray crystal structure also revealed that the H-3a of 22 was
pseudo-axial while H-1a was pseudo equatorial. Thus the
regioselective enolate formation toward the C-3 position would be
possible, and we were convinced that the desired compound 23
would be formed selectively among possible regio- and stereo-
isomeric products from the enolate methylation of 22.
O
a
3
)
a
C
11
4
5
e
b
)
)
s
T
O
H
O
c
d
HO
)
H
O
H
O
)
19
20
21
Scheme 6. Reagents and conditions: a) PDC, celite, TBHP, DCM, 0 °C; b) OsO4,
NMO, acetone, water, 0 °C to r.t.; c) TsCl, DMAP, DCM, r.t., 39% for 2 steps; d)
DBU, DMF, 115 °C, 50%; e) PDC, DCM, r.t., 68%. PDC = pyridinium dichromate,
TBHP = 1,1-dimethylethyl hydroperoxide, NMO = N-methylmorpholine N-oxide,
DMAP = N,N-dimethylpyridin-4-amine, DBU = 1,8-diazabicycloundec-7-ene,
DMF = N,N-dimethylformamide.
Figure 2. ORTEP of 22.
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2319; c) H.-Y. Lee, Y. Kim, J. Am. Chem. Soc. 2003, 125, 10156-10157;
d) H.-Y. Lee, W.-Y. Kim, S. Lee, Tetrahedron Lett. 2007, 48, 1407-1410;
e) H.-Y. Lee, Y. Yoon, Y.-H. Lim, Y. Lee, Tetrahedron Lett. 2008, 49,
5693-5696; f) H.-Y. Lee, Y. Jung, Y. Yoon, B. G. Kim, Y. Kim, Org. Lett.
2010, 12, 2672-2674 g) H.-Y. Lee, S.-S. Shin, W.-Y. Kim, Chem. Asian.
J. 2012, 7, 2450-2456; h) H.-Y. Lee, S.-B. Song, T. Kang, Y. J. Kim, S.
J. Geum, J. Pure Appl. Chem. 2013, 85, 741-753; i) Y.-J. Kim, Y. Yoon,
H.-Y. Lee, Tetrahedron 2013, 69, 7810-7816; j) S. Geum, H.-Y. Lee,
Org.Lett. 2014, 16, 2466-2469; k) T. Kang, S. B. Song, W.-Y. Kim, B. G.
Kim, H.-Y. Lee, J. Am. Chem. Soc. 2014, 136, 10274-10276.
K. Mori, K. Matsui, Tetrahedron 1966, 22, 879-884.
As anticipated, a typical alkylation condition of a ketone
enolate using LiHMDS and iodomethane afforded the desired
methylated product 23 without any other isomers. The final
introduction of methylene group using regular Wittig type
olefination reaction did not proceed at all due to the steric
congestion of 23 and methylation with MeMgBr followed by
dehydration produced undesired olefin isomers including 3.
Finally, the target natural product
1
was obtained by
methylenation of 23 using the Petasis reagent.[18] Comparison of
the spectroscopic data of the final product 1 and the reported data
for waihoensene confirmed the structural integrity of both
compounds.
[6]
[7]
a) L. Lombardo, Tetrahedron Lett. 1982, 23, 4293-4296; b) K. Takai, Y.
Hotta, K. Oshima, H. Nozaki, Tetrahedron Lett. 1978, 19, 2417-2420; c)
J.-I. Hibino, T. Okazoe, K. Takai, H. Nozaki, Tetrahedron Lett. 1985, 26,
5579-5580.
In summary, the first total synthesis of the complex diterpene
waihoensene was completed in 18 steps starting from 9. The key
transformation was intramolecular TMM diyl mediated tandem
cycloaddition reaction which served to establish the tetracyclic
core structure of waihoensene with three contiguous quaternary
carbon centres at once. Since enantiomerically pure ketoester 9
is known in the literature,[19] the current total synthesis could be
easily extended to the asymmetric total synthesis of waihoensene
and would confirm the absolute stereochemistry of waihoensene
as well as laurenene.
[8]
[9]
a) Z. Wang, Comprehensive Organic Name Reactions and Reagents
2010, 1767-1771. b) D. Stoermer, S. Caron, C. H. Heathcock, J. Org.
Chem. 1996, 61, 9115-9125. c) A. Srikrishna, S. A. Nagamani, S. G.
Jagadeesh, Tetrahedron: Asymmetry, 2005, 16, 1569-1571.
a) M. Hudlicky, Reductions in Organic Chemistry, Ellis Horwood Limited,
England, 1984; b) I. K. Youn, G. H. Yon, C. S. Pak, Tetrahedron Lett.
1986, 27, 2409-2410.
[10] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769-3772.
[11] G. M. Kaufman, J. A. Smith, G. G. Vander Stouw, H. Shechter, J. Am.
Chem. Soc. 1965, 87, 935-937.
[12] R. J. Crawford, D. M. Cameron, J. Am. Chem. Soc. 1966, 88, 2589-2590.
[13] D. A. Cichra, C. D. Duncan, J. A. Berson, J. Am. Chem. Soc. 1980, 102,
6527-6533.
Keywords: natural product • tandem cycloaddition reaction •
Trimethylenemethane diyl • total synthesis • waihoensene
[14] a) E. J. Parish, T.-Y. Wei, Synth. Commun. 1987, 17, 1227-1233; b) C.
Baralotto, M. chanon, M. Julliard, J. Org. Chem. 1996, 61, 3576-3577; c)
J.-Q. Yu, E. J. Corey, Org. Lett. 2002, 4, 2727-2730.
[1]
a) D. B. Clarke, S. F. R. Hinkley, R. T. Weavers, Tetrahedron Lett. 1997,
38, 4297-4300; b) A. F. O. Chin, D. B. Clarke, S. F. R. Hinkely, N. B.
Perry, R. T. Weavers, Aust. J. Chem. 2001, 54, 205-211.
R. E. Corbett, D. R. Lauren, R. T. Weavers, J. Chem. Soc., Perkin Trans.
1 1979, 1774-1790.
[15] Y. Morita, M. Suzuki, R. Noyori, J. Org. Chem. 1989, 54, 1785-1787.
[16] a) B. H. Lipshutz, D. A. Parker, J. A. Kozlowski, S. L. Nguyen,
Tetrahedron Lett. 1984, 25, 5959-5962; b) L. V. Hijfte, R. D. Little, J. L.
Petersen, K. D. Moeller, J. Org. Chem. 1987, 52, 4647-4661.
[17] See the supporting information
[2]
[3]
M. Buschleb, S. Dorich, S. Hanessian, D. Tao, K. B. Schenthal, L. E.
Overman, Angew. Chem. Int. Ed. 2016, 55, 4156-4186.
[18] a) N. A. Petasis, E. I. Bzowej, J. Am. Chem. Soc. 1990, 112, 6392-6394;
b) R. Csuk, B. I. Glanzer, Tetrahedron 1991, 47, 1655-1664.
[19] a) T. Katoh, K. Awasaguchi, D. Mori, H. Kimura, T. Kajimoto, M. Node,
Synlett, 2005, 2919-2922.
[4]
[5]
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a) T. Kang, W.-Y. Kim, Y. Yoon, B. G. Kim, H.-Y. Lee, J. Am. Chem. Soc.
2011, 133, 18050-18053; b) H.-Y. Lee, Acc. Chem. Res. 2015, 48, 2308-
b) P. Q. Huang, W. S. Zhou, Tetrahedron: Asymm. 1991, 2, 875-878.
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Title
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Dr. Hongsoo Lee, Dr. Taek Kang and
Prof. Dr. Hee-Yoon Lee*
NaH
NaH
N
N
Ts
Ts
110 ooC
N
N
110
C
Page No. – Page No.
H
H
Total Synthesis of (±)-Waihoensene
waihoensene
waihoensene
Total synthesis of waihoensene, a tetracyclic diterpene natural product with four
contiguous quaternary carbon centres was achieved through the tandem
cycloaddition reaction of an allenyl diazo substrate via trimethylenemethane (TMM)
intermediate.
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