Enantioselective total synthesis and absolute configuration of apiosporic acid

Article abstract of DOI:10.1021/jo300519g

The first total synthesis of the polyketide apiosporic acid is presented. Key steps are a Julia-Kocienski olefination, a Suzuki-Miyaura cross-coupling, and an intramolecular Diels-Alder reaction. The absolute configuration of the natural product was determined.

Full text of DOI:10.1021/jo300519g

Note
pubs.acs.org/joc
Enantioselective Total Synthesis and Absolute Configuration of
Apiosporic Acid
Martin Gartner, David Kossler, Daniel Pflasterer, and Gunter Helmchen*
̈
̈
̈
Organisch-Chemisches Institut der Ruprecht-Karls-Universitat Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg,
̈
Germany
S
* Supporting Information
ABSTRACT: The first total synthesis of the polyketide apiosporic acid is
presented. Key steps are a Julia−Kocienski olefination, a Suzuki−Miyaura cross-
coupling, and an intramolecular Diels−Alder reaction. The absolute configuration
of the natural product was determined.
ndophytic microorganisms have proven to be a rich source
of biologically active compounds.1 Some secondary
metabolites containing a trans-decalin moiety were isolated
from the marine endophytic fungus Apiospora montagnei
Saccardo (Figure 1).2,3 Apiosporamide (2) exhibits potent
Scheme 1. Retrosynthetic Analysis (Σ = Protecting Group)
E
prepared in our group via a regio- and enantioselective iridium-
catalyzed allylic alkylation.8 Alternatively, a chiral sulfone could
be employed for olefination. An issue of concern was the Z/E
selectivity of the olefination step; however, as the E,E-diene is
expected to react much faster in the Diels−Alder reaction than
any of the isomers, a marked kinetic preference for the correct
bicyclic product was foreseen. As a protecting group, trityl was
chosen as this was expected to be cleaved in situ during a Lewis
acid catalyzed Diels−Alder reaction.
The aldehyde 5, required for the Wittig-based route (Scheme
2), was prepared from ester 4 (enantiomeric purity of 97% ee)
according to our previously published procedure starting with
an iridium-catalyzed enantioselective allylic substitution.9 The
absolute configuration of ester 4 has been firmly established by
chemical correlation with quinine.10 The sulfone needed for the
Julia-based route was prepared as follows. Reduction of 4 with
DIBAL-H in THF furnished alcohol 6. This was transformed by
Mitsunobu reaction into the sulfide 7, which was subjected to
molybdenum-catalyzed oxidation with H2O2 to furnish the
phenyltetrazolylsulfone 8.
Figure 1. Polyketides isolated from Apiospora montagnei Saccardo.
antifungal and antibacterial activity, and the ketone 3 shows
cytotoxicity against HeLa S3 cell cultures.4 The related
apiosporic acid (1) was found to be inactive in antibacterial,
antifungal, and antialgal assays; cytotoxic properties were not
evaluated.3
The relative configurations displayed in Figure 1 were
determined by NMR spectroscopy. Compounds 2 and 3 have
been synthesized by Williams et al. using an ex chiral pool
approach, which allowed assignment of the absolute config-
urations.5 Here, we report the first enantioselective total
synthesis of apiosporic acid (1). By our synthesis, the
anticipated structure is confirmed, and the absolute config-
uration is established. The substitution pattern of the
cyclohexene ring suggests a synthetic strategy with an
intramolecular Diels−Alder reaction (IMDA)6 as key step
(Scheme 1).7 This has been discussed as possibility for the
biosynthesis of apiosporamide (2)2 and has also been applied in
the synthesis of apiosporamide.5
Of the two envisaged approaches to a conjugated diene,
olefination of aldehyde 5 (Table 1) constitutes the shorter
The precursor was anticipated to be accessible via hydro-
boration/Suzuki coupling at the vinyl group of the triene
described in Scheme 1. The 1,3-diene moiety was planned to be
introduced by olefination of an aldehyde, which has been
Received: March 19, 2012
© XXXX American Chemical Society
A
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Note
Scheme 2. Syntheses of the Chiral Building Blocks 5 and 8
(Σ = CPh3)
Scheme 3. Suzuki−Miyaura and Intramolecular Diels−Alder
Reactions
subsequent Suzuki coupling with methyl (2E)-3-iodoacrylate
applying Pd(dppf)Cl2/Ph3As19 as catalyst furnished ester 11 in
good yield. A short reaction time (5 min) in the hydroboration
step was crucial for success in this reaction. When a solution of
11 in CH2Cl2 at −78 °C was treated with Et2AlCl, the mixture
turned yellow immediately, which indicated formation of the
trityl cation. Upon warming to rt, the Diels−Alder products 12
were formed slowly. 1H NMR analysis showed that the
diastereoselectivity of the reaction was excellent (endo-12/exo-
12 >10:1). Finally, saponification with NaOH gave apiosporic
acid (1). Spectral data of synthetic 1 were identical to those of
the natural product, thus confirming the assigned structure. The
optical rotation of the synthetic material ([α]20D −96.8 (c 0.92,
MeOH)) agreed with that reported for the natural product
([α]28D −103.6 (c 0.50, MeOH)).3 The overall yield of 1 from
4 was 23%.
Cytotoxic properties of 1 against a standard set of human
cancer cell lines were evaluated at the National Cancer
Institute, Bethesda, MD; no significant activity was found
(mean growth: 102%).
The cyclization was also carried out with a mixture of (8E)-
11 and (8Z)-11 obtained by the Wittig olefination according to
entry 1 of Table 1 and Suzuki coupling. Under Lewis acid
catalyzed conditions, only (8E)-11 underwent an intra-
molecular Diels−Alder reaction (Scheme 4). Thus, a chemical
separation of the geometric isomers is possible in the
cyclization step. A yield of 54% was achieved in the IMDA
reaction, and the overall yield of 1 from 4 via this route was
26%. Thus, this route is shorter and proceeds in slightly higher
Table 1. Olefination Reactions17
a
yield
b
entry
conditions
(%)
E/Z
c
1
2
3
4
5
6
7
5 + 10a, KO-t-Bu, toluene, 0 °C
83
64:36
57:43
50:50
31:69
63:37
60:40
80:20
c
5 + 10b, KO-t-Bu, THF, −20 °C
77
10c, KHMDS, DME, then 5, −78 °C → rt
10c, LiHMDS, DME, then 5, −78 °C → rt
5 + 10d, KHMDS, DME, −78 °C → rt
10d, LiHMDS, DME, then 5, −78 °C → rt
8, LiHMDS, DME, then crotonaldehyde, −78
90
quant.
81
c
62
81
°C → rt
d
8
8 + crotonaldehyde, KHMDS, DME, −78 °C →
69
94:6
c
rt
a
b
c
1
Isolated yield. Determined by H NMR. The base was added to a
d
solution of the other reactants. 83% based on recovered 8.
route, and this was investigated first. As a rule, the Wittig
olefination11 of aldehydes with ylides derived from allylic
triphenylphosphonium salts proceeds with low Z/E selectivity.
Tamura et al. reported E-selective olefinations with allyltribu-
tylphosphonium salts;12 this method gave excellent results in
the preparation of E,Z-dienes.13 In our hands, this procedure
gave a 2:1 mixture of E/Z-isomers, which we could not separate
(entry 1). The Wittig reaction starting with phosphonium salt
10b14 proceeded with even lower E/Z selectivity (entry 2).
Julia−Kocienski olefinations15 applying heteroarylsulfones 10c
and 10d16 also failed to give a useful level of selectivity (entries
3−6). The alternative route starting with tetrazole 8, i.e.,
reaction of metalated sulfone 8 with crotonaldehyde under
Barbier-type conditions, gave an excellent selectivity upon use
of KHMDS as base (entry 8).
Scheme 4. Preparation of Reference Compounds
The enoate moiety was introduced via Suzuki coupling as
follows (Scheme 3).18 Hydroboration of 9 with 9-BBN and
B
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Note
4.9 Hz), 5.13 (1 H, br d, J = 17.3 Hz), 5.17 (1 H, br d, J = 10.5 Hz),
5.66 (1 H, ddd, J = 17.3, 10.2, 8.6 Hz), 7.20−7.25 (3 H, m), 7.26−7.31
(6 H, m), 7.39−7.43 (6 H, m), 7.55−7.64 (3 H, m), 7.65−7.70 (2 H,
m); 13C NMR (CDCl3, 125 MHz) δ 23.8 (CH2), 43.4 (CH), 54.4
(CH2), 66.1 (CH2), 86.8 (Cq), 118.2 (CH2), 125.2 (CH), 127.2 (CH),
128.0 (CH), 128.8 (CH), 129.8 (CH), 131.6 (CH), 133.2 (Cq), 137.6
(CH), 144.0 (Cq), 153.6 (Cq); HR-MS (FT-ICR-ESI+) calcd for
C32H30N4NaO3S [M + Na]+ 573.19308, found 573.19301.
Trityl (2S,4E,6E)-2-Vinylocta-4,6-dien-1-yl Ether (9). Under an
atmosphere of argon, KHMDS (0.5 M in toluene, 0.48 mL, 0.24
mmol) was added dropwise to a solution of 8 (101 mg, 184 μmol) and
crotonaldehyde (23 μL, 0.28 mmol) in dry DME (2 mL) at −78 °C.
The solution was allowed to warm to rt within 16 h when no further
conversion was detected [TLC: Rf(8) = 0.34, Rf(9) = 0.80, PE/EtOAc
5:1]. Water (5 mL) was added, and the aqueous layer was separated
and extracted with Et2O (2 × 30 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. Purification by
flash chromatography (silica, PE/EtOAc 20:1) yielded 9 (49.6 mg,
69%, 83% based on recovered 8) as a colorless oil in addition to
recovered 8 (17.1 mg, 17%). The ratio E/Z = 94:6 was determined by
1H NMR: [α]20D +1.5 (c 0.81, CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 1.71 (3 H, d, J = 6.4 Hz), 2.13 (1 H, dt, J = 14.3, 7.2 Hz), 2.28−2.40
(2 H, m), 2.99−3.08 (2 H, m), 4.99−5.06 (2 H, m), 5.35−5.45 (1 H,
m), 5.48−5.59 (1 H, m), 5.72 (1 H, ddd, J = 17.4, 10.5, 7.9 Hz), 5.90−
5.99 (2 H, m), 7.18−7.32 (9 H, m), 7.40−7.47 (6 H, m); 13C NMR
(CDCl3, 125 MHz) δ 18.2 (CH3), 34.7 (CH2), 44.7 (CH), 66.2
(CH2), 86.4 (Cq), 115.6 (CH2), 127.0 (CH), 127.2 (CH), 127.8
(CH), 128.9 (CH), 129.5 (CH), 131.7 (CH), 131.9 (CH), 140.1
(CH), 144.5 (Cq); HR-MS (FT-ICR-ESI+) calcd for C29H30NaO [M
+ Na]+ 417.21889, found 417.21861.
Methyl (2E,6R,8E,10E)-6-[[(Triphenylmethyl)oxy]methyl]-
dodeca-2,8,10-trienoate (11). Under an atmosphere of argon, a
solution of 9 (391 mg, 991 μmol) and 9-BBN (247 mg, 2.03 mmol) in
dry THF (8 mL) was heated at 65 °C. Complete conversion was
reached after 5 min [TLC: Rf(9) = 0.80, Rf(11) = 0.59, PE/EtOAc
5:1]. After being cooled to rt, the solution was added to a suspension
of Pd(dppf)Cl2 (37 mg, 51 μmol), Ph3As (30.9 mg, 101 μmol),
Cs2CO3 (593 mg, 1.82 mmol), and methyl (2E)-3-iodoacrylate (238
mg, 1.11 mmol) in DMF/H2O 15:1 (3 mL). The suspension was
vigorously stirred at rt overnight. Then, water (10 mL) was added, and
the solution was extracted with Et2O (3 × 20 mL). The organic layer
was dried over MgSO4 and concentrated in vacuo. Purification by flash
overall yield than the route via 8. In the thermal Diels−Alder
reaction (Scheme 4), a low diastereoselectivity was observed
(endo/exo 1.25:1). Cleavage of the trityl group under acidic
conditions furnished endo-12 and exo-12 required for the
characterization of the compounds of the exo series and
determination of endo/exo selectivity.
In summary, we have presented the first enantioselective
synthesis of the polyketide apiosporic acid. Key steps were a
Julia−Kocienski olefination, a Suzuki−Miyaura reaction, and an
intramolecular Diels−Alder reaction. The chiral starting
material of known absolute configuration was prepared by
iridium-catalyzed allylic alkylation. Thus, the absolute config-
uration of the natural product has been established.
EXPERIMENTAL SECTION
■
(3S)-3-[(Trityloxy)methyl]pent-4-en-1-ol (6). DIBAL-H (1 M in
hexanes, 3.2 mL, 3.2 mmol) was added dropwise to a solution of 4
(497 mg, 1.29 mmol) in dry THF (10 mL) at −55 °C. Complete
conversion was reached after 1 h [TLC: Rf(4) = 0.54, Rf(6) = 0.27,
PE/EtOAc 3:1]. MeOH (0.5 mL) was added, and the solution was
allowed to warm to rt. Saturated aqueous sodium potassium tartrate
solution (10 mL) was added, and the mixture was extracted with Et2O
(3 × 20 mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo. Purification by flash chromatography
(silica, PE/EtOAc 3:1) yielded 6 (415 mg, 90%) as colorless oil:
1
[α]20 +23.5 (c 0.93, CHCl3); H NMR (CDCl3, 300 MHz) δ 1.52−
D
1.65 (2 H, m), 1.72−1.84 (1 H, m), 2.37−2.50 (1 H, m), 3.00−3.14 (2
H, m), 3.54−3.69 (2 H, m), 5.03−5.13 (2 H, m), 5.73 (1 H, ddd, J =
17.3, 10.1, 8.7 Hz), 7.18−7.33 (9 H, m), 7.40−7.47 (6 H, m); 13C
NMR (CDCl3, 75 MHz) δ 34.8 (CH2), 41.9 (CH), 61.2 (CH2), 67.1
(CH2), 86.7 (Cq), 116.1 (CH2), 127.1 (CH), 127.9 (CH), 128.8
(CH), 140.1 (CH), 144.3 (Cq); HR-MS (FT-ICR-ESI+) calcd for
C25H26NaO2 [M + Na]+ 381.18250, found 381.18217.
1-Phenyl-5-[[(3S)-3-[(trityloxy)methyl]pent-4-en-1-yl]thio]-
1H-tetrazole (7). DEAD (40 wt % in toluene, 1.3 mL, 2.9 mmol) and
PBu3 (0.71 mL, 2.9 mmol) were added to a solution of 6 (415 mg,
1.16 mmol) and 1-phenyl-1H-tetrazole-5-thiol (405 mg, 2.3 mmol) in
dry THF (15 mL) at 0 °C. Complete conversion was reached after 2 h
[TLC: Rf(6) = 0.27, Rf(7) = 0.51, PE/EtOAc 3:1]. Water (20 mL) was
added, and the solution was extracted with Et2O (3 × 30 mL). The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography (silica, PE/EtOAc 10:1)
chromatography (silica, PE/Et2O 50:1) yielded 11 (315 mg, 66%) as a
1
colorless oil: [α]20 +5.5 (c 0.51, CHCl3); H NMR (CDCl3, 500
D
MHz) δ 1.41−1.55 (2 H, m), 1.61−1.68 (1 H, m), 1.73 (3 H, d, J =
6.5 Hz), 1.95−2.08 (2 H, m), 2.13 (1 H, dt, J = 13.8, 6.9 Hz), 2.25 (1
H, dt, J = 13.8, 6.9 Hz), 2.96 (1 H, dd, J = 9.1, 5.5 Hz), 3.05 (1 H, dd, J
= 9.0, 4.7 Hz), 3.71 (3 H, s), 5.38 (1 H, dt, J = 14.1, 7.0 Hz), 5.55 (1
H, dq, J = 13.3, 6.6 Hz), 5.71 (1 H, d, J = 15.6 Hz), 5.88−6.03 (2 H,
m), 6.88 (1 H, dt, J = 15.6, 6.9 Hz), 7.20−7.34 (9 H, m), 7.40−7.49 (6
H, m); 13C NMR (CDCl3, 125 MHz) δ 18.2 (CH3), 29.6 (CH2), 29.7
(CH2), 35.0 (CH2), 38.9 (CH), 51.5 (CH3), 64.5 (CH2), 86.4 (Cq),
121.0 (CH), 127.0 (CH), 127.3 (CH), 127.9 (CH), 128.9 (CH),
129.5 (CH), 131.7 (CH), 132.3 (CH), 144.4 (Cq), 149.7 (CH), 167.2
(Cq); HR-MS (FT-ICR-ESI+) calcd for C33H36NaO3 [M + Na]+
503.25567, found 503.25533.
Methyl (1R,2R,4aS,6R,8aR)-6-Hydroxy-2-methyl-1,2,4a,
5,6,7,8,8a-octahydronaphthalene-1-carboxylate (endo-12).
Et2AlCl (1.8 M in toluene, 0.18 mL, 0.32 mmol) was added dropwise
to a solution of 11 (50 mg, 104 μmol) in dry CH2Cl2 (1.5 mL) at −78
°C. The solution was allowed to warm to rt. Complete conversion was
reached after 22 h [TLC: Rf(11) = 0.77, Rf(endo-12) = 0.39, PE/
EtOAc 1:1]. Water (5 mL) was added dropwise; the aqueous layer was
separated and extracted with Et2O (3 × 20 mL). The combined
organic layers were dried over MgSO4 and concentrated in vacuo.
Purification by flash chromatography (silica, PE/EtOAc 1:1) yielded
endo-12 (18.7 mg, 75%) as a colorless oil. The ratio endo/exo > 10:1
was determined by 1H NMR: [α]20D −70.2 (c 1.40, CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 0.83 (1 H, q, J = 12.4 Hz), 0.90 (3 H, d, J = 6.9
Hz), 0.92−0.99 (1 H, m), 1.09 (1 H, qd, J = 12.9, 3.7 Hz), 1.41 (1 H,
yielded 7 (512 mg, 85%) as colorless needles (mp 109−112 °C
1
(EtOAc/PE)): [α]20 +17.8 (c 1.05, CHCl3); H NMR (CDCl3, 500
D
MHz) δ 1.75−1.84 (1 H, m), 2.10 (1 H, dddd, J = 13.5, 8.7, 7.4, 4.6
Hz), 2.39−2.48 (1 H, m), 3.04 (1 H, dd, J = 8.9, 6.5 Hz), 3.10 (1 H,
dd, J = 9.0, 5.8 Hz), 3.23 (1 H, ddd, J = 13.0, 8.5, 7.5 Hz), 3.42 (1 H,
ddd, J = 13.0, 8.9, 5.1 Hz), 5.08−5.15 (2 H, m), 5.69 (1 H, ddd, J =
17.1, 10.3, 8.7 Hz), 7.19−7.24 (3 H, m), 7.24−7.30 (6 H, m), 7.39−
7.43 (6 H, m), 7.51−7.58 (5 H, m); 13C NMR (CDCl3, 125 MHz) δ
30.7 (CH2), 31.3 (CH2), 43.9 (CH), 66.5 (CH2), 86.6 (Cq), 117.3
(CH2), 124.0 (CH), 127.1 (CH), 127.9 (CH), 128.8 (CH), 129.9
(CH), 130.2 (CH), 133.9 (Cq), 138.7 (CH), 144.2 (Cq), 154.4 (Cq);
HR-MS (FT-ICR-ESI+) calcd for C32H30N4NaOS [M + Na]+
541.20325, found 541.20317.
1-Phenyl-5-[[(3S)-3-[(trityloxy)methyl]pent-4-en-1-yl]-
sulfonyl]-1H-tetrazole (8). Aqueous H2O2 (35 wt %, 1.2 mL, 14
mmol) was added to a suspension of 7 (511 mg, 985 μmol) and
(NH4)6Mo7O24·4H2O (241 mg, 195 μmol) in EtOH (10 mL) and
EtOAc (2 mL). The mixture was stirred for 1 d at rt [TLC: Rf(8) =
Rf(7) = 0.51, PE/EtOAc 3:1]. Water (30 mL) was added, and the
solution was extracted with Et2O (3 × 50 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo. Purification
by flash chromatography (silica, PE/EtOAc 5:1) yielded 8 (440 mg,
81%) as colorless oil: [α]20D +10.1 (c 1.17, CHCl3); 1H NMR (CDCl3,
500 MHz) δ 1.88−1.97 (1 H, m), 2.20−2.28 (1 H, m), 2.40−2.48 (1
H, m), 3.04 (1 H, dd, J = 9.2, 6.9 Hz), 3.16 (1 H, dd, J = 9.2, 5.3 Hz),
3.61 (1 H, ddd, J = 14.6, 11.1, 6.3 Hz), 3.69 (1 H, ddd, J = 14.8, 11.2,
C
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Note
qd, J = 11.2, 2.8 Hz), 1.56−1.68 (2 H, m), 1.71−1.81 (1 H, m), 1.81−
1.88 (2 H, m), 2.01 (1 H, dq, J = 12.4, 3.0 Hz), 2.52−2.61 (2 H, m),
3.44−3.52 (2 H, m), 3.68 (3 H, s), 5.41 (1 H, d, J = 9.9 Hz), 5.58 (1
H, ddd, J = 9.8, 3.9, 2.8 Hz); 13C NMR (CDCl3, 125 MHz) δ 18.0
(CH3), 29.65 (CH2), 29.68 (CH2), 32.7 (CH), 36.1 (CH2), 36.8
(CH), 41.0 (CH), 41.6 (CH), 49.7 (CH), 51.4 (CH3), 68.7 (CH2),
130.9 (CH), 131.4 (CH), 174.6 (Cq); HR-MS (FT-ICR-ESI+) calcd
for C14H22NaO3 [M + Na]+ 261.14612, found 261.14613.
ICR-ESI+) calcd for C33H36NaO3 [M + Na]+ 503.25567, found
503.25558.
Methyl (1R,2R,4aS,6R,8aR)-6-Hydroxy-2-methyl-
1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate (endo-
12).
Removal of Trityl Group. A solution of endo-13 (107.0 mg, 223
μmol) in 80% aqueous acetic acid (3 mL) was heated at 50 °C.
Complete conversion was reached after 45 min [TLC: Rf(endo-13) =
0.81, Rf(endo-12) = 0.39, PE/EtOAc 1:1]. The solution was
neutralized with saturated aqueous NaHCO3 and extracted with
Et2O (4 × 20 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. Purification by flash chromatog-
raphy (silica, PE/EtOAc 5:1) yielded endo-12 (42.1 mg, 79%) as a
colorless oil.
Methyl (1R,2S,4aR,6R,8aR)-6-Hydroxy-2-methyl-
1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate (exo-
12).
Removal of Trityl Group. A solution of exo-13 (154 mg, 320 μmol)
in 80% aqueous acetic acid (4 mL) was heated at 50 °C. Complete
conversion was reached after 1 h [TLC: Rf(exo-13) = 0.76, Rf(exo-12)
= 0.22, PE/EtOAc 3:1]. The solution was neutralized with saturated
aqueous NaHCO3 and extracted with Et2O (3 × 40 mL). The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography (silica, PE/EtOAc 3:1)
(1R,2R,4aS,6R,8aR)-6-(Hydroxymethyl)-2-methyl-
1,2,4a,5,6,7,8,8a-octahydro-1-naphthalenecarboxylic Acid
(Apiosporic Acid, 1). Aqueous NaOH (1 M, 5 mL) was added to
a solution of endo-12 (84 mg, 0.35 mmol) in MeOH (2 mL).
Complete conversion was reached after 27 h at rt [TLC: Rf(endo-12) =
0.39, Rf(1) = 0.22, PE/EtOAc 1:1]. The solution was acidified with
HCl (1 M, 1 mL) until pH 2 was reached. The solution was extracted
with ethyl acetate (5 × 15 mL), and the combined organic layers were
dried over MgSO4 and concentrated in vacuo. Purification by flash
chromatography (silica, PE/EtOAc 1:1) yielded 1 (72.5 mg, 91%) as
colorless needles: [α]20D −96.8 (c 0.92, MeOH) [lit.3 [α]28D −103.6 (c
1
0.50, MeOH)]; H NMR (acetone-d6, 500 MHz) δ 0.79 (1 H, q, J =
12.5 Hz), 0.94 (3 H, d, J = 6.9 Hz), 0.90−1.00 (1 H, m), 1.04 (1 H,
qd, J = 12.4, 3.4 Hz), 1.28−1.37 (1 H, m), 1.52−1.63 (1 H, m), 1.72−
1.79 (1 H, m), 1.82−1.89 (2 H, m), 2.11 (1 H, dd, J = 12.1, 3.1 Hz),
2.53 (1 H, dd, J = 11.4, 6.0 Hz), 2.55−2.60 (1 H, m), 2.60−3.90 (1 H,
br s), 3.38 (2 H, dd, J = 6.2, 1.9 Hz), 5.41 (1 H, d, J = 9.9 Hz), 5.59 (1
H, ddd, J = 9.8, 4.2, 2.8 Hz), 9.60−11.50 (1 H, br s); 13C NMR
(acetone-d6, 125 MHz) δ 18.0 (CH3), 30.1 (CH2), 30.2 (CH2), 33.0
(CH), 37.0 (CH2), 37.5 (CH), 41.9 (CH), 42.2 (CH), 49.7 (CH),
68.1 (CH2), 131.7 (CH), 131.8 (CH), 174.7 (Cq); HR-MS (FT-ICR-
ESI-) calcd for C13H19O3 [M − H]− 223.13397, found 223.13413.
Methyl (1R,2R,4aS,6R,8aR)-2-Methyl-6-[[(triphenylmethyl)-
oxy]methyl]-1,2,4a,5,6,7,8, 8a-octahydronaphthalene-1-car-
boxylate (endo-13) and Methyl (1R,2S,4aR,6R,8aR)-2-Methyl-
6-[[(triphenylmethyl)oxy]methyl]-1,2,4a,5,6,7,8,8a-octahydro-
naphthalene-1-carboxylate (exo-13).
yielded exo-12 (57.6 mg, 75%) as colorless needles (mp 94−96 °C
1
(EtOAc/PE)): [α]20 −11.1 (c 0.97, CHCl3); H NMR (CDCl3, 500
D
MHz) δ 0.98 (3 H, d, J = 7.2 Hz), 1.29−1.44 (3 H, m), 1.52−1.60 (3
H, m), 1.61−1.69 (1 H, m), 1.78−1.86 (1 H, m), 2.06 (1 H, dq, J =
9.4, 4.7 Hz), 2.19−2.26 (1 H, m), 2.39 (1 H, dd, J = 9.4, 8.6 Hz),
2.48−2.56 (1 H, m), 3.58−3.63 (2 H, m), 3.69 (3 H, s), 5.44 (1 H, dt,
J = 9.9, 1.8 Hz), 5.53 (1 H, ddd, J = 9.9, 4.0, 2.7 Hz); 13C NMR
(CDCl3, 125 MHz) δ 20.7 (CH3), 23.3 (CH2), 24.7 (CH2), 31.0
(CH2), 31.3 (CH), 33.9 (CH), 35.7 (CH), 36.2 (CH), 48.1 (CH),
51.6 (CH3), 64.8 (CH2), 130.8 (CH), 131.0 (CH), 176.7(Cq); HR-
MS (FT-ICR-ESI+) calcd for C14H22NaO3 [M + Na]+ 261.14612,
found 261.14613.
Thermal Intramolecular Diels−Alder Reaction. A solution of 11
(349 mg, 727 μmol, (8E)-11/(8Z)-11 = 2:1) and di-tert-butylhy-
droquinone (0.5 mg) in dry and degassed toluene (8 mL) was heated
at 130 °C in a sealed tube. No further conversion was detected after 4
d [TLC: Rf(11) = 0.25, Rf(endo-13) = Rf(exo-13) = 0.31, PE/EtOAc
20:1]. The solvent was removed in vacuo, and the residue was
subjected to flash chromatography (silica, PE/EtOAc 50:1) to yield a
mixture of endo-13 and exo-13 (164 mg, 47%). The ratio endo-13/exo-
13 = 1.25:1 was determined by 1H NMR. Further purification by
preparative HPLC (silica, PE/Et2O 50:1) yielded endo-13 (92 mg,
26%) as colorless needles (mp 126−129 °C (Et2O/PE)) and exo-13
(61 mg, 17%) as a colorless oil.
Methyl (1R,2R,4aS,6R,8aR)-6-Hydroxy-2-methyl-
1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate (endo-
12).
Lewis Acid Catalyzed Intramolecular Diels−Alder Reaction
Starting from a Mixture of (8E)-11 and (8Z)-11. Et2AlCl (1.8 M in
toluene, 1.1 mL, 1.98 mmol) was added dropwise to a solution of 11
(314.9 mg, 0.66 mmol, (8E)-11/(8Z)-11 = 2:1) in dry CH2Cl2 (6 mL)
at −78 °C. The solution was allowed to warm to rt. Complete
conversion was reached after 65 h [TLC: Rf(11) = 0.77, Rf(12) = 0.44,
Rf(14) = 0.47, PE/EtOAc 1:1]. Water (6 mL) and saturated aqueous
potassium sodium tatrate (3 mL) were added, and the aqueous layer
was separated and extracted with CH2Cl2 (2 × 50 mL). The combined
organic layers were dried over MgSO4, and the solvent was removed in
vacuo. The residue was subjected to flash chromatography on silica
(PE/EtOAc 1:1) to yield a mixture of endo-12 and 14, which was
dissolved in THF (4 mL). The solution was treated with aqueous
LiOH (1 M, 10 mL). Complete consumption of 14 was reached after
45 min (TLC). The solution was extracted with diethyl ether (3 × 20
mL), and the combined organic layers were dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography on silica
(PE/EtOAc 3:1) yielded endo-12 (83.5 mg, 54%) as a colorless oil.
endo-13: [α]20 +20.5 (c 1.32, CHCl3); 1H NMR (CDCl3, 600
D
MHz) δ 0.82−1.00 (2 H, m), 0.90 (3 H, dd, J = 6.8, 0.8 Hz), 1.12 (1
H, qd, J = 12.6, 2.9 Hz), 1.39 (1 H, q, J = 10.9 Hz), 1.71−1.85 (2 H,
m), 1.85−1.94 (2 H, m), 1.98 (1 H, d, J = 12.4 Hz), 2.52−2.62 (2 H,
m), 2.83−2.96 (2 H, m), 3.68 (3 H, d, J = 0.6 Hz), 5.42 (1 H, d, J =
9.9 Hz), 5.53−5.57 (1 H, m), 7.23 (3 H, t, J = 7.3 Hz), 7.29 (6 H, t, J =
7.7 Hz), 7.44 (6 H, dd, J = 8.4, 0.8 Hz); 13C NMR (CDCl3, 150 MHz)
δ 17.9 (CH3), 29.6 (CH2), 30.2 (CH2), 32.5 (CH), 36.58 (CH), 36.62
(CH2), 39.0 (CH), 41.6 (CH), 49.5 (CH), 51.2 (CH3), 68.6 (CH2),
86.2 (Cq), 126.9 (CH), 127.8 (CH), 128.9 (CH), 130.9 (CH), 131.1
(CH), 144.6 (Cq), 174.5 (Cq); HR-MS (FT-ICR-ESI+) calcd for
C33H36NaO3 [M + Na]+ 503.25567, found 503.25558.
1
The ratio endo-12/exo-12 >10:1 was determined by H NMR.
exo-13: [α]20D +14.6 (c 0.83, CHCl3); 1H NMR (CDCl3, 600 MHz)
δ 0.98 (3 H, d, J = 7.1 Hz), 1.21−1.27 (1 H, m), 1.30−1.35 (1 H, m),
1.35−1.40 (1 H, m), 1.41−1.47 (1 H, m), 1.53−1.69 (2 H, m), 1.90−
1.97 (2 H, m), 1.99−2.05 (1 H, m), 2.39 (1 H, t, J = 9.0 Hz), 2.46−
2.53 (1 H, m), 3.05−3.09 (2 H, m), 3.69 (3 H, s), 5.41 (1 H, dt, J =
10.0, 1.5 Hz), 5.47 (1 H, ddd, J = 9.9, 3.7, 2.8 Hz), 7.23 (3 H, tt, J =
7.1, 1.1 Hz), 7.27−7.31 (6 H, m), 7.43−7.47 (6 H, m); 13C NMR
(CDCl3, 150 MHz) δ 20.7 (CH3), 23.7 (CH2), 24.7 (CH2), 31.4
(CH), 31.6 (CH2), 33.5 (CH), 34.1 (CH), 36.1 (CH), 47.9 (CH),
51.6 (CH3), 64.7 (CH2), 86.2 (Cq), 127.0 (CH), 127.8 (CH), 128.9
(CH), 130.8 (CH), 131.1 (CH), 144.5 (Cq), 176.8 (Cq); HR-MS (FT-
ASSOCIATED CONTENT
■
S
* Supporting Information
Determination of diastereoselectivities, 1H and 13C NMR
spectra of all new compounds, and test results from the
D
dx.doi.org/10.1021/jo300519g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(18) Reviews: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457−2483. (b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002,
58, 9633−9695. (c) Chemler, S. R.; Trauner, D.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2001, 40, 4544−4568.
(19) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115,
11014−11015.
National Cancer Institute, Bethesda, MD, for compound 1.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: g.helmchen@oci.uni-heidelberg.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Deutsche Forschungsgemein-
schaft (SFB 623). We thank Olena Tverskoy for experimental
assistance, Prof. Dr. K. Ditrich (BASF SE) for enantiomerically
pure 1-arylethylamines, and the National Cancer Institute,
Bethesda, MD, for testing compound 1.
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