Development of a 5-exo, 6-exo tandem radical cyclization to access bisabosqual A

Article abstract of DOI:10.1016/j.tet.2019.05.001

Substrates were designed to undergo tandem radical cyclizations to afford the cis, cis-fused hexahydrobenzofurobenzopyran ring system of the bisabosquals. Studies with these revealed that different initiating systems gave different yields and somewhat different diastereomeric ratios. A photocatalytic cyclization was also successful with the bisabosqual substrate.

Full text of DOI:10.1016/j.tet.2019.05.001

Accepted Manuscript
Development of a 5-exo, 6-exo tandem radical cyclization to access bisabosqual A
Christopher W. am Ende, Kathlyn A. Parker
PII:
S0040-4020(19)30508-3
https://doi.org/10.1016/j.tet.2019.05.001
TET 30322
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 March 2019
Revised Date: 29 April 2019
Accepted Date: 1 May 2019
Please cite this article as: am Ende CW, Parker KA, Development of a 5-exo, 6-exo tandem radical
cyclization to access bisabosqual A, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.05.001.
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ACCEPTED MANUSCRIPT
Graphical Abstract
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Development of a 5-exo, 6-exo tandem radical cyclization to access
bisabosqual A
Christopher W. am Ende† and Kathlyn A. Parker*
Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United
States
Abstract:
Substrates were designed to undergo tandem radical cyclizations to afford the cis, cis-fused
hexahydrobenzofurobenzopyran ring system of the bisabosquals. Studies with these revealed
that different initiating systems gave different yields and somewhat different diastereomeric
ratios. A photocatalytic cyclization was also successful with the bisabosqual substrate.
Keywords. tandem • radical • cyclization • cascade • photoredox • cis fused ring system
Dedicated to Professor Stephen L. Buchwald in tribute to his manyclever and practical contributions to
synthetic organic chemistry
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1. Introduction
Radical cyclization is an effective approach to the construction of cis-fused ring systems.
The penchant for cis-selectivity is a result of geometric constraint and it has been exploited in the
construction of cis-fused 5,5-,1 6,5-2 and 6,6-3 ring systems. The utility of this preference was
powerfully demonstrated early on by Curran and coworkers who prepared both linear and
angular triquinanes by exploiting tandem 5-exo, 5-exo cyclizations.4
A 5-exo, 6-exo tandem radical cyclization which affords the cis, cis-fused
hexahydrobenzofurobenzopyran ring system served as the key step in our total synthesis of (+)-
bisabosqual A (1, Figure 1).5 Our cyclization substrate 2 was designed with ester groups as
functional equivalents of the required aldehydes. Also, we selected the β-aryloxy α,α’–dienone
moiety as the radical trapping sidechain; the vinylogous ester moiety can be introduced cleanly,
it is relatively stable, and it was expected to favor the 6-exo closure. While we were confident
that the ring junctures at 4,5 and 5,6 in the cyclization product would be cis, the stereochemistry
to be produced at C-7 was not predictable.
Figure 1. Bisabosqual A and radical cyclization substrates explored.
In order to test the behavior of a vinylogous ester sidechain in the system of interest, we
prepared model substrate 3 and examined its behavior in a tandem ring closure. Here we
describe the results of those studies and their extension to the cyclization of substrate 2.
2. Results and Discussion
2.1 Synthesis and Cyclization of Model Substrate 3
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The model cyclization substrate 3 was readily assembled in three steps as shown in
Scheme 1. Iodination of commercially available ester 4 by the procedure of Kim and coworkers6
afforded the tetrasubstituted resorcinol 5. Subsequent DABCO-catalyzed 1,4-addition of
compound 5 to ethyl allenecarboxylate proceeded regioselectively to install the vinylogous
carbonate side chain.7 A Mitusunobu reaction completed the sequence, providing cyclization
substrate 3 (Scheme 1).
O
I2, NaHCO3
THF/H2O, rt, 3h
H2C
CO2Me
OH
CO2Me
OH
OEt
DABCO
THF, rt, 22h
82%
46%
HO
HO
I
4
5
CO2Me
OH
CO2Me
OH
O
O
O
I
I
DIAD, PPh3
THF, rt, 3h
94%
Me
Me
EtO
EtO
O
O
6
3
Scheme 1. Assembly of radical cyclization substrate 3.
In a preliminary experiment, compound 3 underwent the desired 5-exo, 6-exo radical
cyclization upon exposure to n-tributyltin hydride and azobisisobutyronitrile (AIBN) at elevated
temperature (Table 1, Entry 1). The reaction proceeded with complete selectivity at the C-5 and
C-6 carbons (numbering system to correspond to bisabosqual numbering) to produce the cis, cis-
fused ring system while affording modest selectivity (dr = 3:2, 7:C-7-epi-7) at the C-7
quaternary center. The identity of each diastereomer was established by NOE and confirmed by
an X-ray crystal structure of the minor isomer (Figure 2 and Supporting Information).
Thus, we were able to access the bisabosqual hexahydrobenzofurobenzopyran ring
system via a tandem radical cyclization; however, the yield was low (35%). Furthermore, the
use of toxic tin reagents is undesirable. Therefore, we screened alternative conditions for this
step. We varied the initiator, the solvent, and the temperature and examined the 1H NMR
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spectrum of the crude material obtained in each case. Experiments that gave what appeared to be
the most promising product mixtures were scaled up for purification.
Tris(trimethylsilyl)silane, which has relatively low toxicity, has emerged as an alternative
to n-tributyltin hydride.8 The stronger bond dissociation (5 kcal/mol) of the Si-H as compared to
the Sn-H has been exploited in radical cyclization reactions to reduce the amounts of premature
reduction products.8 When subjected to (TMS)3SiH and AIBN in toluene at 60, 80 and 120 °C
(Table 1, Entries 2-4), substrate 3 afforded the bisabosqual tetracyclic core (7 + C-7-epi-7) with
no change in diastereoselectivity but with a slight improvement in yield at 80 °C.
Table 1. Radical Cyclizations of Model Substrate 3.
Entry Reducing Agent Initiator
Solvent
Temperature Time Yielda
1b
2c
3c
4c
5d
6e
7f
nBu3SnH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
AIBN
AIBN
AIBN
AIBN
Et3B
Benzene
100 °C
60 °C
80 °C
120 °C
rt
48 h
20 h
20 h
4 h
35%
37%
45%
25%
Toluene
Toluene
Toluene
EtOH
30 m 52%
30 m 61%
Et3B
CH2Cl2
rt
sBu3B
2-MeTHF
rt
30 m 49%
b
adiastereoselecivity = 3:2 (7:C-7-epi-7) in all entries. Reaction conditions: nBu3SnH (3 equiv),
AIBN (0.2 equiv), conc. 0.025 M, c(TMS)3SiH (2 equiv), AIBN (0.1 equiv), conc. 0.025 M,
d(TMS)3SiH (1.2 equiv), Et3B (5 equiv), conc. 0.025 M, e(TMS)3SiH (1.2 equiv), Et3B (2 equiv),
conc. 0.025 M, f(TMS)3SiH (1.2 equiv), Et3B (5 equiv), conc. 0.025 M.
The triethylborane/O2 radical initiating system is noteworthy because it is operative at
low temperatures.9 Again, we tested the approach with a variety of conditions in small scale
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reactions and scaled up those with the most promising NMR spectra of crude materials. Indeed,
treatment of substrate 3 with the (TMS)3SiH /Et3B/O2 radical reducing system at room
temperature resulted in increased yields, shorter reaction times, and milder reaction conditions
(Table 1, Entries 5 and 6). While solvent did not seem to play a significant role,
dichloromethane provided a slightly higher yield and overall cleaner conversion relative to other
solvents explored. Attempts to alter the diastereoselectivity by adding Lewis acids or by
decreasing the temperature typically resulted in lower yields with no noticeable effect on C-7
diastereoselectivity (not shown).
In this model cyclization, we also examined sBu3B/O2 as the initiating reagent
combination. Scaleup of the reaction in 2-methyltetrahydrofuran gave results comparable to
those obtained with the Et3B/O2 system (Table 1, Entry 7).
Figure 2. Identification of isomers obtained in the radical cyclization of model system 3 by
nuclear Overhauser effects and structure of phenol side product 8.
A common side product in the radical cyclization of substrate 3 was phenol 8 (Figure 2).
We speculated that this side product was a result of a 1,4-hydrogen migration process in which
the aryl radical abstracts the allylic hydrogen adjacent to the ether bond (Scheme 2). Typically,
there is a strong preference for 1,5-hydrogen atom transfers;10 however, 1,4-hydrogen abstraction
is viable if geometric and steric constraints allow proper orientation to be achieved.11 In this
case, the resulting radical would be stabilized by both the oxygen and the double bond.
Quenching of this radical would give an enol ether, expected to hydrolyze in the workup,
releasing the phenol (Scheme 2).
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Scheme 2. Postulated Mechanism for Formation of Phenol 8.
To test this premise, we examined the deuterium-labeled substrate 3-D (see Scheme 3).
1-d-Cyclohex-2-ene-1-ol, prepared by Baldwin’s procedure,12 had greater than 90% deuterium
incorporation at the desired position as determined by 1H NMR. A subsequent Mitsunobu
reaction with phenol 6 generated the deuterium labeled cyclization substrate 3-D. Subjecting
compound 3-D to the (TMS)3SiH/Et3B/O2 radical reducing system afforded the expected
deuterium labeled cyclization products in 62% yield; isolated 7-D appeared to be >90%
deuterated at the position numbered 4.
Scheme 3. Deuterated products from substrate 3-D
In addition, a 20% yield of the deuterium-labeled phenol 8-D was obtained. However,
the C-3 position of the aromatic ring was only 65% labeled; thus it appears that there must be at
least one additional pathway that leads to the reduced and dealkylated phenol structure. In fact, a
competing 1,5-hydrogen migration in the aryl radical followed by a fragmentation would give
unlabeled 8.
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2.2 Cyclization of Bisabosqual Precursor 2
When applied to the fully elaborated substrate 2, tandem radical cyclization was
generally the major pathway (Table 2). With the (TMS)3SiH/AIBN system (Entry 1), a 51%
yield of a 3:2 mixture of tetracyclic diastereomers 9 and C-7-epi-9 was obtained. The
(TMS)3SiH / triethylborane system gave somewhat lower yields and, in methylene chloride
(Entry 2), the desired epimer 9 was slightly disfavored. However, when dichloromethane was
replaced with a potentially coordinating solvent (acetonitrile), the selectivity at the C-7 center
was restored to favor the desired epimer 9 (Table 2, Entry 3).
Postulating that the Lewis acidic triethylborane could be playing a role beyond acting as a
radical initiator in the reaction, we next explored the effect of a bulkier trialkylborane as the
radical initiator. Replacing triethylborane with sec-butylborane had an impressive effect on the
reaction, increasing the yield of tetracycle to 72% (Table 2, Entry 4). To our knowledge, this is
the first example of the (TMS)3SiH/sBu3B/O2 system in radical initiation / reduction.
Additional experiments in which the solvent was varied or in which the reaction was performed
at elevated temperatures resulted in minor decreases in yield (Table 2, Entries 5-7). However,
when the reaction was cooled to -40 °C, a modest improvement in the diastereoselectivity at the
C-7 quaternary carbon was observed (dr =5:2, 9:C-7-epi-9); unfortunately, this was accompanied
by a reduction in yield (Table 2, Entry 8).
Table 2. Tandem radical cyclization of substrate 2.
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Yieldb
51%
31%
39%
72%
60%
58%
62%
46%
drc
3:2
2:3
3:2
3:2
3:2
3:2
3:2
5:2
Entry Reducing Agent Initiator
Solvent
Toluene
CH2Cl2
CH3CN
CH2Cl2
Toluene
CH2Cl2
2-MeTHF
CH2Cl2
Temperature
Time
3 h
1d
2e
3e
4f
5f
6f
7f
8g
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
AIBN
Et3B
70 °C
rt
30 m
30 m
30 m
30 m
15 m
15 m
4 h
Et3B
rt
sBu3B
sBu3B
sBu3B
sBu3B
sBu3B
rt
rt
40 °C
50 °C
-40 °C
aSmall amounts of the phenolic side product 10 were observed in all reactions (See Experimental
Section), bYield is reported as the mixture of diastereomers (9 and C-7-epi-9), cdr = 9:C-7-epi-9,
d
Reaction conditions: (TMS)3SiH (2 equiv), AIBN (0.1 equiv), conc. 0.025 M, e(TMS)3SiH (1.5
equiv), Et3B (2 equiv), conc. 0.025 M, f(TMS)3SiH (1.5 equiv), sBu3B (1 equiv), conc. 0.015 M,
g(TMS)3SiH (1.5 equiv), sBu3B (3 equiv), conc. 0.015 M.
We note that, although it would be beneficial if the cyclization afforded only the desired
9 and not C-7-epi-9, the formation of the pair does not necessarily result in a major loss of
advanced material. As noted in our original report,5 the epimeric product (C-7-epi-9) can be
equilibrated to a diastereomeric mixture by a retro-Michael / Michael procedure.
Intrigued by the touted benefits of photoredox conversions, we noted Stephenson’s
photoredox-initiated reductive radical cyclizations of aryl iodides.13 We subjected our
bisabosqual substrate 2 to a slight variation of the recommended reaction conditions (visible
light, fac-Ir(ppy)3 [5 mol%], nBu3N, HCO2H) and obtained 60% yield of a 2:1 mixture of
tetracyclic 9 and C-7-epi-9 (Scheme 4).
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Scheme 4. Visible light initiated tandem radical cyclization.
The yield and diastereomeric ratio are roughly equivalent to those obtained with more
classical approaches. Therefore, the potential advantages of the photoredox approach to this and
related cyclizations lie in the benign nature of the reagents, convenience in handling, and
opportunities for scaleup, particularly by means of flow systems.14
3. Conclusions
Tandem radical cyclization converts readily assembled substrates to tetracyclic
hexahydrobenzofurobenzopyrans with ring junction stereochemistry established as completely
cis, cis. The stereochemistry at the fourth new stereocenter is not controlled and is slightly
variable. We also identified the origin of a by-product as a 1,4-hydrogen shift to the initially
formed aryl radical. In addition, the cascade reaction was readily adapted to a photoredox
procedure.
Acknowledgment.
This work was supported by the National Institutes of Health (GM 74776) and by Pfizer Inc.
The authors thank Kathleen A. Farley for NMR support, Brian M. Samas and Ivan Samardjiev
for X-ray crystal structures, James Bradow for separations, and Martin Pettersson, John M.
Humphrey, Christopher J. Helal, Patrick B. Mullins, Thayalan Navaratnam, Michael E. Green,
Todd W. Butler, Matthew E. Calder, Anabella Villalobos and Christopher J. O’Donnell for
insightful discussions and support.
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Notes
†Present address: Pfizer Worldwide Research and Development, Eastern Point Road, Groton,
Connecticut 06340, United States. The authors declare the following competing financial
interest: C.W.A is an employee of Pfizer Inc.
Experimental
General Considerations: Unless otherwise stated, all air and moisture-sensitive reactions were
performed in oven-dried glassware under nitrogen and all commercially available chemicals,
reagents and solvents were used as received. Triethylborane and tri-sec-butylborane were
purchased from Sigma-Aldrich as solutions in THF or hexanes. Compounds 2, 9 and C-7-epi-9
were synthesized and characterized previously (see J. Am. Chem. Soc. 2013, 135, 582-585).
Reactions were monitored by thin layer chromatography (TLC) performed on Analtech, Inc.
silica gel GF 250 ꢀm plates and were visualized with ultraviolet (UV) light (254 nm) and/or
KMnO4 staining or by UPLC-MS (Waters Acquity, ESCI (ESI +/-, APCI +/-)). Gas
chromatography – mass spectrometry (GC-MS) was performed with an Agilent 5890 GC Oven
and an Agilent 5973 Mass Selective Detector. Silica gel flash chromatography was performed
with RediSep®Rf normal phase silica flash columns on a CombiFlash Rf system from Teledyne
Isco, Inc. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Varian-
Inova 400 (400 MHz and 101 MHz, respectively), a Bruker 400 (400 MHz and 101 MHz,
respectively), or a Bruker 500 (500 MHz and 126 MHz, respectively) spectrometer. Chemical
shifts are reported in ppm relative to CHCl3 (1H, δ = 7.26 and 13C NMR δ = 77.0). The
multiplicities are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; spt, septet; m,
multiplet; br s, broad singlet. Melting points are uncorrected. Infrared (IR) spectra were
recorded with a Thermo-Nicolet Avatar 360 FT-IR. High-resolution mass spectra (HRMS) were
acquired on an Agilent model 6220 MS(TOF).
Methyl 2,4-dihydroxy-3-iodobenzoate (5): To a solution of resorcinol 4 (20.0 g, 0.119 mol) in
THF (150 mL) and water (150 mL) at 0 °C was added I2 (30.2 g, 0.119 mol, 1 equiv.) in one
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portion followed by NaHCO3 (11.0g, 0.131 mol, 1.1 equiv.) portionwise over a period of 30
minutes. The mixture was allowed to warm to room temperature and stirred at this temperature
for 3 hours. The mixture was extracted with Et2O (2x). The combined organic solution was
dried with anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was
purified by recrystallization from EtOAc/Heptane to afford 5 (16.1 g, 46% yield) as a light pink
1
crystals. H NMR (400 MHz, CDCl3) δ 11.93 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 6.59 (d, J = 8.8
Hz, 1H), 5.92 (br. s., 1H), 3.94 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.9, 162.0, 161.0,
131.5, 106.9, 105.7, 76.6, 52.5. FTIR (cm-1) = 3285, 1635, 1434, 1412, 1271, 1017. mp = 141 –
143 °C. HRMS (ESI) calculated for C8H8IO4 [M+H]+ 294.9462, found 294.9458.
(E)-Methyl 4-(4-ethoxy-4-oxobut-2-en-2-yloxy)-2-hydroxy-3-iodobenzoate (6): To a solution
of 5 (2.6 g, 8.8 mmol) in THF (90 mL) were added 4 Å molecular sieves (500 mg) and DABCO
(200 mg, 1.8 mmol, 0.2 equiv.) followed by ethyl buta-2,3-dienoate (1.0 g, 8.8 mmol, 1 equiv.)
in one portion. The mixture was stirred at room temperature for 22 hours. The mixture was
poured into water and the resulting solution was extracted with Et2O (2x). The combined
organic solution was washed with brine (1x), dried over anhydrous MgSO4 and concentrated
under reduced pressure. The crude residue was purified by silica gel flash chromatography
1
(EtOAc/Heptane) to afford 6 (2.95 g, 82% yield) as a white solid. H NMR (400 MHz, CDCl3) δ
11.89 (br. s., 1H), 7.88 (d, J = 8.6 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 4.82 (s, 1H), 4.09 (q, J = 7.2
Hz, 2H), 3.98 (s, 3H), 2.53 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
170.0, 169.6, 166.9, 162.8, 159.4, 131.3, 113.4, 109.8, 97.7, 82.2, 59.8, 52.9, 18.1, 14.2. FTIR
(cm-1) = 2981, 1712, 1675, 1640, 1437, 1319, 1256, 1204, 1126, 1035. mp = 95 – 96 °C. HRMS
(ESI) calculated for C14H16IO6 [M+H]+ 406.9986, found 406.9984.
(E)-Methyl 2-(cyclohex-2-enyloxy)-4-(4-ethoxy-4-oxobut-2-en-2-yloxy)-3-iodobenzoate (3):
To a solution of compound 6 (1.50 g, 3.69 mmol), 2-cyclohexen-1-ol (0.435 g, 4.43 mmol, 1.2
equiv.) and PPh3 (1.55 g, 5.90 mmol, 1.6 equiv.) in THF (40 mL) at room temperature was added
DIAD (1.19 g, 5.90 mmol, 1.6 equiv.) dropwise over a period of five minutes. After stirring an
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additional 19 hours, the reaction mixture was concentrated under reduced pressure. Et2O was
added and the resulting mixture was washed with 0.5 N HCl (1x), saturated NaHCO3 (1x) and
brine (1x). The organic fraction was dried with anhydrous MgSO4 and concentrated under
reduced pressure. The crude residue was subjected to silica gel flash chromatography
(EtOAc/Heptane) to afford 3 (1.67 g, 95% yield) of a white crystalline solid. 1H NMR (400
MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.00 - 5.93 (m, 1H), 5.86 -
5.79 (m, 1H), 4.76 (s, 1H), 4.60 - 4.54 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 2.53 (s,
3H), 2.23 - 2.10 (m, 1H), 2.10 - 1.93 (m, 3H), 1.83 - 1.72 (m, 1H), 1.66 - 1.54 (m, 1H), 1.22 (t, J
13
= 7.1 Hz, 3H). C NMR (101 MHz, CDCl3) δ 170.2, 166.9, 165.9, 159.2, 157.3, 132.9, 132.4,
125.8, 123.5, 117.2, 97.2, 92.6, 79.4, 59.6, 52.4, 28.7, 25.1, 18.7, 18.1, 14.2. FTIR (cm-1) = 2946,
1713, 1640, 1581, 1393, 1281, 1243, 1212, 1127, 1039. mp = 84.5 – 85 °C. HRMS (ESI)
calculated for C20H23INaO6 [M+Na]+ 509.0432, found 509.0432.
(±)-(2S,2aR,2a1S,5aS)-Methyl 2-(2-ethoxy-2-oxoethyl)-2-methyl-2a,2a1,3,4,5,5a-hexahydro-
2H-benzofuro[4,3,2-cde]chromene-7-carboxylate (7): Nitrogen was bubbled through a
solution of 3 (102 mg, 0.210 mmol) in CH2Cl2 (8 mL) for 5 minutes, followed by addition of
Et3B (0.42 mL, 1M in hexanes, 0.42 mmol, 2 equiv.) and (TMS)3SiH (78 mg, 0.315 mmol, 1.5
equiv.). Next, air was added via syringe (10 mL) over a period of 15 minutes. The mixture was
stirred an additional 30 minutes at room temperature and then concentrated under reduced
pressure. The 1H NMR spectrum of the crude material indicated a 3:2 mixture of diastereomers
about C-7, favoring 7. This was subjected to silica gel flash chromatography (EtOAc/Heptane)
to afford 7 and C-7-epi-7 (46 mg, 61% yield) as a 3:2 mixture of diastereomers. The isomers
were combined with additional material from other cyclization experiments and separated by
chiral HPLC (Phenomenex Luna (2) C18 150 x 21.2 mm 5ꢀ, 5 to 95% 0.1% formic acid in water
1
to 0.1% formic acid in methanol, flow = 28 mL/min) to yield separated 7 and C-7-epi-7. H
NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 8.8, 1.0 Hz, 1H), 6.34 (d, J = 8.6 Hz, 1H), 5.20 (dt, J =
9.1, 7.6 Hz, 1H), 4.17 - 4.08 (m, 2H), 3.84 (s, 3H), 3.60 (t, J = 7.0 Hz, 1H), 2.69 - 2.52 (m, 2H),
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2.32 - 2.22 (m, 1H), 2.07 - 1.98 (m, 1H), 1.75 - 1.66 (m, 1H), 1.64 - 1.56 (m, 1H), 1.54 (s, 3H),
1.23 (t, J = 7.1 Hz, 3H), 1.09 - 0.91 (m, 2H), 0.84 - 0.71 (m, 1H). 13C NMR (101 MHz, CDCl3) δ
169.8, 165.5, 160.8, 155.6, 132.0, 110.8, 108.0, 107.5, 87.8, 80.3, 60.6, 51.6, 43.0, 35.9, 33.8,
27.6, 23.4, 21.4, 20.6, 14.1. FTIR (cm-1) = 2943, 1706, 1628, 1609, 1431, 1257, 1188. HRMS
(ESI) calculated for C20H25O6 [M+H]+ 361.1645, found 361.1634
(±)-(2R,2aR,2a1S,5aS)-Methyl 2-(2-ethoxy-2-oxoethyl)-2-methyl-2a,2a1,3,4,5,5a-hexahydro-
1
2H-benzofuro[4,3,2-cde]chromene-7-carboxylate (C-7-epi-7): H NMR (400 MHz, CDCl3) δ
7.67 (dd, J = 8.8, 1.0 Hz, 1H), 6.36 (d, J = 8.8 Hz, 1H), 5.22 (dt, J = 9.0, 7.6 Hz, 1H), 4.18 (q, J
= 7.2 Hz, 2H), 3.87 (s, 3H), 3.56 (t, J = 7.0 Hz, 1H), 2.87 - 2.74 (m, 2H), 2.38 - 2.31 (m, 1H),
2.09 - 2.01 (m, 1H), 1.77 - 1.71 (m, 1H), 1.64 - 1.57 (m, 1H), 1.45 (s, 3H), 1.29 (t, J = 7.1 Hz,
3H), 1.10 - 0.95 (m, 2H), 0.83 - 0.70 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 169.9, 165.7,
160.7, 155.4, 131.9, 111.2, 108.2, 107.4, 87.8, 80.6, 60.7, 51.7, 42.9, 36.2, 33.5, 27.7, 23.9, 21.8,
20.7, 14.2. FTIR (cm-1) = 2943, 1706, 1628, 1609, 1431, 1257, 1188. HRMS (ESI) calculated for
C20H25O6 [M+H]+ 361.1645, found 361.1634. An X-ray structure of C-7-epi-7 was obtained –
see attached .cif file for details.
(E)-Methyl 4-(4-ethoxy-4-oxobut-2-en-2-yloxy)-2-hydroxybenzoate (8): An analytical
sample of phenol 8 was obtained by combining material from several runs and subjecting it to a
1
second flash chromatography. H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 7.85 (d, J = 8.6 Hz,
1H), 6.63 (d, J = 2.1 Hz, 1H), 6.55 (dd, J = 8.7, 2.2 Hz, 1H), 5.04 (s, 1H), 4.10 (q, J = 7.0 Hz,
2H), 3.95 (s, 3H), 2.45 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.8,
170.0, 167.2, 163.3, 159.4, 131.7, 112.5, 109.8, 109.7, 98.6, 59.7, 52.4, 18.1, 14.3
(±)-Methyl (E)-2-((cyclohex-2-en-1-yl-1-d)oxy)-4-((4-ethoxy-4-oxobut-2-en-2-yl)oxy)-3-
iodobenzoate (3-D): To a solution of 6 (1.02 g, 2.51 mmol), 1-d-cyclohex-2-ene-1-ol (348 mg,
3.52 mmol, 1.4 equiv.) and PPh3 (988 mg, 3.77 mmol, 1.5 equiv.) in THF (10 mL) at room
temperature was added DIAD (761 mg, 3.77 mmol, 1.5 equiv.) dropwise over a period of two
minutes. After stirring an additional 30 minutes, the reaction mixture was concentrated under
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reduced pressure. The crude residue was purified by silica gel flash chromatography
(EtOAc/Heptane) to afford 3-D (1.17 g, 96% yield) of a white solid. 1H NMR (400 MHz,
CDCl3) δ 7.78 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 5.97 (dt, J = 10.1, 3.5 Hz, 1H), 5.83
– 5.81 (m, 1H), 4.76 (s, 1H), 4.09 (q, J = 7.3 Hz, 2H), 3.90 (s, 3H), 2.53 (s, 3H), 2.21 - 2.11 (m,
13
1H), 2.08 - 1.94 (m, 3H), 1.81 - 1.73 (m, 1H), 1.66 - 1.58 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H). C
NMR (100 MHz, CDCl3) δ 170.5, 167.3, 166.2, 159.5, 157.7, 133.3, 132.7, 126.0, 123.8, 117.5,
97.5, 92.9, 60.0, 52.7, 29.0, 28.9, 25.4, 19.0, 18.4, 14.5. FTIR (cm-1) = 2945, 1712, 1639, 1580,
1432, 1389, 1281, 1242, 1212, 1126. HRMS (ESI) calculated for C20H23DIO6 [M+H]+ 488.0675,
found 488.0678.
(±)-Methyl (3aS,3a1S,9S,9aR)-9-(2-ethoxy-2-oxoethyl)-9-methyl-2,3,3a,3a1,9,9a-hexahydro-
1H-benzofuro[4,3,2-cde]chromene-5-carboxylate-3a-d (7-D): To a solution of 3-D (134 mg,
0.275 mmol) and (TMS)3SiH (82 mg, 0.33 mmol, 1.2 equiv.) in EtOH (10 mL) at room
temperature was simultaneously added Et3B (0.50 mL, 1M in hexanes, 0.50 mmol, 2 equiv.) and
air via a syringe (10 mL). The addition procedure took place over a period of 30 minutes. The
mixture was stirred an additional 15 minutes at room temperature and then concentrated under
reduced pressure. The crude 1H NMR spectrum indicated a 3:2 mixture of diastereomers about
C-7, favoring 7-D. The crude residue was subjected to silica gel flash chromatography
(EtOAc/Heptane) to afford a mixture (62 mg, 62% yield) of a 3:2 (7-D:C-7-epi-7-D) mixture of
diastereomers as a colorless oil. An additional silica gel chromatography on the mixture of
1
diastereomers (7-D:C-7-epi-7-D) resulted in an analytical sample of 7-D for characterization: H
NMR (400 MHz, CDCl3) δ 7.68 (dd, J = 8.7, 0.9 Hz, 1H), 6.37 (d, J = 8.6 Hz, 1H), 4.20 - 4.10
(m, 2H), 3.88 (s, 3H), 3.62 (d, J = 6.2 Hz, 1H), 2.73 - 2.57 (m, 2H), 2.34 - 2.25 (m, 1H), 2.08 -
2.01 (m, 1H), 1.78 - 1.69 (m, 1H), 1.66 - 1.60 (m, 1H), 1.57 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H),
13
1.11 - 0.94 (m, 2H), 0.89 - 0.75 (m, 1H). 13C NMR: C NMR (100 MHz, CDCl3) δ 169.9, 165.7,
160.9, 155.7, 132.1, 110.9, 108.1, 107.6, 99.8, 80.4, 60.7, 51.7, 43.1, 36.0, 33.7, 27.6, 23.5, 21.5,
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20.8, 14.2. FTIR (cm-1) = 2945, 1706, 1629, 1609, 1429, 1254, 1188. HRMS (ESI) calculated for
C20H24DO6 [M+H]+ 362.1708, found 362.1716.
Methyl (E)-4-((4-ethoxy-4-oxobut-2-en-2-yl)oxy)-2-hydroxybenzoate-3-d (8-D): A separate
1
reaction run on 2.22 mmol scale was used to isolate 8-D (125 mg, 20% yield). H NMR (400
MHz, CDCl3) δ 10.92 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 6.57 - 6.53 (m, 1H), 5.04 - 5.03 (m, 1H),
4.10 (q, J = 7.0 Hz, 2H), 3.95 (s, 3H), 2.45 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H. 13C NMR (101 MHz,
CDCl3) δ 170.8, 170.0, 167.1, 163.3, 159.3, 131.7, 112.5, 109.8, 109.7, 98.6, 59.7, 52.4, 18.1,
14.3. FTIR (cm-1) = 2956, 1712, 1676, 1639, 1609, 1440, 1334, 1255, 1125. HRMS (ESI)
calculated for C14H16DO6 [M+H]+ 282.1082, found 282.1079.
(±)- (2S,2aR,2a1S,5R,5aR)-Dimethyl 5-(tert-butyldimethylsilyloxy)-2-methyl-2-(4-methyl-2-
oxopent-3-enyl)-2a,2a1,3,4,5,5a-hexahydro-2H-benzofuro[4,3,2-cde]chromene-7,8-
dicarboxylate (9): To a solution of 2 (99 mg, 0.14 mmol) in MeCN (10 mL) was added
tributylamine (269 mg, 1.45 mmol, 10 equiv.), formic acid (66.7 mg, 1.45 mmol, 10 equiv.) and
fac-Ir(ppy)3 (4.8 mg, 0.0072 mmol, 0.05 equiv.) in a 30 mL vial. The bright yellow solution was
degassed by passing nitrogen through the solution for a period of 45 minutes. A household
lightbulb (GE Helical 26 W) was placed ~5 cm from the reaction vial (see Figure below) and the
mixture was stirred at room temperature until TLC indicated consumption of starting material (4
hours). The mixture was poured over water and extracted with CH2Cl2 (4x). The combined
organic fraction was dried with anhydrous MgSO4 and concentrated under reduced pressure.
The 1H NMR of the crude product indicated a 2:1 mixture of diastereomers about C-7, favoring
9. The crude residue was purified by flash chromatography (EtOAc/Heptane) to afford a mixture
of 9 and C-7-epi-9 (49 mg, 60% yield as a 2:1 (9:C-7-epi-9) mixture of diastereomers) as a
colorless gum. The spectroscopic data are in full agreement with those previously reported (see
J. Am. Chem. Soc. 2013, 135, 582-585).
Dimethyl (E)-3-hydroxy-5-((6-methyl-4-oxohepta-2,5-dien-2-yl)oxy)phthalate (10): Phenol
10 (120 mg, 11% yield) was obtained from cyclization of 2 (2.10 g, 3.07 mmol scale) by the
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1
procedure described in J. Am. Chem. Soc. 2013, 135, 582-585. H NMR (400MHz, CDCl3) δ
10.89 (s, 1H), 6.72 (d, J = 2.3 Hz, 1H), 6.62 (d, J = 2.3 Hz, 1H), 5.90 - 5.87 (m, 1H), 5.51 (s,
1H), 3.93 (s, 3H), 3.89 (s, 3H), 2.45 (s, 3H), 2.15 (d, J = 1.2 Hz, 3H), 1.85 (d, J = 0.8 Hz, 3H).
13C NMR (100MHz, CDCl3) δ 189.8, 169.1, 168.9, 168.5, 163.2, 158.7, 154.9, 137.6, 126.3,
112.3, 111.0, 109.6, 106.9, 53.0, 52.8, 27.7, 20.6, 18.4. LRMS [M+H]+ 349.2. An X-ray
structure of 10 was obtained – see attached .cif file for details.
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