A nature-inspired Diels-Alder reaction facilitates construction of the bicyclo[2.2.2]octane core of andibenin B

Article abstract of DOI:10.1016/j.tet.2009.06.063

A rapid synthesis of the bicyclo[2.2.2]octane core of andibenin B via a nature-inspired intramolecular [4+2] cycloaddition is described. This cycloaddition permits the construction of a sterically congested bicycle and simultaneously establishes three new

Full text of DOI:10.1016/j.tet.2009.06.063

Tetrahedron 65 (2009) 6739–6745
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A nature-inspired Diels–Alder reaction facilitates construction
of the bicyclo[2.2.2]octane core of andibenin B
*
Jillian E. Spangler, Erik J. Sorensen
Frick Chemical Laboratory, Princeton University, Princeton, NJ 08544-1009, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 June 2009
Received in revised form 15 June 2009
Accepted 16 June 2009
Available online 21 June 2009
A rapid synthesis of the bicyclo[2.2.2]octane core of andibenin B via a nature-inspired intramolecular
[4þ2] cycloaddition is described. This cycloaddition permits the construction of a sterically congested
bicycle and simultaneously establishes three new all-carbon quaternary stereogenic centers in a highly
efficient fashion.
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated with respect and admiration to
Professor Larry Overman
1. Introduction
In 1976, Dunn and co-workers published the crystallographic
structure of a novel metabolite, andibenin B (1) (Fig. 1), isolated
from the static cultures of Aspergillus variecolor.1 Subsequent
studies showed this compound to be a member of a small family of
C25 meroterpenoids that includes andibenins A–C and andilesins
A–C (Fig. 2).2 The polycyclic architecture of andibenin B includes
a congested bicyclo[2.2.2]octane core with a fused tetrasubsituted
cyclohexane ring and a pendant spiro-d-lactone. In addition,
andibenin B has seven fully substituted carbons and seven stereo-
genic centers, six of which are contiguous. The structure contains
a total of five all-carbon quaternary stereogenic centers, three of
which are contiguous and four of which are densely arrayed on the
bicyclo[2.2.2]octane core.
While these intricate structures have been known for over thirty
years, there have been no published efforts towards the total syn-
thesis of any of the members of this family of complex natural
products. The complex cyclic topology and dense array of stereogenic
Figure 2. The andibenin family of meroterpenoids.
centers of andibenin B and its relatives piqued our interest in these
compounds as objectives for research in chemical synthesis. Our
rapid synthesis of the bicyclo[2.2.2]octane core of andibenin B
through a biomimetic Diels–Alder reaction is the focus of this article.
2. Concept for synthesis
Our synthetic route towards andibenin B was inspired by the
proposed biosynthesis of this family of natural products (Scheme 1).
During several decades of research, Simpson and co-workers de-
termined via labeling and feeding studies that andibenin B is of
mixed polyketide and terpenoid origins.3,4 The proposed precursor
to this family of natural products is cyclohexadienone 7, an
Figure 1. The molecular architecture of andibenin B (1).
* Corresponding author.
E-mail address: ejs@princeton.edu (E.J. Sorensen).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.063

6740
J.E. Spangler, E.J. Sorensen / Tetrahedron 65 (2009) 6739–6745
Scheme 1. Proposed biosynthesis of andibenin B (1) featuring an intramolecular [4þ2] cycloaddition.
intermediate that would arise by the alkylative dearomatization of
dimethylorsellinic acid with farnesyl pyrophosphate. A subsequent
epoxide-initiated cyclization of polyene 7 would generate triene 8,
which is proposed to undergo an intramolecular [4þ2] cycloaddi-
tion to generate the bicyclo[2.2.2]octane core of the andibenins.
Subsequent oxidative rearrangements would transform polycycle 9
into andibenin B.
as 10,5 in intramolecular [4þ2] cycloadditions to generate sterically
congested bicyclo[2.2.2]octane structures.6 Their efforts enhanced
our confidence in the potential success of this synthetic strategy.
3. Results and discussion
This provocative biosynthetic hypothesis prompted us to in-
vestigate a synthesis of the sterically congested pentacyclic core of
andibenin B featuring an intramolecular Diels–Alder reaction
(Scheme 2). To confidently judge the feasibility of this attractive
concept, we set out to evaluate the internal cycloaddition that
would transform allylic alcohol 11 into the isomeric polycycle 12. If
successful, this transformation would establish three new all-car-
bon quaternary stereogenic centers and the signature architectural
feature of the andibenin family of meroterpenoids. We surmised
that the resultant secondary alcohol of compound 12 could provide
a functional handle for subsequent formation of the fused cyclo-
We initiated our effort with a synthesis of the polyfunctional
aldehyde 10 from 2,6-dimethylbenzoquinone (13) (Scheme 3). The
Lewis acid-mediated Diels–Alder union of 13 and acetoxy-1,3-bu-
tadiene in the presence of a stoichiometric amount of BF3 Et2O
C
provided bicycle 14 in excellent yield as a single regio- and di-
astereoisomer; this construction established the first of four qua-
ternary stereogenic centers. Unfortunately, all attempts to
deprotect the allylic acetate 14 were undermined by its propensity
to undergo rapid b-elimination. However, a site- and face-selective
oxidation to diol 15 was accomplished using the method described
by Pleikter and co-workers.7 Dihydroxylation of 14 using 0.25 mol %
RuCl3 furnished diol 15 in good yield as a single diastereoisomer.
Subsequent methanolysis of the acetate group then proceeded in
excellent yield to provide triol 16.
hexane ring and pendant spiro-d-lactone. Studies by Danishefsky
and co-workers en route to a total synthesis of (þ/ꢀ)-tashironin
demonstrated the high reactivity of cyclohexa-2,4-dienones, such
Scheme 2. A planned construction of the bicyclo[2.2.2]octane substructure of andibenin B (1) featuring a nature-inspired Diels–Alder reaction.

J.E. Spangler, E.J. Sorensen / Tetrahedron 65 (2009) 6739–6745
6741
Scheme 3. Synthesis of bicyclic lactol 18 from 2,6-dimethylbenzoquinone (13).
With triol 16 in hand, we next sought to perform a tandem
oxidative cleavage to excise the superfluous carbon from the sys-
tem. After extensive screening, it was found that anhydrous and
mildly acidic conditions were necessary to achieve this desired
transformation. Sodium periodate bound to silica gel8 proved to be
uniquely effective, providing the desired dialdehyde in good yield
as a mixture of tautomers 17 and 18.
that treatment with triflic anhydride in the presence of a hindered
pyridine base cleanly provided dialdehyde triflate 20. While this
compound was prone to facile decomposition, we found that 20
could be regioselectively reduced in situ by quenching the triflation
with a bulky aluminum hydride source, lithium tris[(3-ethyl-3-
pentyl)oxy]aluminohydride (LTEPA).10 This delicate tandem re-
action sequence provided the stable lactol 21 as an inseparable
mixture of diastereoisomers. Interestingly, reduction of dialdehyde
20 after aqueous workup provided the diol (resulting from bis-re-
duction of the dialdehyde) as the major product.
We anticipated that lactol 18 would be particularly nucleophillic
0
at the C7 carbonyl due to electronic donation from the vinylogous
ester and, therefore, reasoned that conversion of our tautomeric
mixture (17þ18) exclusively into the lactol form would permit
Subsequent carbonylation of triflate 21 was successful using
10 mol % PdCl2(dppf) under an atmosphere of carbon monoxide.
Without an alcoholic additive we observed extensive de-
composition and minimal formation of lactone 10. The addition of
a regioselective triflation of the C7 ketone (Scheme 4).9 Fortu-
0
itously, we found that treatment of the mixture of 17 and 18 with
chlorotriethylsilane and 2,6-lutidine provided silyl lactol 19 as
a single diastereoisomer in excellent yield. We then examined the
reactivity of 19 towards electrophillic triflating reagents and found
0
methanol provided the C7 methyl ester (with the lactol intact) as
the major product. Although this compound could be subsequently
Scheme 4. Synthesis of 10 via a palladium-mediated carbonylative lactone formation. Tf2O¼trifluoromethane sulfonic anhydride; DTBMP¼2,6-di-tert-butyl-4-methylpyridine;
LTEPA¼lithium tris[(3-ethyl-3-pentyl)oxy]aluminohydride; dppf¼1,10-bis(diphenylphosphino)ferrocene.

6742
J.E. Spangler, E.J. Sorensen / Tetrahedron 65 (2009) 6739–6745
Scheme 5. Synthesis of polycycle 25 via an intramolecular Diels–Alder cycloaddition. DMP¼Dess–Martin periodinane.
converted into 10, the strongly basic conditions required for the
lactonization provided the lactone 10 in low yield over two steps.
Fortunately we achieved a one-pot carbonylative lactone formation
by the use of phenol as our alcohol additive, providing lactone 10 in
good yield. We suspect that intermediacy of a reactive phenyl ester
correlations, as indicated in Figure 3. Gratifyingly, the 13C chemical
shifts and NOE correlations observed for cycloadducts 24a and 24b
correspond closely to those observed for the bicyclo[2.2.2]octane
core of andibenin B (1).3b
Interestingly, only the major epimer from the carbonyl addition
(22) appeared to provide a regioisomeric mixture of products;
formation of the fourth possible product of our cycloaddition was
not observed. The regioisomeric cycloadducts formed in this re-
action were separated by preparative thin layer chromatography to
provide regioisomer 24 as a mixture of diastereoisomers. Sub-
sequent oxidation of 24a and 24b with Dess–Martin periodinane
(DMP) proceeded in good yield to provide ketone 25, verifying that
the carbinols (24a and 24b) were only diastereomeric at the alco-
hol-bearing stereogenic center.
likely facilitated formation of the desired
g-butenolide under
mildly basic conditions to provide lactone 10 in good yield.
With aldehyde 10 in hand we were poised to append a dien-
ophile and test the feasibility of our pivotal intramolecular Diels–
Alder cycloaddition. Treatment of aldehyde 10 with isopropenyl-
magnesium bromide provided allylic alcohol 22 in modest yield as
an inseparable mixture of diastereoisomers (Scheme 5).11 Sub-
sequent heating of the epimeric mixture of carbinols to 80 ꢁC in
toluene for five days induced our desired Diels–Alder cycloaddition.
While the isolated yield of this reaction was high, we were disap-
pointed to find that the major diastereoisomer of allylic alcohol 22
provided both possible Diels–Alder regioisomers in a 1:1.8 ratio
(23/24a), marginally favoring the desired regioisomer 24a.12 Regio-
and stereochemical assignments were elucidated by NOE
0
Comparison of the chemical shifts of the C6 vinylic protons of 23
0
0
and 24 (Scheme 6) indicated that the C6 –C7 olefin of our undesired
regioisomer (23) was in limited conjugation with the adjacent
g
-butyrolactone,13 suggesting that 24 could be the thermodynam-
ically preferred regioisomer of our cycloaddition. Our hypothesis
Figure 3. NOE correlations observed for cycloadducts 23, 24a, and 24b.

J.E. Spangler, E.J. Sorensen / Tetrahedron 65 (2009) 6739–6745
6743
was confirmed by heating regioisomer 23 at reflux in toluene for
five days, providing a 10:1 ratio of 24a and 23, strongly favoring our
desired regioisomer. In contrast, no reactivity was observed when
23 was heated for an extended period of time at 80–100 ꢁC, sug-
gesting an elevated temperature requirement for the retro-Diels–
Alder reaction necessary for equilibration of our cycloadducts.
When 24a was heated under identical conditions (toluene, 110 ꢁC, 5
days), no equilibration was observed.
plates (60 F254) using UV light as a visualizing agent and aqueous
ceric sulfate/phosphomolybdic acid and heat as developing agents.
E. Merck silica gel 60 (230–400 mesh) was used for flash column
chromatography. Analtech silica gel GF with UV254 were used for
analytic purification. Instrumentation: FTIR spectra were obtained
on a Perkin–Elmer Paragon 500 FT-IR (film) or a Perkin–Elmer
spectrum 100 FT-IR (neat) and are reported inwavenumbers (cmꢀ1).
NMR spectra were obtained on
a
Bruker-500 spectrometer
values inppm
(500 MHz/125 MHz). Chemical shifts are reported as
d
referenced to the residual solvent peak. The multiplicities are ab-
breviated as follows: s (single), d (doublet), t (triplet), q (quartet), m
(multiplet), br (broad singlet), ap (apparent). High resolution mass
spectra were obtained on an Agilent ESI-TOF mass spectrometer.
5.1.1. Diels–Alder adduct 14
2,6-Dimethylbenzoquinone (13) (1.0 g, 7.35 mmol, 1.0 equiv)
was dissolved in toluene (70 ml) and cooled to 0 ꢁC with an ice
bath. 1-Acetoxy-1,3-butadiene (2.2 ml, 18.37 mmol, 2.5 equiv) was
added slowly followed by dropwise addition of BF3$OEt2 (0.9 ml,
7.35 mmol, 1.0 equiv). The resultant solution was stirred vigorously
for 90 min at 0 ꢁC before quenching with 1.0 M pH 7 phosphate
buffer (5 ml). The biphasic solution was filtered and poured into
a 250 mL separatory funnel containing 60 mL phosphate buffer and
Scheme 6. Thermal equilibration of cycloadducts 23 and 24a.
In light of this result, we performed the cycloaddition of allylic
alcohol 22 at elevated temperatures (Table 1). We were pleased to
find that the regioselectivity improved significantly when the re-
action was conducted at 120 ꢁC.14
Table 1
Regioselectivity of [4þ2] cycloaddition as a function of reaction temperature
Entry
Temperature
% Yield (23þ24aþ24b)
Ratio (23:24a)
1
2
3
80
100
120
87
85
87
1:1.8
1:2.5
1:8.6
4. Conclusion
100 mL diethyl ether. The organic layer was separated and the
aqueous phase was extracted with 100 mL diethyl ether. The
combined organic extracts were dried over anhydrous Na2SO4, fil-
tered, and the solvent removed under reduced pressure. The re-
sultant white solid was purified by flash chromatography (SiO2,
1:9/1:3 acetone/hexanes) to give 1.84 g of 14 as a white solid
(98%), mp 96–98 ꢁC. TLC: Rf¼0.40 (SiO2, 1:5 acetone/hexanes); IR
(film) 1741, 1695, 1677, 1262, 1234 cmꢀ1; 1H NMR (500 MHz, CDCl3)
We have rapidly constructed the bicyclo[2.2.2]octane core of
andibenin B (1) in 10 steps and 14% overall yield from 2,6-dimethyl-
benzoquinone. The high yield and regioselectivity of the key
intramolecular [4þ2] cycloaddition, in which we simultaneously
construct three of the five all-carbon quaternary stereogenic cen-
ters in andibenin B, provides a sound basis for our planned syn-
thesis of andibenin B featuring this nature-inspired pericyclic
reaction. Efforts to extend this chemistry into a concise total syn-
thesis of andibenin B are currently underway and will be described
in due course.
d
6.60 (s,1H), 6.00 (ddd, J¼10.1, 4.7, 2.9 Hz,1H), 5.89 (ddd, J¼6.9, 4.6,
2.2 Hz, 1H), 5.38 (dd, J¼4.7, 4.7 Hz, 1H), 3.17 (dd, 1H), 3.06 (d,
J¼4.7 Hz, 1H), 2.07 (s, 3H), 1.84 (m, 4H), 1.38 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 194.7, 192.3, 163.3, 144.0,130.7,125.6, 116.7, 61.0,
51.1, 39.4, 25.1, 23.0, 14.9, 11.1; HRMS (ESI-TOF) C14H16O4 m/z calcd
5. Experimental
5.1. General
for [MþNa]þ: 271.0941; found: 271.0944.
5.1.2. Diol 15
Dihydroxylation was performed according to the procedure of
Pleitker.7 50 mL round-bottom flask equipped with a magnetic stir
bar was charged with NaIO4 (642 mg, 3 mmol, 1.5 equiv). H2O
(1.55 mL) and a solution of 2 N H2SO4 (0.4 mL, 0.4 mmol, 0.2 equiv)
were added sequentially and the resultant slurry was heated gently
until all solids were dissolved. The solution was cooled to 0 ꢁC with
an ice bath and an aqueous solution of RuCl3$xH2O (0.1 M,
0.050 mL, 0.005 mmol, 0.0025 equiv) was added dropwise. The
bright yellow solution was stirred at 0 ꢁC for 5 min. EtOAc (6 mL)
was added and the biphasic solution was stirred vigorously for
Unless otherwise noted, all reactions were carried out under an
atmosphere of argon. Tetrahydrofuran (THF), toluene, diethyl ether,
methylene chloride (CH2Cl2), and acetonitrile (CH3CN) were dried
by passing through activated alumina columns. Commercial re-
agents of high purity were purchased and used without further
purification with the following exceptions: Triethylamine, triethyl-
chlorosilane, lutidene were distilled from calcium hydride at at-
mospheric pressure. Reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25 mm Merck silica gel

6744
J.E. Spangler, E.J. Sorensen / Tetrahedron 65 (2009) 6739–6745
5 min. CH3CN (6 mL) was added and stirring was continued for
further 5 min. Diels–Alder adduct 14 (498 mg, 2.0 mmol,
5.54H), 1.90 (dd, J¼13.8, 10.5 Hz, 1.24H), 1.51 (s, 1.61H), 1.43 (s,
3.76H), 1.35 (s, 3.01H); 13C NMR (125 MHz, CHCl3)
200.9, 192.0,
a
d
1.0 equiv) was then added as a single portion and the resultant
slurry was stirred vigorously for 2 min. The biphasic reaction
mixture was poured into a 125 mL separatory funnel containing
EtOAc (40 mL), saturated aqueous NaHCO3 (18 mL), and saturated
aqueous Na2S2O3 solution (20 mL). The layers were separated and
the aqueous layer was extracted with EtOAc (5ꢂ40 mL). The com-
bined organic extracts were dried over anhydrous Na2SO4, filtered,
and the solvent removed under reduced pressure. Purification by
flash chromatography (SiO2, 1:4/1:1 acetone/hexanes) provided
530 mg of 15 as a white solid (82%), mp 186–90 ꢁC. TLC: Rf¼0.40
(SiO2, 1:2 EtOAc/hexane); IR (film) 3458, 1729, 1668, 1376,
198.0, 185.5, 184.9, 184.3, 182.78, 173.1, 151.2, 149.2, 147.9, 147.7,
145.6, 138.9, 138.6, 135.9, 116.2, 115.9, 115.5, 110.2, 94.5, 93.7, 54.2,
44.5, 44.2, 35.8, 32.0, 29.1, 28.4, 27.5, 17.0, 16.9, 16.7; HRMS (ESI-
TOF) C11H12O4 m/z calcd for [MþH]þ: 209.0808; found: 209.0808.
5.1.5. Silyl lactol 19
To a slurry of dialdehyde 17/18 (1.0 g, 4.8 mmol, 1.0 equiv) in dry
CH2Cl2 (12 mL) was added freshly distilled 2,6-lutidene (1.29 g,
12 mmol, 3.0 equiv) at which point all solids went into solution.
Freshly distilled triethylchlorosilane (1.5 g, 9.6 mmol, 2.5 equiv)
was added resulting in the immediate formation of a white pre-
cipitate. The reaction was stirred for 24 h at room temperature,
diluted with diethyl ether (150 mL) and washed with ice cold sat-
urated aqueous NaHCO3 (2ꢂ25 mL). The organic layer was dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The resultant yellow oil was dried by azeotropic distillation from
toluene (3ꢂ100 mL), and placed under high vacuum (0.25 Torr) for
48 h to remove lutidene. Subsequent purification by flash chro-
matography (Florasil, 1:9 Et2O/hexanes) provided 1.58 g (98%) of 19
as a bright yellow oil. TLC: Rf¼0.15 (SiO2,1:9 diethyl ether/hexanes);
1223 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
6.58 (s,1H), 5.24 (dd, J¼3.3,
3.3 Hz, 1H), 3.94 (br, 2H), 3.11 (d, J¼2.3 Hz, 1H), 2.48 (dd, J¼5.3,
13.0 Hz, 1H), 2.34 (s, 1H, exchanges with D2O), 2.04 (s, 3H), 1.89 (br,
1H, exchanges with D2O), 1.84 (s, 3H), 1.47 (dd, J¼12.8, 11.8 Hz, 1H),
1.29 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 201.0, 198.5, 168.7, 150.1,
137.1, 73.5, 68.4, 64.9, 54.3, 47.3, 34.1, 29.2, 20.6, 17.0; HRMS (ESI-
TOF) C14H18O6 m/z calcd for [MþH]þ: 283.1176; found: 283.1182.
5.1.3. Triol 16
A slurry of diol 15 (415 mg, 1.47 mmol, 1.0 equiv) in anhydrous
MeOH (60 mL) was cooled to 0 ꢁC with an ice bath. Anhydrous
K2CO3 (228 mg, 1.65 mmol, 1.1 equiv) was added in a single portion
and the deep red reaction solution was stirred vigorously for
90 min at the same temperature. The reaction mixture was diluted
with ice water (300 mL) and exhaustively extracted (15ꢂ300 mL,
3:7 2-propanol/CHCl3). The combined organic extracts were dried
over anhydrous Na2SO4, filtered, and the solvent removed under
reduced pressure. The resultant white foam can be taken on to the
next step without further purification. An analytical sample is
prepared by flash chromatography (SiO2, 3:2 acetone/hexanes) to
provide 350 mg of 16 as a white solid (99%), mp 188–192 ꢁC. TLC:
Rf¼0.13 (SiO2, 1:1 acetone/hexane); IR (neat) 3352.2, 1688, 1655,
IR (film) 1691, 1666, 1593, 1210, 1167, 1133, 1104 cmꢀ1
;
1H NMR
(500 MHz, CDCl3)
d
7.38 (s, 1H), 6.64 (s, 1H), 5.48 (dd, J¼2.2, 10.1 Hz,
1H), 2.21 (dd, J¼2.2, 14.0 Hz, 1H), 2.03 (s, 3H), 1.93 (dd, J¼10.1,
14.0 Hz, 1H), 1.42 (s, 3H), 0.96 (m, 9H), 0.75–0.62 (m, 6H); 13C NMR
(125 MHz, CHCl3) d 200.3, 185.2, 151.6, 147.8, 138.9, 115.5, 95.0, 44.6,
37.1, 29.2, 17.0, 6.6, 4.8; HRMS (ESI-TOF) C17H26O4Si m/z calcd for
[MþH]þ: 323.1673; found: 323.1679.
5.1.6. Lactol triflate 21
A solution of silyl lactol 19 (1.54 g, 4.8 mmol, 1.0 equiv) and 2,6-
di-tert-butyl-4-methylpyridine (1.5 g, 7.3 mmol, 1.5 equiv) in
CH2Cl2 (48 mL) was cooled to ꢀ50 ꢁC and treated dropwise with
Tf2O (1.52 g, 5.4 mmol, 1.1 equiv). The reaction was then allowed to
warm slowly to ꢀ35 ꢁC over 1 h, stirred an additional 30 min at this
temperature, and then cooled to ꢀ78 ꢁC. The cold reaction mixture
was diluted by rapid cannulation into a flask containing an addi-
tional 450 mL of CH2Cl2 precooled to ꢀ78 ꢁC. A solution of lithium
tris[(3-ethyl-3-pentyl)oxy]aluminohydride (0.5 M in THF, 19.2 mL,
9.6 mmol, 2.0 equiv) was then added slowly by syringe pump ad-
dition over 12 h at ꢀ78 ꢁC. The reaction was quenched by the ad-
dition of 1 M pH 7 phosphate buffer (50 mL). The resultant biphasic
mixture was poured into a 1 L seperatory funnel and the layers
were separated. The aqueous layer was extracted with CH2Cl2
(50 mL). The combined organics were dried over anhydrous Na2SO4
and concentrated under reduced pressure. Purification by flash
chromatograpy (SiO2, 1:19/1:9 acetone/hexanes) provided 1.07 g
(66%) of 21 as a pale yellow oil as a 1.2:1 mixture of lactol di-
astereoisomers. TLC: Rf¼0.57 (SiO2, 1:2 EtOAc/hexanes); IR (film)
1632, 1058, 1026 cmꢀ1; 1H NMR (500 MHz, DMSO-d6)
d 6.59 (s, 1H),
5.17 (d, J¼3.7 Hz, 1H, exchanges with D2O), 4.90–4.72 (br, 1H, ex-
changes with D2O), 4.59–4.24 (br, 1H, exchanges with D2O), 3.76 (d,
J¼3.2 Hz, 1H), 3.72–3.65 (m, 1H), 3.55 (s, 1H), 2.71 (d, J¼2.6 Hz, 1H),
2.07 (dd, J¼4.6, 12.3 Hz, 1H), 1.90 (s, 3H), 1.30 (ap t, J¼12.3 Hz, 1H),
1.10 (s, 3H); 13C NMR (125 MHz, DMSO-d6)
d 201.4, 201.2, 149.9,
137.2, 73.0, 71.1, 63.2, 56.6, 46.2, 34.2, 29.1, 16.5; HRMS (ESI-TOF)
C12H16
O
5 m/z calcd for [MþH]þ: 241.1071; found: 241.1073.
5.1.4. Dialdehyde 17/18
To a vigorously stirred slurry of triol 16 (3.54 g, 14.75 mmol,
1.0 equiv) in 300 mL dry CH2Cl2 was added silica-bound NaIO4
(prepared according the procedure of Zhong and Shing8) (88.5 g,
88.5 mmol, 6.0 equiv) in a single portion. The slurry was stirred
vigorously for 6 h with formation of a bright yellow coloration. The
reaction was then filtered over a coarse fritted glass funnel. The
solid was washed with dry CH2Cl2 (3ꢂ300 mL) and the combined
filtrate was concentrated under reduced pressure. The resultant
yellow foam was dissolved in diethyl ether and concentrated under
reduced pressure to provide the desired compound as a bright
yellow solid which could be used crude for the next transformation
or purified by recrystallization from diethyl ether to provide 2.31 g
(75%) of the desired product as bright yellow crystals as a 1:2.2:2.7
mixture of tautomeric forms. Mp 96–98 ꢁC. IR (film) 2284, 1684,
1683, 1654, 1420, 1216, 1139 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 7.19
(s, 1.00H), 7.09 (s, 0.20H), 5.31 (d, J¼17.6 Hz, 1.01H), 5.04 (d,
J¼17.7 Hz, 0.23H), 4.95 (d, J¼17.7 Hz, 0.20H), 4.91 (s, 2.35H), 4.82 (s,
1.26H), 3.85 (s, 1.25H), 2.60 (dd, J¼14.2, 10.1 Hz, 0.22H), 2.51 (d,
J¼14.1 Hz, 1.00H), 2.01 (d, J¼4.2 Hz, 3.77H), 1.95 (d, J¼17.1 Hz,
0.33H), 1.81 (dd, J¼14.2, 9.7 Hz, 1.00H), 1.71 (s, 3.88H), 1.39 (s,
0.71H), 1.37 (s, 3.00H); 13C NMR (126 MHz, CHCl3)
d 202.69, 201.68,
138.09, 137.05, 136.03, 135.94, 135.65, 135.39, 132.97, 132.89, 118.4
(q, J¼320.4 Hz), 118.36 (q, J¼320.3 Hz), 92.9, 92.0, 59.4, 53.5, 48.2,
46.8, 39.3, 36.7, 26.7, 25.1, 15.6, 15.5; HRMS (ESI-TOF) C12H13F3O6S
m/z calcd for [MþH]þ: 343.0458; found: 343.0457.
1653, 1577; 1H NMR (500 MHz, CHCl3)
d
14.69 (d, J¼3.2 Hz, 0.96H),
9.49 (s, 0.95H), 8.86 (d, J¼3.1 Hz, 0.97H), 7.39 (s, 1.14H), 7.37 (s,
0.46H), 6.88 (d, J¼1.3 Hz, 0.99H), 6.70–6.62 (m, 1.69H), 5.76 (t,
J¼2.8 Hz, 0.46H), 5.51 (ddd, J¼10.1, 7.5, 2.3 Hz, 1.24H), 3.51 (d,
J¼18.7 Hz, 1.00H), 3.41 (d, J¼7.6 Hz, 1.13H), 3.30–3.23 (m, 0.46H),
3.15 (d, J¼18.6 Hz, 1.00H), 2.37 (dd, J¼13.9, 2.5 Hz, 1.25H), 2.29 (dd,
J¼14.7, 1.3 Hz, 0.48H), 2.07 (d, J¼1.3 Hz, 3.29H), 2.06–2.01 (m,
5.1.7. Aldehyde 10
To a flask charged with lactol 21 (165 mg, 0.48 mmol, 1.0 equiv)
was added PdCl2(dppf) (45 mg, 0.048 mmol, 0.1 equiv) and phenol
(45 mg, 0.48 mmol, 1.0 equiv). The flask was evacuated and refilled

J.E. Spangler, E.J. Sorensen / Tetrahedron 65 (2009) 6739–6745
6745
three times with a balloon of carbon monoxide. 5 mL of CH3CN
(degassed 20 min with a balloon of carbon monoxide) was added
followed by dropwise addition of NEt3 (0.135 mL, 0.96 mmol,
2.0 equiv). The reaction was heated to 60 ꢁC for 90 min under
a balloon pressure of carbon monoxide and then cooled to room
temperature. Silica gel (2 g) was added and the solvent was re-
moved under reduced pressure. Purified by flash chromatography
(SiO2, 1:9/1:6/1:4 acetone/hexanes) to provide 86 mg (77%) of
10 as an off-white solid. TLC: Rf¼0.14 (SiO2, 1:3 EtOAc/hexanes); IR
(film) 1734, 1683, 1654, 1420, 1215, 1139 cmꢀ1; 1H NMR (500 MHz,
51.2, 50.2, 49.0, 43.7, 36.5, 21.8, 18.8, 17.0; HRMS (ESI-TOF) C15H18O4
m/z calcd for [MþH]þ: 263.1278; found: 263.1277. 23. TLC: Rf¼0.25
(SiO2, 1:3:6 MeOH/EtOAc/hexanes); IR (film) 3482, 1733,
1652 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 6.49 (s, 1H), 4.60 (d,
J¼10.3 Hz, 1H), 4.30 (d, J¼10.3 Hz, 1H), 3.89–3.78 (m, 1H), 2.20
(d, J¼14.5 Hz, 1H), 1.92 (d, J¼12.0 Hz, 1H), 1.54 (s, 3H), 1.42 (d,
J¼14.5 Hz, 1H), 1.37 (d, J¼12.1 Hz, 1H), 1.16–1.08 (m, 6H); 13C NMR
(125 MHz, CDCl3)
d 211.1, 166.0, 141.3, 137.3, 74.4, 71.6, 58.1, 48.5,
47.4, 43.8, 41.8, 40.3, 20.4, 17.0, 15.4; HRMS (ESI-TOF) C15H18O4 m/z
calcd for [MþH]þ: 263.1278; found: 263.1278.
CDCl3)
4.60 (d, J¼18.0 Hz, 1H), 3.61 (d, J¼18.9 Hz, 1H), 2.79 (d, J¼18.9 Hz,
1H), 1.97 (s, 3H), 1.26 (s, 3H); 13C NMR (125 MHz, CHCl3)
202.1,
d
9.51 (s, 1H), 7.12 (d, J¼1.4 Hz, 1H), 4.79 (d, J¼18.0 Hz, 1H),
5.1.10. Polycyclic diketone 25
d
Anhydrous NaHCO3 (16 mg, 0.19 mmol, 3.0 equiv) was added to
a solution of 24a and 24b (3:1 ratio) (16.6 mg, 0.063 mmol,
1.0 equiv) in CH2Cl2 (5.0 mL). Dess–Martin periodinane (67 mg,
0.16 mmol, 2.5 equiv) was added in a single portion and the re-
sultant heterogeneous mixture was stirred vigorously for 1 h. The
reaction was poured into a separatory funnel, diluted with CH2Cl2
(5 mL), and washed sequentially with saturated aqueous NaHCO3
(2 mL) and saturated aqueous Na2S2O3 (2 mL). The organic layer
was dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography (SiO2,
1:3 EtOAc/hexanes) to give 14.9 mg (92%) of 25 as a clear oil. TLC:
Rf¼0.14 (SiO2, 1:3 EtOAc/hexanes); IR (film) 1766, 1747, 1726, 1662,
197.9, 170.6, 169.2, 135.4, 129.5, 121.5, 68.8, 52.4, 47.2, 25.9, 16.6;
HRMS (ESI-TOF) C12H12O4 m/z calcd for [MþCH3]þ: 235.0965;
found: 235.0962.
5.1.8. Allylic alcohol 22
A solution of aldehyde 10 (55 mg, 0.25 mmol, 1.0 equiv) in THF
(2.5 mL) was cooled to ꢀ78 ꢁC and isopropenylmagnesium bromide
(0.5 M in THF, 0.55 mL, 0.275 mmol, 1.1 equiv) was added dropwise.
The yellow solution was stirred for 1 h at this temperature and then
quenched with saturated aqueous NH4Cl (1 mL). The biphasic so-
lution was allowed to warm to room temperature and poured into
a separatory funnel diluted with diethyl ether (10 mL). The layers
were separated and the organic layer was dried over anhydrous
Na2SO4 and concentrated under reduced pressure to a yellow oil.
The residue was purified by flash chromatography (SiO2, 1:6 ace-
tone/hexanes) to provided 35.5 mg (55%) of 22 as a clear oil as
a 4.8:1 mixture of alcohol diastereoisomers. TLC: Rf¼0.43 (SiO2, 1:3
1453, 1352 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.10 (s, 1H), 4.53 (d,
J¼10.7 Hz, 1H), 4.45 (d, J¼10.7 Hz, 1H), 2.52 (d, J¼19.5 Hz, 1H), 2.14
(d, J¼19.5 Hz, 1H), 1.72 (d, J¼14.1 Hz, 1H), 1.44 (d, J¼14.1 Hz, 1H),
1.38 (s, 3H), 1.27 (s, 3H), 1.15 (s, 3H); 13C NMR (125 MHz, CHCl3)
d
213.4, 210.6, 165.1, 139.8, 132.0, 65.7, 56.2, 54.1, 50.1, 47.3, 45.5,
42.7, 17.2, 16.6, 15.9; HRMS (ESI-TOF) C15H16O4 m/z calcd for
[MþH]þ 261.1121; found 261.1128.
EtOAc/hexanes); IR (film) 3520, 1740, 1730, 1722 cmꢀ1
(500 MHz, CDCl3)
;
1H NMR
d
7.19 (s, 1.00H), 7.09 (s, 0.20H), 5.31 (d, J¼17.6 Hz,
1.01H), 5.04 (d, J¼17.7 Hz, 0.23H), 4.95 (d, J¼17.7 Hz, 0.20H), 4.91 (s,
2.35H), 4.82 (s, 1.26H), 3.85 (s, 1.25H), 2.60 (dd, J¼14.2, 10.1 Hz,
0.22H), 2.51 (d, J¼14.1 Hz, 1.00H), 2.01 (d, J¼4.2 Hz, 3.77H), 1.95 (d,
J¼17.1 Hz, 0.33H), 1.81 (dd, J¼14.2, 9.7 Hz, 1.00H), 1.71 (s, 3.88H),
Acknowledgements
We gratefully acknowledge NIGMS (GM065483), Princeton
University, the Merck Research Laboratories, and Boehringer-
Ingelheim, and a predoctoral fellowship from the National Science
Foundation (J.E.S.) for supporting this work.
1.39 (s, 0.71H), 1.37 (s, 3.00H); 13C NMR (125 MHz, CHCl3)
d 206.2,
203.4, 173.7, 171.1, 169.6, 169.3, 147.4, 146.8, 136.1, 134.6, 129.9, 127.6,
119.5, 115.7, 111.5, 110.9, 73.5, 73.2, 70.0, 69.4, 51.4, 50.2, 45.9, 44.4,
27.7, 26.4, 18.2, 17.7, 16.5, 16.1; HRMS (ESI-TOF) C15H18O4 m/z calcd
for [MþH]þ: 263.1278; found: 263.1276.
References and notes
1. Dunn, A. W.; Johnstone, R. W.; Sklarz, B. J. Chem. Soc., Chem. Commun. 1976, 270.
2. (a) Dunn, A. W.; Johnstone, R. A. W.; Sklarz, B.; Lessinger, L.; King, T. J. J. Chem.
Soc., Chem. Commun. 1978, 533–534; (b) Dunn, A. W.; Johnstone, R. W. J. Chem.
Soc., Perkin Trans. 1 1979, 2113–2117; (c) Simpson, T. J. J. Chem. Soc., Perkin Trans.
1 1979, 2118–2121.
3. For a review on the biosynthesis of the andibenin family of natural products
see: (a) Simpson, T. J. Chem. Soc. Rev. 1975, 4, 497–522; (b) Simpson, T. J.;
Ahmed, S. A.; McIntyre, R.; Scott, F. E.; Sadler, I. H. Tetrahedron 1997, 53, 4013–
4034; (c) Simpson, T. J. Top. Curr. Chem. 1998, 195, 1–48.
4. (a) Holker, J. S. E.; Simpson, T. J. J. Chem. Soc., Chem. Commun. 1978, 626–627; (b)
McIntyre, C. R.; Simpson, T. J.; Moore, R. N.; Trimble, L. A.; Vederas, J. C. J. Chem.
Soc., Chem. Commun. 1984, 1498–1499; (c) Bartlett, A. J.; Holker, J. S. E.; O’Brien,
E. J. Chem. Soc., Chem. Commun. 1981, 1198–1200.
5. Danishefsky and co-workers synthesized cyclohexa-2,4-dienones by the re-
gioselective oxidative dearomatization of orthoquinones with phenyliodine(III)
diacetate.
5.1.9. Cycloadducts 23 and 24
Allylic alcohol 22 (25.2 mg, 0.0962 mmol, 1.0 equiv) was dis-
solved in toluene (2 mL) and heated to 80 ꢁC in a sealed vial under
an atmosphere of argon for five days. The reaction was cooled to
room temperature and concentrated under reduced pressure. Pu-
rification by column chromatography (SiO2, 1:3/2:3 EtOAc/hex-
anes) provided 21.9 mg (87%) of the desired cycloadducts as
a mixture of products (23/24a/24b¼1.0:1.8:0.6). Analytical samples
were obtained by preparatory thin layer chromatography (SiO2, 1:3
EtOAc/hexanes/4:6:1 EtOAc/hexanes/MeOH). 24b. TLC: Rf¼0.32
(SiO2, 1:3:6 MeOH/EtOAc/hexanes); IR (film) 3472, 1755, 1725, 1711,
1666 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 6.92 (s, 1H), 4.79 (d,
J¼11.2 Hz, 1H), 4.56 (d, J¼11.2 Hz, 1H), 3.92 (d, J¼6.5 Hz, 1H), 2.28
(dd, J¼15.5, 6.5 Hz, 1H), 1.63 (d, J¼15.5 Hz, 1H), 1.42 (d, J¼13.8 Hz,
1H), 1.36–1.30 (m, 4H), 1.18 (s, 3H), 1.15 (s, 3H); 13C NMR (125 MHz,
6. (a) Cook, S. P.; Gaul, C.; Danishefsky, S. J. Tetrahedron Lett. 2005, 46, 843–847; (b)
Cook, S. P.; Polara, A.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 16440–16441;
(c) Polara, A.; Cook, S. P.; Danishefsky, S. J. Tetrahedron Lett. 2008, 5906–5908.
7. Plietker, B.; Niggermann, M. Org. Lett. 2003, 5, 3353–3356.
8. Zhong, Y.; Shing, T. J. Org. Chem. 1997, 62, 2622–2624.
CDCl3)
d 213.3, 167.3, 139.1, 134.2, 79.4, 68.9, 58.4, 51.2, 51.2, 51.0,
9. Numbering corresponds to that previously assigned for the carbons in andi-
benin B.2a
46.5, 44.9, 19.2, 18.6, 17.1; HRMS (ESI-TOF) C15H18O4 m/z calcd for
[MþH]þ: 263.1278; found: 263.1276. 24a. TLC: Rf¼0.26 (SiO2, 1:3:6
10. Krishnamurthy, S. J. Org. Chem. 1981, 46, 4628–4629.
MeOH/EtOAc/hexanes); IR (film) 3477, 1760, 1726, 1662 cmꢀ1 1H
;
11. The relative stereochemistry of the major and minor diastereoisomers of allylic
alcohol 22 was deduced by the stereochemical assignments for cycloadducts 23
and 24.
NMR (500 MHz, CDCl3)
d 6.92 (s, 1H), 4.45–4.32 (m, 2H), 3.90 (dd,
12. Similar ‘twisted’ Diels–Alder adducts were also observed by Danishefsky and
J¼8.4, 5.1 Hz, 1H), 2.15 (d, J¼13.9 Hz, 1H), 2.01 (dd, J¼14.9, 10.0 Hz,
1H), 1.83 (d, J¼3.5 Hz, 1H, exchanges with D2O), 1.52 (dd, J¼14.9,
6.0 Hz, 1H), 1.32 (s, 3H), 1.04 (s, 6H), 0.91 (d, J¼13.9 Hz, 1H); 13C
co-workers during their studies en route to tashironin.6a
13. 13C shifts for these olefins also support this hypothesis. See Experimental data.
14. Heating to temperatures above 120 ꢁC led to the formation of several un-
characterized side products and reduced yield.
NMR (125 MHz, CDCl3)
d 213.1, 1667.0, 140.9, 133.2, 76.9, 67.5, 58.4,