Total Synthesis of (+)-Lophirone H and Its Pentamethyl Ether Utilizing an Oxonium-Prins Cyclization

Article abstract of DOI:10.1021/acs.orglett.7b00642

The first total synthesis of (+)-lophirone H (1) and its pentamethyl ether 29, featuring an oxonium-Prins cyclization/benzylic cation trapping reaction, is described.

Full text of DOI:10.1021/acs.orglett.7b00642

Letter
pubs.acs.org/OrgLett
Total Synthesis of (+)-Lophirone H and Its Pentamethyl Ether
Utilizing an Oxonium−Prins Cyclization
Hossay Abas,† Sean M. Linsdall,† Mathias Mamboury, Henry S. Rzepa, and Alan C. Spivey*
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, U.K.
S
* Supporting Information
ABSTRACT: The first total synthesis of (+)-lophirone H (1) and its pentamethyl ether 29, featuring an oxonium−Prins
cyclization/benzylic cation trapping reaction, is described.
ophirone H is a pentaphenolic flavonoid1 natural product
related motif in which the tetrahydrofuran ring is replaced by a
Lthat was first isolated by Bodo and Martin et al. in 1990 from dihydrobenzofuran unit. Synthetic approaches to these and other
natural tetra- and dihydrofurans have been reviewed.25,26
Herein, we demonstrate the utility of a highly stereoselective
the stem bark of Lophira lanceolate (“African Oak”, genus
Ochnaceae)2 collected in Cameroon.3 It was subsequently
SnCl4-mediated oxonium−Prins cyclization as a key step in the
preparation of (+)-lophirone H and its pentamethyl ether.
Mechanistic Considerations. In 2010, we published a
diastereoselective synthesis of cis-fused 4H-furo[3,2-c]-
benzopyran (7) by the Lewis acid promoted cyclocondensation
of styryl homoallylic alcohol 5 with salicylaldehyde (6). We
envisioned this reaction proceeding via a stepwise, oxonium−
Prins/cation-trapping pathway involving 5-endo-trig cyclization
via an envelope transition state with trapping of the resulting
benzylic cation by the phenolic hydroxyl group from the most
accessible face (Figure 2).27
isolated by Ranga Rao et al. from the root bark of Ochna
squarrosa (“Yerra Juvvi”, genus Ochnaceae).4 The Ochnaceae
genus generally comprises small flowering trees, the extracts of
which are widely used as components of traditional medicines in
the African savannah.5 Although the specific biological activity of
lophirone H has not been reported, some of its biogenetically
related coisolates (i.e., lophirones A,6 B−C,7 D−E,8 F−G,3 I−J,9
K,10 and L−M11) exhibit a range of interesting activities. These
include anticancer (i.e., PKC and EBV inhibition),12 antiox-
idant,13 anti-inflammatory,4,14,15 analgesic,4 and antibacterial/
microbial16 activity. The lophirones appear to derive from
dimerization of the triphenolic natural chalcone, isoliquiritigenin
(3),17 which itself displays a wide range of biological activity.18
Lophirone H is unique in having a cis-fused 4H-furo[3,2-
c]benzopyran core (Figure 1).
The 4H-furo[3,2-c]benzopyran ring system19−21 is also found
in other bioactive natural products, notably cordigol,22 which
differs from lophirone H only by the presence of an additional
phenolic hydroxyl group (Figure 1). The pterocarpans,21,23,24
which are a large family of bioactive isoflavonoids, contain a
Figure 2. Our SnCl4-mediated synthesis of the cis-fused core of
lophirone H via a proposed oxonium−Prins pathway.27
Recently, Zhao et al. reported a related method for the
synthesis of trans-fused 4H-furo[3,2-c]benzopyrans (e.g., 9) by
the Brønsted acid promoted cyclocondensation of homoprenyl
alcohols 8 with salicaldehyde 6.28 They proposed a mechanism
via a concerted o-quinonemethide formation/[π2s + π4s]-hetero-
Diels−Alder (HDA) pathway (Figure 3).
Intrigued by the stereochemical divergence of these trans-
formations, we have investigated each of them computationally
and conclude that both reactions proceed via the oxonium−Prins
Figure 1. Putative biogenesis of lophirone H (1) via homodimerization
of isoliquiritigenin (3) (and cordigol (2) via heterodimerization of
isoliquiritigenin (3) and naringenin chalcone (4)).
Received: March 2, 2017
© XXXX American Chemical Society
A
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Scheme 2. Synthesis of Homoallylic Alcohol 16
Figure 3. Zhao et al.’s acid mediated synthesis of trans-fused 4H-
furo[3,2-c]benzopyrans via a proposed HDA pathway.28
during their synthesis of the 2,8-dioxabicyclo[4.4.0]decane
skeleton of blepharocalyxin D.34,35
Figure 4. Computed geometry of the rate-limiting transition state for
SnCl4-mediated cyclization to form cis-fused 4H-furo[3,2-c]benzopyran
7 (bond lengths in Å).29
Synthesis. Enantiomerically pure enone 10 was prepared from
reaction of crotonyl chloride with the Davies (S)-configured35
SuperQuat chiral auxiliary in 75% yield (Scheme 2).36
Enone 10 was then subjected to an asymmetric aldol reaction
using dibutylboron triflate to give terminal alkene 12 as a single
(2S,3S) diastereoisomer in 78% yield.37 All attempts to remove
the chiral auxiliary at this stage or to perform a Heck coupling on
this compound proved unsuccessful due to its tendency to
undergo a facile retro-aldol reaction. Consequently, the hydroxyl
group was protected as tert-butyldimethylsilyl (TBS) ether 13
(95%) prior to performing the Heck reaction to give styrene 15.
This reaction gave yields >80% on a small scale (<30 mg) using
an aryl bromide partner, but we were unable to scale this up. On a
preparative scale we employed a protocol38 using aryl iodide 14
which furnished styrene 15 in 48% yield along with 46%
unreacted starting material 13 which could be readily recycled.
Acidic conditions were required for removal of the TBS group
from product 15 to give alcohol 16 (98%); use of TBAF resulted
in retro-aldol reaction.
cyclocondensation pathway.29 The SnCl4-mediated cyclization
selectively delivers the cis-3a,9a-stereochemistry required for
lophirone H as the result of two oxygen atoms and the tin atom
participating in the crucial 5-endo-trig cyclization transition state
(Figure 4).
In the absence of these crucial interactions, the analogous
proton-mediated transition state leading to the trans stereo-
chemistry (Figure 3) is computed29 as being 2.7 kcal/mol lower
in free energy than the alternative cis stereoisomer (B3LYP
+D3BJ/Def2-TZVPP/SCRF = CH2Cl2 model), consistent with
the observations of Zhao et al.28
Retrosynthetic Analysis. The 4H-furo[3,2-c]benzopyran core
of lophirone H contains five contiguous stereocenters. Our initial
retrosynthetic design invoked the use of an Evans-type
asymmetric aldol reaction to control the absolute stereo-
chemistry of the C2 and C3 stereocenters. A Heck reaction of
the aldol adduct would then set up the styrenyl motif of the
homoallylic alcohol 16 for the SnCl4-mediated oxonium−Prins
reaction, which would control the formation of the remaining
C3a, C4 and C9a stereocenters. Finally, either a Friedel−Crafts
acylation (not shown) or an aryl metal-mediated acylation
reaction would introduce the benzoyl unit at C3 (Scheme 1).
We investigated various conditions to achieve an efficient
oxonium−Prins reaction between alcohol 16 and aldehyde 17
(e.g., Table 1).
Using the conditions we had previously optimized,27 the
desired 4H-furo[3,2-c]benzopyran 18 was obtained in 23% yield
together with 60% of alkene 19, which results from retro-aldol
reaction of alcohol 16 (Table 1, entry 1). Stability studies showed
that while benzopyran 18 was stable to the reaction conditions,
Scheme 1. Initial Retrosynthetic Analysis of Lophirone H
Table 1. Optimization of the Oxonium−Prins Cyclization (16
→ 18)
yield (%) of 18
entry
x
y
conditions
and 19
a
1
2
3
1.0
1.4
1.4
1.1 rt (24 h)
23, 60
67, trace
81, 0
The Davies SuperQuat chiral auxiliary30 was selected over the
standard Evans auxiliary31 for control of the asymmetric aldol
reaction as this auxiliary is known to impart enhanced levels of
stereoinduction and offer milder deprotection conditions.32,33
Our choice of p-toluenesulfonyl (Ts) protection for the phenolic
hydroxyl groups followed from the observations of Willis et al.
b
1.2 −78 °C (4 h) → rt (24 h)
1.2 −78 °C (16 h) → 0 °C (9 h) →
b
rt (10 h)
a
b
No premixing; all reagents added together. SnCl4 and aldehyde 17
premixed for 20−30 min prior to addition of alcohol 16 at −78 °C.
B
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alcohol 16 decomposed readily when exposed to SnCl4 at room
temperature (rt). Consequently, an excess of aldehyde 17 (1.4
equiv) relative to SnCl4 (1.2 equiv) was premixed at −78 °C
followed by addition of alcohol 16 to minimize its exposure to
SnCl4. No reaction was seen at −78 °C after 4 h; however, after
allowing the reaction to stir at rt for 24 h, a 67% yield of
benzopyran 18 and only a trace amount of alkene 19 were
isolated (Table 1, entry 2). After further optimization, it was
found that allowing the reaction mixture to warm slowly to 0 °C
and then stirring at rt overnight improved the yield of
benzopyran 18 to 81% with no trace of alkene 19 (Table 1,
entry 3).
Scheme 4. Synthesis of (+)-Lophirone H (1) and Its
Pentamethyl Ether (29)
The relative stereochemistry of oxonium−Prins product 18
was determined by analysis of its NMR spectra (see Supporting
Information).
With all of the stereocenters now established, the remaining
challenge was to exchange the auxiliary in compound 18 for the
required resorcinol-derived ketone without epimerization at C3.
Attempts to achieve this by direct reaction of compound 18 with
various arylmetal species resulted in no reaction, so hydrolysis of
the auxiliary was performed by stirring as a 0.01 M solution in
methanol with basic aqueous hydrogen peroxide.37,39 This
yielded a ca. 1:2 mixture of the expected carboxylic acid 20 and
the methyl ester 21 in a near-quantitative yield (Scheme 3).
Treatment of ketone 24 with K2CO3 in refluxing methanol
gave triphenol 27 (81% yield), which upon reaction with Cs2CO3
and MeI in acetone gave lophirone H pentamethyl ether 29 in
60% yield. The spectroscopic data (1H and 13C NMR, MS, IR)
for this derivative matched exactly those reported by Bodo and
Martin et al.3 for the corresponding derivative of the isolated
natural product. Their natural derivative had an optical rotation
value [α]D22 −47 (c = 0.4, acetone), and they did not determine
its absolute configuration. Our (2S,3S,3aS,4S,9bR)-pentamethyl
Scheme 3. Removal of the Chiral Auxiliary and Attempted
Ketone Formation
20
ether 29 had an optical rotation value [α]D +65 (c = 0.3,
acetone), indicating that natural lophirone H is the antipode of
that prepared.
Next, we turned our attention to preparing lophirone H itself,
which has not been characterized in the literature: neither Bodo
and Martin et al.3 nor Rao et al.4 report its data. As we were
unable to deprotect the p-methyl ether in aryl ketone 27 we
installed a MOM ether at this position. Thus, acylation of methyl
ester 21 with the MOM-protected aryl bromide 25 gave ketone
26 (56%), which upon removal of the Ts groups using K2CO3 in
refluxing methanol, followed by a rapid acidic workup to remove
the MOM group, gave tetraphenol 28 in 78% yield. Treatment of
this unstable compound with BBr3/TBAI in acetonitrile for 15
min gave (+)-lophirone H in 54% yield. More than the previous
polyphenolic compounds, lophirone H proved to be exceedingly
unstable and decomposition occurred while recording its 13C
NMR spectrum. Its complete conversion to the pentamethyl
ether 29 upon treatment with Cs2CO3 in acetone-d6, however,
confirmed its identity.
To conclude, (−)-lophirone H (ent-1) is a highly labile
pentaphenolic flavonoid natural product which has previously
been characterized only as its more stable pentamethyl ether
(−)-29. We have developed the first total synthesis of
(+)-lophirone H in 9 steps and 11.5% overall yield from
crotonate 10. Our spectroscopic characterization of this material
and its transformation into its pentamethyl ether (+)-29
establishes the absolute configuration of the natural product
for the first time: (−)-(2R,3R,3aR,4R,9bS)-lophirone H (i.e., the
antipode of that depicted in Figure 1). The synthesis features an
oxonium−Prins cyclization/benzylic cation-trapping reaction
which sets up three of the five contiguous stereocenters of the cis-
fused 4H-furo[3,2-c]benzopyran core. DFT calculations have
illuminated the intimate role of SnCl4 in mediating this highly
diastereoselective ring-forming reaction, which we are currently
Functionalization of acid 20 was attempted before investing
efforts at suppressing the ester formation. In parallel, it was found
that acid 20 could be esterified in 80% yield using oxalyl chloride
and methanol, thereby allowing a total yield of 93% of methyl
ester 21 from oxazolidinone 18. Acid 20 could be quantitatively
converted to the corresponding acid chloride 22 using Ghosez’s
reagent.40 Attempted Friedel−Crafts acylation reactions of both
acid 20 and acid chloride 22 with resorcinol, 1,3-dimethox-
ybenzene, and 1,3-ditosyloxybenzene catalyzed by a range of
Lewis acids resulted in complex inseparable mixtures of products,
as did attempted Pd-catalyzed coupling between (2,4-
dimethoxyphenyl)boronic acid and acid chloride 22.41 A range
of aryl metal reagents generated from 1-bromo or 1-iodo-2,4-
ditosyloxybenzene also failed to provide any ketone from acid
chloride 22. By contrast, the aryllithium species generated from
1-bromo-2,4-dimethoxybenzene 23 reacted with acid chloride 22
to provide ketone 24 in 20% yield along with numerous side
products which were difficult to separate. Use of methyl ester 21
in place of the acid chloride 22 resulted in a cleaner reaction and
the formation of ketone 24 in 47% yield; no tert-alcohol was
isolated (Scheme 4).
C
DOI: 10.1021/acs.orglett.7b00642
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00642.
■
(20) Bruns, A.; Wibbeling, B.; Frohlich, R.; Hoppe, D. Synthesis 2006,
2006, 3111.
(21) Feng, Z.-G.; Bai, W.-J.; Pettus, T. R. R. Angew. Chem., Int. Ed.
2015, 54, 1864.
(22) Cordigol was first isolated as an antifungal constituent of Cordia
goetzei Gurke by Hostettmann et al. in 1988,42 who tentatively assigned
it as having a trans-2,3-ring fusion by 1H NMR J value analysis. However,
the key coupling constants of its core are almost identical to those
reported for lophirone H. The cis-2,3-ring fusion in lophirone H was
established by NOESY in 1990,3 and in 1996 by Hostettmann et al.43
depicted cordigol as having the same relative stereochemistry as
lophirone H. This has become accepted.20,28,44,45
̈
̈
S
Full experimental details, copies of NMR spectra for all
new compounds, and links to the DFT calculations and
NMR MNova files (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: a.c.spivey@imperial.ac.uk.
ORCID
(23) Goel, A.; Kumar, A.; Raghuvanshi, A. Chem. Rev. 2013, 113, 1614.
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(24) Jimenez-Gonzalez, L.; Alvarez-Corral, M.; Munoz-Dorado, M.;
́ ́
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Rodríguez-García, I. Phytochem. Rev. 2008, 7, 125.
(25) Rainier, J. D. In Synthesis of Saturated Oxygenated Heterocycles I,
Topics in Heterocyclic Chemistry 35; Cossy, J., Ed.; Springer: Berlin, 2014;
pp 1−41.
Alan C. Spivey: 0000-0001-5114-490X
Author Contributions
†H.A. and S.M.L. contributed equally.
(26) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261.
(27) Spivey, A. C.; Laraia, L.; Bayly, A. R.; Rzepa, H. S.; White, A. J. P.
Org. Lett. 2010, 12, 900.
Notes
(28) Zhao, L.-M.; Zhang, A.-L.; Gao, H.-S.; Zhang, J.-H. J. Org. Chem.
2015, 80, 10353.
The authors declare no competing financial interest.
(29) Abas, H.; Linsdall, S. M.; Mamboury, M.; Rzepa, H. S.; Spivey, A.
C. Imperial College HPC Data Repository 2016, DOI: 10.14469/hpc/
436.
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(31) Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L. Tetrahedron
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(33) Bull, S. D.; Davies, S. G.; Garner, A. C.; Kruchinin, D.; Key, M.-S.;
Roberts, P. M.; Savory, E. D.; Smith, A. D.; Thomson, J. E. Org. Biomol.
Chem. 2006, 4, 2945.
(34) Bunt, A. J.; Bailey, C. D.; Cons, B. D.; Edwards, S. J.; Elsworth, J.
D.; Pheko, T.; Willis, C. L. Angew. Chem., Int. Ed. 2012, 51, 3901.
(35) Willis et al.34 found that a para-phenolic styrenyl homoallylic
alcohol required an sulfonate protecting group to avoid polymerization
during a Lewis acid promoted 6-endo-trig oxonium−Prins reaction.
(36) At the outset, the choice of enantiomer was arbitrary since the
absolute configuration of natural (−)-lophirone H was unknown.
(37) Davies, S. G.; Elend, D. L.; Jones, S.; Roberts, P. M.; Savory, E. D.;
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Siegel, D. S. WO2013185103A1, 2013.
ACKNOWLEDGMENTS
■
We thank Wang Hei (Elvis) Ng and Shuyue (Peter) Zhang
(Imperial College London) for preliminary experiments relating
to this synthesis.
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