An intramolecular para-phenolic allylation free radical cyclization strategy for the synthesis of alkaloids and terpenes with spiro[4.5]decane architectures

Article abstract of DOI:10.1016/j.tetlet.2017.07.003

A Tsuji-Trost variant of the Winstein-Masamune reaction has been investigated for the synthesis of the AC spirocyclic ring system 9 bearing a quaternary carbon found in the fawcettimine type Lycopodium alkaloids magellanine 1 and lycojaponicumin B 2 and cyclopiane diterpenes such as conidiogenone 3. Annulation of the B ring for the synthesis of tricyclic ABC cores was demonstrated utilizing a 5-exo-trig free radical cyclization of a primary carbon radical onto a cyclohexadienone generated with tri-n-butylgermanium hydride (9?→?11).

Full text of DOI:10.1016/j.tetlet.2017.07.003

Accepted Manuscript
An Intramolecular para-Phenolic Allylation Free Radical Cyclization Strategy
for the Synthesis of Alkaloids and Terpenes with Spiro[4.5]decane Architectures
Matthew G. Donahue, Nicholas G. Jentsch, Erin C. Realini
PII:
S0040-4039(17)30840-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.003
TETL 49085
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 March 2017
15 June 2017
1 July 2017
Please cite this article as: Donahue, M.G., Jentsch, N.G., Realini, E.C., An Intramolecular para-Phenolic Allylation
Free Radical Cyclization Strategy for the Synthesis of Alkaloids and Terpenes with Spiro[4.5]decane Architectures,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.003
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An Intramolecular para-Phenolic Allylation
Free Radical Cyclization Strategy for the
Synthesis of Alkaloids and Terpenes with
Spiro[4.5]decane Architectures
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Matthew G. Donahue, Nicholas G. Jentsch, and Erin C. Realini

1
Tetrahedron Letters
journal homepage: www.els evier.com
An Intramolecular para-Phenolic Allylation Free Radical Cyclization Strategy for the
Synthesis of Alkaloids and Terpenes with Spiro[4.5]decane Architectures
Matthew G. Donahuea, ∗ Nicholas G. Jentscha, and Erin C. Realinia
aUniversity of Southern Mississippi, 118 College Drive #5043, Hattiesburg, MS 39406 USA
ARTICLE INFO
ABSTRACT
Article history:
Received
A Tsuji-Trost variant of the Winstein-Masamune reaction has been investigated for the synthesis
of the AC spirocyclic ring system 9 bearing a quaternary carbon found in the fawcettimine type
Lycopodium alkaloids magellanine 1 and lycojaponicumin B 2 and cyclopiane diterpenes such as
conidiogenone 3. Annulation of the B ring for the synthesis of tricyclic ABC cores was
demonstrated utilizing a 5-exo-trig free radical cyclization of a primary carbon radical onto a
cyclohexadienone generated with tri-n-butylgermanium hydride (9→11).
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Allylation
Dearomatization
Palladium
Spirocyclization
Quaternary
The control of stereochemistry in the installation of quaternary
carbons remains an enduring challenge in complex total synthesis
of natural products.1 The Lycopodium alkaloids magellanine 12
and lycojaponicumin B 2,3 Cyclopiane diterpene conidiogenone
3,4 and Acorane terpene colletoic acid 45 shown in Figure 1 are
prime examples of such molecules. Each contains a stereogenic
spirocyclic quaternary carbon embedded within a
nucleophiles as vinylogous enolates in the intramolecular Tsuji-
Trost allylation had been relatively unexplored over the past half
century. Therefore a Tsuji-Trost Winstein-Masamune phenolic
allylation would be an ideal solution for the syntheses of
molecules such as 1-4 as a vinyl group is deposited at the
electrophilic carbon for post-cyclization modifications.
spiro[4.5]decane core. The complexity of these polycyclic
architectures is further increased by the presence of contiguous
chirality centers.
To synthesize the spiro[4.5]decane substructures found in 1-
4, we envisioned utilizing a phenolic dearomatization strategy.6
Specifically, the classic Winstein-Masamune7 anionic phenolic
dearomatization that proceeds via an Ar1,5 mechanism generates a
spiro[4.5]decane substructure of 1-4. To wit, potassium tert-
butoxide (an exogenous base) in refluxing tert-butanol
deprotonates the phenol 5 which subsequently reacts via
vinylogous enolate reactivity to displace an electrophile at an sp3-
hybridized carbon terminus to afford spiro[4.5]deca-1,4-diene-3-
one 6 (Fig 2). This strategy8 has been demonstrated in
contemporary complex molecule syntheses such as
galanthamine,9a resiniferatoxin,9b and platensimycin.9c
A limitation of the traditional Winstein-Masamune reaction is
the carbon bearing the leaving group is sp3 hybridized. Further
functionalization of that carbon is therefore particularly difficult.
Recently, two independent publications by the Hamada10 and
You11 groups utilizing palladium (7→9) and iridium catalysis
(8→10) have effected a Tsuji-Trost12 5-exo-trig allylation variant
Figure 1. Alkaloid and Terpene Natural Products Bearing the
Spiro[4.5]decane Core Architecture.
of the classic Winstein-Masamune reaction. The use of phenol
———
∗ Corresponding author. Tel.: +1-601-266-4166; fax: +1-601-266-6075; e-mail: matthew.donahue@usm.edu

2
Tetrahedron
quantitatively cleaved with TBAF in THF at ambient temperature
giving the desired precursor 13 in 96% yield.
E
E
E
NaH, THF, 0°C;
15, rt
E
Z
80%
OE
TBSO
16 E = CO2CH3
RO
17 R = TBS
13 R = H
TBAF, THF, rt
96%
OR1
R
OH
ClCO2CH3, py
45%
MsCl, py
70%
Z
OR2
OCO2CH3
15 R = OMs
21 R = Cl
OH
18
19 R1 = H; R2 = CO2CH3
20 R1 = R2 = CO2CH3
Figure 2. Classical Winstein-Masamune Spirocyclization (5→6) and
the Contemporary Tsuji-Trost Transition Metal Variants (7/8→9/10).
Scheme 2. Synthesis of TTWM Spirocyclization Precursor 13
Utilizing bis-Electrophile 15.
Our general retrosynthetic strategy for the construction of the
ABC tricyclic cores found in 1-3 is depicted in Scheme 1. To
expeditiously validate this strategy, we chose a generic model
system 11 that lacks a D ring. The B ring of the angular tricyclic
carbon backbone in 11 would arise via a 5-exo-trig radical
cyclization of a primary carbon radical onto the β-carbon of a
cyclohexadienone. The radical would be generated from
halohydrin 12 that would arise from chemo- and regioselective
difunctionalization of the more electron rich alkene in 9. The
spiro[4.5]decane 9 and quaternary carbon would be synthesized
by deploying the Tsuji-Trost Winstein-Masamune intramolecular
phenolic allylation of 13. This ultimately leads back to a para-
substituted phenol 14 and a bis-electrophile 15. The phenol 14 is
an ideal platform to commence synthetic efforts given the high
degree of unsaturation that is conserved through the TTWM
reaction to the cyclohexadienone 9.
Installation of the allylic carbonate utilized a new bis-
electrophile synthesis that is amenable to regioselective
alkylation (Scheme 2). To that end, cis-1,4-butanediol 18 was
treated with one equivalent of methyl chloroformate in
tetrahydrofuran to afford a 1:1 mixture of the mono-19 and di-20
that were readily separable by normal phase silica gel column
chromatography. The allylic alcohol 19 was rapidly sulfonylated
with methanesulfonyl chloride at 0°C in less than one hour to
afford 15 in 70% yield.13 It should be noted that extended
reaction times lead to chloride displacement of the mesylate 15 to
the allylic chloride 21. The methylene groups of 20 are readily
differentiated by 1H NMR with the allylic CH2 near the sulfonate
at 4.74 ppm and that of the carbonate at 4.87 ppm. This
differentially protected allylic 1,4-diol is an ideal annulating
agent for the intramolecular phenolic para-allylation.
With gram quantities of the spirocyclization precursor 13 in
hand, we examined the palladium-catalyzed conditions shown in
Table 1. Entries 1-4 at ambient temperature showed clean
conversion of 13 to 9 after 6 hours by TLC, however the isolated
yields after workup and purification were poor to moderate (13-
42%). We sought to reduce the reaction time by utilizing
microwave heating in a closed system to minimize catalyst
inactivation.
Scheme 1. Retrosynthetic strategy for the synthesis of tricyclic
architecture 11.
Our efforts toward 11 commenced with the synthesis of
benzylidene malonate 16 shown in Scheme 2 prepared in 3-steps
from 4-hydroxybenzaldehyde according to the Hamada
protocol.10 Briefly, Knoevenagel condensation of 4-
hydroxybenzaldehyde with dimethylmalonate was carried out in
toluene in the presence of piperidine and catalytic acetic acid at
reflux to afford benzylidene malonate in 99% yield. Subsequent
hydrogenation of the olefin with hydrogen gas in the presence of
10% palladium on carbon in methanol smoothly afforded reduced
malonate in 97% yield. The phenol was protected as the tert-
butyldimethylsilyl ether with TBSCl, imidazole and catalytic
DMAP in DMF giving in 95% yield. At this stage the allylic
carbonate was installed via alkylation of the sodium enolate with
the bis-electrophile 15. The silyl protecting group of 17 was

3
Table 1. Palladium Catalyzed Intramolecular Phenolic Allylation of
13 under Thermal and Microwave Heating.
then leads to subsequent fissure of bond a and ensuing radical
rearrangement processes.
Independent reports from the Beckwith and Clive groups have
demonstrated the utility of tri-n-butylgermanium hydride to
selectively generate carbon radicals from alkyl iodides in the
presence of cyclohexadienones.14 We were pleased to observe
that upon treatment of iodide 22c with nBu3GeH and AIBN in
refluxing toluene, the desired tricyclic compound was indeed
produced in 43% yield. The structure of 11 was fully elucidated
using extensive 1D and 2D NMR experiments.
We discovered that with strict degassing of the reaction
mixture at ambient temperature by sparging nitrogen gas for at
least 15 minutes was crucial to the successful conversion of 13 to
9. The optimal temperature and time with microwave heating was
40°C for a total of 40 minutes. After the first 20 minutes, 1H
NMR showed 51% conversion and the remaining material was
fully converted after an additional 20 minute heating cycle.
While the microwave heating showed full conversion to product
by 1H NMR, the isolated yields of 9 were typically between 50-
60%.
With usable quantities of alkene 9 in hand, we set out to
chemoselectively functionalize the more electron rich pendant
alkene in a regioselective fashion as either the selenohydrin 22a
or halohydrins 22b/22c. As the cyclohexadienone alkenes in 9
are electron-deficient we anticipated that reagents such as NBS,
NIS and PhSeCl in aqueous acetonitrile would install a secondary
hydroxyl group along with a primary halide or selenide. Table 2
summarizes the best results of these electrophile initiated
oxidation experiments. The selenohydrin 22a was isolated in
87% yield while the bromohydrin 22b and iodohydrin 22c were
typically lower isolated yields hovering around 55%.
H3CO2C
H3CO2C
Electrophile (1 equiv)
CH3CN-H2O (0.3 M)
0ºC→25ºC
CO2CH3
CO2CH3
Scheme 3. Rearomatization (22b/c→23) with tin hydride versus
cyclization with germanium hydride (22c→11).
H
H
O
O
OH
Given the geometrical constraints of this system, the primary
carbon radical 24 is forced to add to the electron deficient β-
carbon of the proximal alkene of the spiro[4.5]cyclohexadienone
from the bottom face. This addition gives cis ring fusion in the
bicyclo[4.3.0]nonane, whereas addition from the top face would
give a strained trans ring junction. The ensuing stabilized radical
25 is then quenched by nBu3GeH and concomittantly sets the
correct desired trans relationship between Hf and Hk. Based on
the stereochemistry of the spirocycle 9, the stereochemistry of Hk
(pointing down) is conserved. It should be noted that the radical
addition to the distal olefin would result in an energetically
disfavored trans ring junction about the bicycle[3.3.0]octane
9
22a-c
Time
X
Entry
22
Electrophile
X
% Yield 22
87a
1
2
3
4
22a
22b
22c
22c
PhSeCl
NBS
NIS
PhSe
4 hr
22 hr
22 hr
1.5 hr
Br
55a
56a
I
I
NIS
not isolatedb
aIsolated yield after silica gel chromatography.; bCrude material carried
on without purification.
Table 2. Chemo- and regio-selective alkene halo(seleno)hydrin
formation.
With substrates 22a-c now synthesized, our focus now shifted
toward investigating carbon radical initiation to induce a 5-exo-
trig radical cyclization thereby constructing the angular tricylic
ABC cores found in 1-3. During our investigation employing tin
hydride reagents, we observed smooth conversion of 22a or 22b
to a more polar spot by TLC (Rf = 0.30 (1:1 hexanes-acetone).
Examination of the 1H NMR revealed a structure other than the
desired tricyclic compound that contained both aromatic protons
and an internal alkene functionality (signals at 5.74 and 5.62
ppm). This material was fully characterized with 2D NMR and
determined to be the rearomatized phenol 23 containing a
primary allylic alcohol. The trans conformation of the alkene was
established based on the coupling constant (3Jc,f = 15.7 Hz).
COSY NMR was used to identify the spin systems in the
structure located at the alkene (Hl ꢀ Hf ꢀ Hc ꢀ Hh) and the
phenol (Hg ꢀ Hd). HSQC and HMBC confirmed the connectivity
of the phenol. Additionally, 13C chemical shifts supported the
presence of the phenol (155 ppm) and primary alcohol (63 ppm).
We speculate that addition of nBu3Sn• to the cyclohexadienone
carbonyl of 22 is more favorable than generation of the primary
carbon radical. The formation of a stabilized ring divinyl radical
H
H
CO2CH3
CO2CH3
CO2CH3
CO2CH3
H
H
O
O
H
H
H
H
H
OH
H
OH
X
H
H
22c X = I
24 X =
25
He
CO2CH3
CO2CH3
Hg
Hd
Hf
O
Ho
Ho
Hg
Hk
OH
Hn
Hn
Hp
11
substructure.

4
Tetrahedron
Bhalerao, P.; Mobin, S. M. Tetrahedron 2012, 68, 238; (o)
Murphy, R. A.; Sarpong, R. Org. Lett. 2012, 14, 632.
3. Isolation: (a) Wang, X.-J.; Zhang, G.-J.; Zhuang, P.-Y.; Zhang,
Y.; Yu, S.-S.; Bao, X.-Q.; Zhang, D.; Yuan, Y.-H.; Chen, N.-H.;
Ma, S.-g.; Qu, J.; Li, Y. Org. Lett. 2012, 14, 2614; Total
Syntheses: (b) Hou, S.-H.; Tu, Y.-Q.; Liu, L.; Zhang, F.-M.;
Wang, S.-H.; Zhang, X.-M. Angew. Chem. Int. Ed. 2013, 52,
11373; (c) Zheng, N.; Zhang, L.; Gong, J. Yang, Z. Org. Lett.
2017, 19, 2921; Synthetic Studies: (d) Krenske, E. H.; Patel, A.;
Houk, K. N. J. Am. Chem. Soc. 2013, 135, 17638.
Scheme 4. Plausible radical cyclization pathway and structure
elucidation of tricycle 11.
Initial examination of the alkene region of the 1H NMR
revealed loss of the cyclohexadienone symmetry and showed
new peaks at 5.87 (He) and 5.44 (Hd) ppm both integrating for
one proton. COSY correlations, as indicated by the bold black
lines, was used to identify and connect the spin systems in the
structure showing connectivity of the ABC rings (Hg ꢀ Hf ꢀ Hn
ꢀ Hp ꢀ Hk ꢀ Ho) and the alkene region (He ꢀ Hd ꢀ Hf). The
correlation of Hd ꢀ Hf is a result of “W” coupling which was
4. Isolation: (a) Gao, S.-S.; Li, X.-M.; Zhang, Y.; Li, C.-S.; Wang,
B.-G.; Total Syntheses: (b) Hou, S.-H.; Tu, Y.-Q.; Wang, S.-H.;
Xi, C.-C.; Zhang, F.-M.; Wang, S.-H.; Li, Y.-T.; Liu, L. Angew.
Chem. Int. Ed. 2016, 55, 4456.
realized through observation of the 3-dimensional structure. 13
C
5. Isolation: (a) Aoyagi, A.; Ito-Kobayashi, M.; Yaunori, O.;
Furukawa, Y.; Takahashi, M.; Muramatsu, Y.; Umetani, M.;
Takatsu, T. J. Antibiotics 2008, 61, 136; Total Syntheses: (b)
Sawada, T.; Nakada, M. Org. Lett. 2013, 15, 1004; (c) Ling, T.;
Griffith, E.; Mitachi, K.; Rivas, F. Org. Lett. 2013, 15, 5790;
Synthetic Studies: (d) Ling, T.; Gautam, L. N.; Griffith, E.; Das,
S.; Lang, W.; Shadrick, W. R.; Shelat, A.; Lee, R.; Rivas, F. Eur.
J. Med. Chem. 2016, 110, 126.
NMR, DEPT135 and HSQC experiments showed two new CH2
groups at 68.2 ppm and 39.6 ppm belonging to CHg and CHn,
respectively. HMBC, as indicated by the blue arrows, further
supported the connectivity of the tricycle as shown in Scheme 4.
NOESY correlations, as indicated by the red arrows, were
utilized to confirm the major secondary alcohol diastereomer. It
was seen that Hp only showed correlation with Hk and not Hf
implying the alcohol for the major diastereomer pointed up.
6. (a) Roche, S.P.; Porco, Jr., J. A. Angew. Chem. Int. Ed. 2011, 50,
4068; (b) Zhuo, C.-X.; Zhang, W.; You, S.-Y. Angew. Chem. Int.
Ed. 2012, 51, 12662.
In conclusion we have carried out an 8-step synthesis of the
ABC tricyclic core 11 found in numerous alkaloid and terpene
natural products from 4-hydroxybenzaldehyde in 18% yield.
Salient features of this route include the development of a new
orthogonally activated bis-electrophile 15 in the malonate
alkylation of 16, demonstration of the Tsuji-Trost-Winstein-
Masamune spirocyclic allylation 13→9, and nBu3Ge• initiated 5-
exo-trig radical cyclization of 9→11. We are currently
7. (a) Winstein, S.; Baird, R. J. Am. Chem. Soc. 1957, 79, 756; (b)
Baird, G.; Winstein, S. J. Am. Chem. Soc. 1962, 84, 788. (c)
Masamune, S. J. Am. Chem. Soc. 1961, 83, 1009. For a review
see: Murphy, W. S.; Wattanasin, S. Chem. Soc. Rev. 1983, 213.
8. (a) Krapcho, P. A. Synthesis 1974, 383; (b) Pradhan, R.; Patra, M.;
Behera, A. K.; Mishra, B. K.; Behera, R. K. Tetrahedron 2006, 62,
779; (c) Kotha, S.; Deb, A.; Lahiri, K.; Manivannan, E. Synthesis
2009, 2009, 165.
9. (a) Magnus, P.; Sane, N.; Fauber, B. P.; Lynch, V. J. Am. Chem.
Soc. 2009, 131, 16045. (b) Ritter, T.; Zarotti, P.; Carreira, E. M.
Org. Lett. 2004, 6, 4371. (c) Lalic, G.; Corey, E. J. Org. Lett.
2007, 9, 4921.
investigating the application of this strategy to complex alkaloids
and terpenes such as those identified in Figure 1.
10. (a) Nemoto, T.; Ishige, Y.; Yoshida, M.; Kohno, Y.; Kanematsu,
M.; Hamada, Y. Org. Lett. 2010, 12, 5020; (b) Yoshida, M.;
Nemoto, T.; Zhao, Z.; Ishige, Y.; Hamada, Y. Tetrahedron:
Asymmetry 2012, 23, 859; (c) Nemoto, T.; Zhao, Z.; Yokosaka, T.;
Suzuki, Y.; Wu, R.; Hamada, Y. Angew. Chem. Int. Ed. 2013, 52,
2217; (d) Nemoto, T.; Wu, R.; Zhao, Z.; Yokosaka, T.; Hamada,
Y. Tetrahedron 2013, 69, 3403.
Acknowledgments
Funding for the Bruker UltraShield Plus 400 MHz NMR and
ThermoFinnigan LXQ ESI-LC/MS used in this research was
provided by National Science Foundation Major Research
Instrumentation under Grant Numbers 0840390 and 0639208,
respectively. We thank the University of Southern Mississippi
Office of the Vice President for Research for financial support,
laboratory space and facilities. MGD is a 2015 recipient of the
Lucas Award for Faculty Excellence sponsored by the USM
Office of the Provost. NGJ is a 2015 USM INTERFACE
National Science Foundation National Research Trainee under
Grant Number 1449999. ECR is a 2015 recipient of the USM
Center for Undergraduate Research Eagle Spur Award.
11. (a) Wu, Q. F.; Liu, W. B.; Zhuo, C. X.; Rong, Z. Q.; Ye, K. Y.;
You, S. L. Angew. Chem. Int. Ed. 2011, 50, 4455. (b) Zhuo, C.-X.;
Zhang, W.; You, S.-L. Angew. Chem. Int. Ed. 2012, 51, 12662-
12682; (c) Zhuo, C. X.; Zheng, C.; You, S. L. Acc Chem Res 2014,
47, 2558.
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6, 4387. (b) Trost, B. M.; Strege, P. E. J. Am. Chem. Soc. 1977,
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J.; Dietsche, T. J. J. Am. Chem. Soc. 1977, 100, 3416; (d) Trost, B.
M.; Lothar, W.; Strege, P. E.; Fullerton, T. J.; Dietsche, T. J. J.
Am. Chem. Soc. 1977, 100, 3426.
13. Spectral Data of 18: Rf = 0.41 (1:1 hexanes-EtOAc; uv then
PMA); 1H NMR (CDCl3, 400 MHz) 3.05 (s, 3H), 3.80 (s, 3H),
4.74 (d, J = 6.0 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 5.88 (m, 1H),
5.88 (m, 1H); 13C NMR (CDCl3, 100 MHz) 38.1 (q), 55.0 (q),
62.8 (t), 64.7 (t), 126.8 (d), 129.5 (d), 155.5 (s); HRMS (ESI):
Exact mass calcd for C7H12O6S [M+Na]+ 247.0252. Found
247.02450.
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5
Click here to remove instruction text...
• Spiro[4.5]cyclohexadienone is an ideal
scaffold to synthesize complex alkaloids
and terpenes
• 1,4-bis-electrophile composed of an
allylic carbonate and allylic mesylate
has been synthesized
• Intramolecular phenolic allylation
utilized in the synthesis of
spiro[4.5]decane substructure
• Germanium hydride initiated free radical
cyclization achieved angular tricycle
formation