Palladium-catalyzed carbonylation of halo arene-cis-dihydrodiols to the corresponding carboxylates. Access to compounds unavailable by toluene dioxygenase-mediated dihydroxylation of the corresponding benzoate esters

Article abstract of DOI:10.1039/c4ob01417k

A series of arene-cis-dihydrodiol carboxylates was prepared by palladium-catalyzed carbonylation of (1S, 2S-cis)-3-iodo-3,5-cyclohexadiene-1,2-diol, which is obtained in high titers by enzymatic dihydroxylation of iodobenzene. Both the free diol and the corresponding acetonide were subjected to this protocol to produce various arene-cis-dihydrodiol carboxylates that are unavailable by fermentation of the corresponding benzoates or are produced in low yields. The comparison of yields obtained from fermentation versus carbonylation was made for all compounds investigated. Experimental and spectral data are provided for all new compounds. This journal is

Full text of DOI:10.1039/c4ob01417k

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Biomolecular Chemistry
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PAPER
Palladium-catalyzed carbonylation of halo
arene-cis-dihydrodiols to the corresponding
carboxylates. Access to compounds unavailable by
toluene dioxygenase-mediated dihydroxylation of
the corresponding benzoate esters†‡
Cite this: Org. Biomol. Chem., 2014,
12, 7810
Jordan Froese, Jason Reed Hudlicky and Tomas Hudlicky*
A series of arene-cis-dihydrodiol carboxylates was prepared by palladium-catalyzed carbonylation of
(1S, 2S-cis)-3-iodo-3,5-cyclohexadiene-1,2-diol, which is obtained in high titers by enzymatic dihydroxy-
lation of iodobenzene. Both the free diol and the corresponding acetonide were subjected to this proto-
col to produce various arene-cis-dihydrodiol carboxylates that are unavailable by fermentation of the
corresponding benzoates or are produced in low yields. The comparison of yields obtained from fermen-
tation versus carbonylation was made for all compounds investigated. Experimental and spectral data are
provided for all new compounds.
Received 7th July 2014,
Accepted 5th August 2014
DOI: 10.1039/c4ob01417k
www.rsc.org/obc
ment, such as is found in any laboratory engaged in organic
synthesis. The most commonly used metabolites are shown in
Introduction
The enzymatic dihydroxylation of aromatic compounds to the Table 1, along with the yields of fermentation.
corresponding arene-cis-dihydrodiols such as 1, Fig. 1, was dis-
From the table it is clear that only a few substrates produce
covered by Gibson in 1968.1 In the last 25 years many new yields upward of 10 grams L−1. Moreover, the recently investi-
metabolites resulting from this enzymatic oxidation were dis- gated dihydroxylation of various benzoate esters (Me, Et, n-Pr,
covered, cataloged2 and used in enantioselective synthesis of i-Pr, allyl, propargyl) revealed that these are poor substrates, as
natural products.3
evidenced by the low yields of metabolites 11–17.20 This study
The diols derived from single ring aromatics and various was extended to dihydroxylation of methyl halobenzoates23
benzoate esters are available in multigram quantities by fer- and, most recently, to various alkyl halobenzoates in order to
mentation with recombinant organisms such as E. coli JM109 compare regioselectivity of dihydroxylation as a function of
(pDTG601A), which overexpresses toluene dioxygenase. This both, halogen and alkoxy functionalities.24
organism, and others, expressing related dioxygenases for
dihydroxylation of fused aromatics or biphenyls, were also efficient synthesis of oseltamivir21 and its production at higher
developed by Gibson in 1989.4
titers would be beneficial. For any future refinement of the
The diol derived from ethyl benzoate, 12, was used in a very
The yields of arene-cis-dihydrodiols vary from milligrams published synthesis of oseltamivir and its derivatives, the avail-
L−1 to 30 or more grams L−1. Whole-cell fermentation of aro- ability of 12 in larger amounts would be essential. In this
matics with the JM109 clone was investigated at medium paper we report a simple palladium-catalyzed carbonylation
scales (10 to 15 L fermentors) for several common substrates.5 protocol for the preparation of various carboxylates from iodo-
In addition, a procedure was published in Organic Syntheses6 or bromoarene cis-dihydrodiols (entry 6 and 5, respectively).
for the preparation of several halo arene-cis-dihydrodiols by
employing the blocked mutant, Pp39D, and common equip-
Results and discussion
Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge
Avenue, St. Catharines, Ontario L2S 3A1, Canada. E-mail: thudlicky@brocku.ca
†The authors wish to dedicate this paper to the memory of David Gibson
Cross-coupling strategies have been used in order to obtain
homochiral cis-diols that would not be available from the
corresponding aromatic substrates. Thus Boyd prepared a
(deceased July 24, 2014) and in recognition of his lifetime contributions to the
field of biocatalysis.
number of compounds via cross-coupling of various vinyl
halides derived from arene cis-dihydrodiols, in some cases
‡Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob01417k
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Fig. 1 Enzymatic dihydroxylation of arenes by toluene dioxygenase (TDO).
tected as their corresponding acetonides.27 We have prepared
dimers from the acetonide-protected diols 20, 22 and 23,
namely the pentacyclic compounds 30, 31 and 32, shown in
Fig. 2, in order to assess their presence in the carbonylation
reaction mixture.
Table 1 Comparison of yields of enzymatic dihydroxylation of various
substrates
These compounds were prepared in reasonable yields (30 =
38%, 31 = 42%, 32 = 64%) by refluxing a solution of the corres-
ponding acetonides in xylene for 24–40 hours.
Yield (g L−1
Organism or (%)
)
ee
We investigated the palladium-catalyzed carbonylation with
the acetonide-protected diol 20 (EtOH, 40 °C) and were
delighted to find that ethyl ester 23 was produced with high
conversions and good isolated yields at multigram scales,
Scheme 1. The carbonylation of the bromo derivative 21 also
yielded the corresponding ethyl ester 23, although in lower
yield than that obtained with the carbonylation of vinyl iodide
20. As well, the free diols 6 and 5 were subjected to the same
conditions. The carbonylation of 6 (EtOH, 40 °C) produced 12
in good yields, far exceeding those obtained from the biotrans-
formation of ethyl benzoate, Table 2. The substrate scope was
subsequently expanded, and the carbonylation procedure was
utilized to produce the acetonide-protected compounds 22–29,
Table 2. Despite initial concerns, little or no dimerization was
observed under the carbonylation reaction conditions.
Both the free diol 6 and the acetonide-protected diol 20
were subjected to carbonylation in the presence of various
alcohols, to produce ester derivatives which were previously
obtained in low yields by fermentation.20 Furthermore, it was
previously shown that compound 15 was unavailable through
biotransformation,20 and it was demonstrated, as part of this
study, that compound 18 was similarly unavailable through
biotransformation. Compounds 15 and 18, as well as their
corresponding acetonide-protected derivatives 26 and 29, were
accessed through the carbonylation of 6 and 20 respectively.
The comparison of isolated yields is shown in Table 2.
Entry R=
(%) Reference
2
Me
Pp39D
PpUV4
JM109
PpUV4
Pp39D
PpUV4
JM109
Pp39D
PpUV4
JM109
Pp39D
PpUV4
JM109
Pp39D
PpUV4
JM109
Pp39D
PpUV4
JM109
JM109
Pp39D
JM109
Pp39D
JM109
JM109
JM109
JM109
JM109
0.93
—
1b,7,8c
>98 9,10c
4,5
∼60 9b,10c
1b,8,11c
>98 9,10c
(∼60%)
12–15 [16]a
—
—
3
4
F
Cl
0.3–1
—
(80%)
9–11 [12]a
—
(77%)
9–12 [20]a
—
(85%)
7–9 [10]a
(>95%)
(∼30%)
6–8 [12]a
0.05
—
—
5
5
6
7
8
Br
1,12b
>98 10c,13
—
—
5
1
I
>98 10c,13,14b
>98 5,14b
CHvCH2
>98 8b,15c,16
>98 10c
—
—
5
CCH
8b
(∼10%)
>98 10c
3–3.5
—
5
9
10
CH2CH2OAc
CH2CH2Br
3–5 [5]a
0.2
>98 5,17b,c
96 18b,c
6–9 [9]a
2.25
—
—
5
11
CO2Me
19b
1.3 [1.5]a
0.8 [1.0]a
0.07
>98 20c
12
13
14
15
16
17
18
19
CO2Et
>98 20b,c,21
>98 20b,c
>98 20b,c
CO2nPr
CO2iPr
CO2tBu
0.05
—
0.6
—
20b,c
CO2CH2CHCH2 JM109
CO2CH2CCH JM109
CO2CH2(C6H5)d JM109
Cyclopropyl JM109
>98 20b,c
1.0
>98 20b,c
—
—
—
2.5 [8–10]a
>98 22b,c
From Table 2, it is clear that the carbonylation of the
readily available enzymatic metabolite, namely vinyl iodide 6,
a Current yield on 10–15 L scale as obtained in the Hudlicky group.
b Reference to isolation. c Reference to full characterization.
d Attempted fermentation of this ester, performed as part of this study,
did not provide the diol metabolite.
with the diene unit being partially saturated (by potassium
azodicarboxylate (PAD) reduction).25 Banwell successfully per-
formed sp2–sp3 cross-coupling of the vinyl iodide in diol 6 (pro-
tected as acetonide) at elevated temperatures without detriment
to the otherwise labile diene functionality.26 It is well known
that the diene diols of type 1 are prone to stereoselective Diels–
Alder type dimerization even at low temperatures, with the
dimerization proceeding much faster when the diols are pro-
Fig. 2 Diels–Alder dimers produced from the acetonide-protected
diols 20, 22 and 23.
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Scheme 1
Table 2 Comparison of the yields of benzoate metabolites obtained by fermentation with those from the carbonylation of free halodiene 6 or acet-
onide 20
Yield of free diol by fermentations
of benzoate (%) (g L−1 20
Yield of benzoate by carbonylation
Yield of benzoate by carbonylation
Entry
)
of free diol 6 a (%) (g L−1
)
Entry
of acetonide 20 b (%) (g L−1
)
11
R = Me
12
R = Et
13
R = n-Pr
14
R = i-Pr
15
19.2% (1.3)
43.4% (0.8)
5.8% (0.07)
4.1% (0.05)
—
68% (6.8)
22
R = Me
23
R = Et
24
R = n-Pr
25
R = i-Pr
26
68% (6.8)
72% (7.2)
73% (7.3)
62% (6.2)
64% (6.4)
72% (7.2)
76% (7.6)
17% (1.7)
10% (1.0)
R = t-Bu
16
R = allyl
17
R = CH2CCH
R = t-Bu
27
R = allyl
28
R = CH2CCH
52.0% (0.6)
69.1% (1.0)
—
7% (0.7)
27% (2.7)
36% (3.6)
22% (2.2)
18
10% (1.0)
29
71% (7.1)
R = benzyl
R = benzyl
a Hypothetical yield for comparison. Biotransformation of iodobenzene affords up to 10 g L−1 of diol 6. This yield was multiplied by the yield of
the subsequent carbonylation step to reflect the relative amount of compounds 11–18 available through this method. (e.g. 10 g L−1
(biotransformation yield of 6) × 72% (carbonylation yield of 12) = 7.2 g L−1 of compound 12). b Hypothetical yield for comparison.
Biotransformation of iodobenzene affords up to 10 g L−1 of diol 6. This yield was multiplied by the yield of the subsequent carbonylation step to
reflect the relative amount of compounds 22–29 available through this method. (e.g. 10 g L−1 (biotransformation yield of 6) × 73% (carbonylation
yield of 23) = 7.3 g L−1 of compound 23).
provides a much more efficient access to esters 11–14, 17, 18 carbonylation protocol will make it easier to provide improve-
than would a direct fermentation of the corresponding benzo- ments in the synthesis of oseltamivir analogs and other com-
ates. This is also true for the carbonylation of the acetonide- pounds derived from arene-cis-diol carboxylates. Finally, the
protected diol 20, which provided efficient access to com- combination of biocatalysis and traditional synthesis clearly
pounds 22–29.
provides a more effective access to compounds of interest; this
has been articulated in several recent reviews.3c,d,28
Conclusions
Experimental section
General procedure for the carbonylation of compound 6 to
Palladium-catalyzed carbonylation of (1S, 2S-cis)-3-iodo-3,5-
cyclohexadiene-1,2-diol, as well as its corresponding acetonide,
in the presence of an appropriate alcohol led to the synthesis of
various arene-cis-diol carboxylates that are not readily available
by enzymatic dihydroxylation of the parent benzoate esters.
The carbonylation protocol provided the known metabolites of
alkyl benzoates in much higher yields than those obtained
corresponding esters (11–15)
by fermentation. In addition, this protocol provided several A solution of 6 10 (500 mg, 2.10 mmol) was dissolved in
new compounds previously unavailable by fermentation. The alcohol (30 mL), and carbon monoxide was bubbled through
higher yields of benzoate-derived metabolites obtained by the the reaction mixture for 15 minutes, after which triethylamine
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(0.59 mL, 4.2 mmol) was added followed by solid triphenyl- palladium(II) acetate (47 mg, 0.21 mmol). The orange suspen-
phosphine (110 mg, 0.42 mmol) and palladium(II) acetate sion was heated to 40 °C. The reaction was monitored by TLC
(47 mg, 0.21 mmol). The orange suspension was heated to [hexanes–EtOAc (4 : 1)] and consumption of the starting
40 °C. The reaction was monitored by thin layer chromato- material was observed after 1–2.5 hours. Upon cooling to room
graphy (TLC) [hexanes–EtOAc (1 : 1)] and consumption of the temperature, the crude reaction mixture was concentrated to
starting material was observed after 1–2.5 hours. Upon cooling dryness under reduced pressure. The residue was then dis-
to room temperature, the crude reaction mixture was concen- solved in diethyl ether, filtered through a plug of Celite, and
trated to dryness under reduced pressure. The residue was concentrated under reduced pressure. The crude material was
then dissolved in diethyl ether, filtered through a plug of purified by flash column chromatography [hexanes–EtOAc
Celite, and concentrated under reduced pressure. The crude (9 : 1)] to yield the corresponding ester.
material was purified by flash column chromatography
[hexanes–EtOAc (1 : 1)] to yield the corresponding ester.
General procedure for the acetonide protection of compound 6
and subsequent carbonylation of compound 20 to
corresponding esters (27–29)
General procedure for the carbonylation of compound 6 to
corresponding esters (16–18)
A solution of 6 10 (500 mg, 2.10 mmol) was dissolved in 2,2-
dimethoxypropane (10 mL), to which was added a catalytic
amount of p-toluenesulfonic acid. The reaction was monitored
by TLC, and was observed to be complete after 0.5 hours. The
reaction mixture was concentrated under reduced pressure,
diluted with EtOAc (15 mL) and washed with a saturated solu-
tion of sodium bicarbonate (2 × 3 mL) and brine (1 × 2 mL).
The reaction mixture was concentrated under reduced pressure,
and dissolved in a solution of THF–alcohol (9 : 1) (30 mL).
Carbon monoxide was bubbled through the reaction mixture
for 15 minutes, after which triethylamine (0.59 mL, 4.2 mmol)
was added followed by solid triphenylphosphine (110 mg,
0.42 mmol) and palladium(II) acetate (47 mg, 0.21 mmol). The
orange suspension was heated to 40 °C. The reaction was moni-
tored by TLC [hexanes–EtOAc (4 : 1)] and consumption of the
starting material was observed after 4–6 hours. Upon cooling to
room temperature, the crude reaction mixture was concentrated
to dryness under reduced pressure. The residue was then dis-
solved in diethyl ether, filtered through a plug of Celite, and
concentrated under reduced pressure. The crude material was
purified by flash column chromatography [hexanes–EtOAc
(9 : 1)] to yield the corresponding ester.
A solution of 6 10 (500 mg, 2.10 mmol) was dissolved in a solu-
tion of THF–alcohol (9 : 1) (30 mL), and carbon monoxide was
bubbled through the reaction mixture for 15 minutes, after
which triethylamine (0.59 mL, 4.2 mmol) was added followed
by solid triphenylphosphine (110 mg, 0.42 mmol) and
palladium(II) acetate (47 mg, 0.21 mmol). The orange suspen-
sion was heated to 40 °C. The reaction was monitored by TLC
[hexanes–EtOAc (1 : 1)] and consumption of the starting
material was observed after 4–6 hours. Upon cooling to room
temperature, the crude reaction mixture was concentrated to
dryness under reduced pressure. The residue was then dis-
solved in diethyl ether, filtered through a plug of Celite, and
concentrated. The crude material was purified by flash column
chromatography [hexanes–EtOAc (1 : 1)] to yield the corres-
ponding ester.
General procedure for the acetonide protection of compound 6
and subsequent carbonylation of compound 20 to
corresponding esters (22–26)
(+)-Methyl (5S,6R)-5,6-dihydroxycyclohexa-1,3-dienecarboxy-
late (11).20
A solution of 6 10 (500 mg, 2.10 mmol) was dissolved in 2,2-
dimethoxypropane (10 mL), to which was added a catalytic
amount of p-toluenesulfonic acid. The reaction was monitored
by TLC, and was observed to be complete after 0.5 hours. The
reaction mixture was concentrated under reduced pressure,
diluted with EtOAc (15 mL) and washed with a saturated solu- 11: (68%); pale yellow oil; Rf = 0.33 [hexanes–EtOAc (1 : 2)];
tion of sodium bicarbonate (2 × 3 mL) and brine (1 × 2 mL). [α]2D0 = +68.8 (c = 0.8, CHCl3) [lit.20 [α]D23 = +71.3 (c = 1.6,
The reaction mixture was concentrated under reduced CHCl3)]; IR (film) ν 3412, 2098, 1690, 1639, 1291, 820,
pressure, and dissolved in alcohol (30 mL). Carbon monoxide 772 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.05 (d, J = 5.3 Hz, 1H,
was bubbled through the reaction mixture for 15 minutes, CH-2), 6.17 (dd, J = 10.3, 0.6 Hz, 1H, CH-4), 6.05 (qd, J = 5.1,
after which triethylamine (0.59 mL, 4.2 mmol) was added fol- 2.2 Hz, 1H, CH-3), 4.53 (m, 1H, CH-6), 4.45 (m, 1H, CH-5), 3.77
lowed by solid triphenylphosphine (110 mg, 0.42 mmol) and (s, 3H, OCH3),; 13C NMR (75 MHz, CDCl3) δ 167.5 (CvO),
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138.6 (CH-4), 134.3 (CH-2), 128.4 (C-1), 122.6 (CH-3), 69.5 14: (72%); colourless crystals; Rf = 0.31 [hexanes–EtOAc (2 : 3)];
(COH-5), 64.8 (COH-6), 52.1 (OCH3); MS (EI) m/z (%) 170 (33), mp 80–82 °C (pentane) [lit.20 mp 83–85 °C (EtOAc–hexanes)];
152 (61), 139 (22), 138 (96), 136 (71), 121 (100), 110 (95), 109 [α]2D2 = +66.5 (c = 1.0, CHCl3) [lit.20 [α]D22 = +64.7 (c = 1.1,
(66), 105 (23), 93 (42), 92 (22) 82 (57), 81 (56), 65 (59), 5 3 (49), CHCl3)]; IR (film) ν 3274, 2981, 1698, 1263, 1241 cm−1 1H
;
51 (22); HRMS (EI) calcd for C8H10O4: 170.0579. Found: NMR (300 MHz, CDCl3) δ 7.05 (ddd, J = 5.5, 1.0, 0.5 Hz, 1H,
170.0580.
CH-2), 6.20 (ddt, J = 9.6, 2,7, 0.9 Hz, 1H, CH-4), 6.08 (ddd, J =
9.6, 5.5, 2.2 Hz, 1H, CH-3), 5.12 (hept, J = 6.3 Hz, 1H, OCH),
4.58 (dd, J = 6.4, 0.5 Hz, 1H, CH-6), 4.48 (br m, 1H, CH-5), 1.30
(d, J = 6.3 Hz, 6H, CH3); 13C NMR (75 MHz, CDCl3) δ 166.5
(CvO), 138.2 (CH-4), 133.6 (CH-2), 128.9 (C-1), 122.63 (CH-3),
69.2 (COH-5), 68.5 (OCH), 64.9 (COH-6), 21.8 (CH3); MS (EI)
m/z (%): 198 (19), 180 (16), 156 (14), 138 (100); HRMS (EI)
calcd for C10H14O4: 198.08921. Found: 198.08896; Anal. calcd
for C10H14O4: C, 60.59; H, 7.12. Found C, 60.68; H, 7.19.
(+)-Ethyl (5S,6R)-5,6-dihydroxycyclohexa-1,3-dienecarboxylate
(12).20
12: (72%); colourless crystals; Rf = 0.31 [hexanes–EtOAc (1 : 2)];
mp 49–50 °C (pentane) [lit.20 mp 48 °C (EtOAc–hexanes)];
[α]D20 = +53.5 (c = 1.6, CHCl3) [lit.20 [α]2D3 = +54.7 (c = 3.8,
CHCl3)]; IR (film) ν 3385, 2981, 2934, 1700, 1280, 1243, 1104,
(+)-t-Butyl (5S,6R)-5,6-dihydroxycyclohexa-1,3-dienecarboxy-
late (15).
1
1068, 825, 771 cm−1; H NMR (300 MHz, CDCl3) δ 7.04 (d, J =
5.3 Hz, 1H, CH-2), 6.15 (dt, J = 9.4, 1.1 Hz, 1H, CH-4), 6.03 (dq,
J = 9.2, 2.3 Hz, 1H, CH-3), 4.52 (m, 1H, CH-6), 4.44 (m, 1H,
CH-5), 4.22 (q, J = 7.0 Hz, 2H, OCH2),), 1.28 (t, J = 7.2 Hz, 3H,
CH3); 13C NMR (75 MHz, CDCl3) δ 167.1 (CvO), 138.7 (CH-4),
134.1 (CH-2), 128.7 (C-1), 122.5 (CH-3), 69.8 (COH-5), 64.5
(COH-6), 60.9 (OCH2), 14.2 (CH3); MS (EI) m/z (%) 184 (9), 166
(20), 138 (26), 122 (33), 121 (52), 105 (100), 77 (39), 51 (21), 45
(20); HRMS (EI) calcd for C9H12O4: 184.0736. Found: 184.0731;
Anal. calcd for C9H12O4: C, 58.69; H 6.57. Found C, 58.77; H, 6.60.
15: (17%); white crystalline solid; Rf = 0.31 [hexanes–EtOAc
(1 : 1)]; mp 88–90 °C (pentane); [α]2D0 = +53.3 (c = 0.3, CHCl3);
IR (film) ν 3382, 2977, 2932, 1699, 1639, 1575, 1477, 1456,
1393, 1368, 1290, 1253, 1159, 1106, 1066, 1024, 993, 889, 849,
1
826, 783, 770 cm−1; H NMR (300 MHz, CDCl3) δ 6.95 (d, J =
5.6 Hz, 1H, CH-2), 6.22 (dd, J = 9.5, 2.8 Hz, 1H, CH-4), 6.11
(ddd, J = 9.5, 5.7, 1.9 Hz, 1H, CH-3), 4.51 (dd, J = 6.4, 4.0 Hz,
1H, CH-6), 4.47 (m, 1H, CH-5), 1.59 (s, 9H, CH3); 13C NMR
(75 MHz, CDCl3) δ 166.4 (CvO), 137.3 (CH-4), 132.9 (CH-2),
129.8 (CH-1), 123.0 (CH-3), 87.5 (OC), 68.6 (COH-5), 65.7
(COH-6), 28.1 (CH3); MS (EI) m/z (%): 195 (15), 194 (100), 165
(6), 162 (5), 157 (10), 156 (96), 154 (21), 152 (6); HRMS (EI)
212.1049 = C11H16O4; calcd for C11H14O3 [(M − 18)+, H2O]:
194.0943. Found: 194.0944.
(+)-n-Propyl (5S,6R)-5,6-dihydroxycyclohexa-1,3-dienecarboxylate
(13).20
13: (62%); waxy solid; Rf = 0.15 [hexanes–EtOAc (1 : 1)]; [α]D20
=
+55.2 (c = 1.4, CHCl3) [lit.20 [α]D22 = +58.8 (c = 1.1, CHCl3)]; IR
(film) ν 3398, 2968, 1700, 1280, 1240 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.08 (d, J = 5.4 Hz, 1H, CH-2), 6.20 (dd, J = 9.5, 2.5 Hz,
1H, CH-4), 6.09 (ddd, J = 9.5, 5.4, 2.2 Hz, 1H, CH-3), 4.58 (d, J =
6.3 Hz, 1H, CH-6), 4.48 (ddd, J = 6.3, 2.5, 2.2 Hz, 1H, CH-5),
4.16 (t, J = 6.7 Hz, 2H, OCH2), 1.72 (qt, J = 7.4, 6.7 Hz, 2H,
CH2), 0.98 (t, J = 7.4 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ
167.1 (CvO), 138.4 (CH-4), 133.9 (CH-2), 128.7 (C-1), 122.6
(CH-3), 69.4 (COH-5), 66.6 (OCH2), 64.8 (COH-6), 22.0 (CH2),
10.4 (CH3); MS (EI) m/z (%): 198 (18), 180 (22), 138 (100), 121
(81), 110 (54), 105 (77); HRMS (EI) calcd for C10H14O4:
198.0892. Found: 198.0892.
(+)-Allyl (5S,6R)-5,6-dihydroxycyclohexa-1,3-dienecarboxylate
(16).20
16: (6%); colourless crystals; Rf = 0.23 [hexanes–EtOAc (1 : 1)];
mp 44–47 °C (pentane) [lit.20 mp 48–50 °C (EtOAc–hexane)];
[α]D20 = +67.4 (c = 0.2, CHCl3) [lit.20 [α]2D2 = +72.5 (c = 1.6,
CHCl3)]; IR (film) ν 3394, 1704, 1273, 1238 cm−1 1H NMR
;
(300 MHz, CDCl3) δ 7.12 (d, J = 5.5 Hz, 1H, CH-2), 6.23 (ddt, J =
9.6, 2,7, 1.0 Hz, 1H, CH-4), 6.11 (ddd, J = 9.5, 5.5, 2.2 Hz, 1H,
CH-3), 5.98 (ddt, J = 17.2, 10.4, 5.7 Hz, 1H, allyl CH), 5.37 (dt,
J = 17.2, 1.5 Hz, 1H, allyl CH2), 5.28 (dt, J = 10.4, 1.3 Hz, 1H,
allyl CH2), 4.72 (ddd, J = 5.7, 1.5, 1.3 Hz, 2H, OCH2), 4.61 (br s,
1H, COH), 4.50 (br s, 1H, COH); 13C NMR (75 MHz, CDCl3)
δ 166.6 (CvO), 138.8 (CH-4), 134.4 (CH-2), 131.9 (allyl CH),
128.4 (C-1), 122.4 (CH-3), 118.3 (allyl CH2), 69.6 (OCH2), 65.5
(+)-i-Propyl (5S,6R)-5,6-dihydroxycyclohexa-1,3-dienecarboxy-
late (14).20
7814 | Org. Biomol. Chem., 2014, 12, 7810–7819
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(COH-5), 64.5 (COH-6); MS (EI) m/z (%): 196 (20), 178 (18), 138
(+)-Methyl (3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]-
(80), 121 (95), 41 (100). HRMS (EI) calcd for C10H12O4: dioxole-4-carboxylate (22).19,25d
196.07356. Found: 196.07364; Anal. calcd for C10H12O4
1/8H2O: C, 60.52; H, 6.22. Found C, 60.52; H, 6.26.
+
(+)-Propargyl (5S,6R)-5,6-dihydroxycyclohexa-1,3-dienecarb-
oxylate (17).20
22: (68%); colourless oil; Rf = 0.45 [hexanes–EtOAc (4 : 1)];
[α]D = +88.5 (c = 0.2, CHCl3); IR (film) ν 2988, 2952, 1715, 1651,
1589, 1437, 1371, 1260, 1160, 1108, 1081, 1030, 881, 864, 762,
707, 631, 522 cm−1 1H NMR (300 MHz, CDCl3) 7.14 (m, 1H,
;
CH-5), 6.11 (m, 2H, CH-6/CH-7), 4.94 (d, J = 8.4 Hz, 1H,
CO-3a), 4.87 (dd, J = 8.5, 1.9 Hz, 1H, CO-7a), 3.83 (s, 3H,
OCH3), 1.46 (s, 3H, CH3), 1.40 (s, 3H, CH3); 13C NMR
(150 MHz, CDCl3) δ 166.7 (CvO), 134.0 (CH-6), 133.9 (CH-5),
126.1 (C-4), 121.3 (CH-7), 105.6 (OCO-2), 72.5 (CO-7a), 68.2
(CO-3a), 52.0 (OCH3), 26.7 (CH3), 25.1 (CH3); MS (EI) m/z (%)
195 (68), 163 (11), 153 (100), 152 (39), 121 (90), 120 (16), 109
(57), 105 (21), 94 (21), 93 (27), 92 (18), 79 (12), 77 (32), 65 (44),
63 (10), 59 (37), 51 (11); HRMS (EI) 210.0892 = C11H14O4; calcd
C10H11O4 [(M − 15)+, CH3]: 195.0657. Found: 195.0655.
17: (36%); colourless crystals; Rf = 0.31 [EtOAc–hexanes (3 : 2)];
mp 67–69 °C (pentane) [lit.20 mp 70–72 °C (EtOAc–Hexanes)];
[α]D20 = +74.3 (c = 0.2, CHCl3) [lit.20 [α]2D2 = +88.20 (c = 1.6,
CHCl3)]; IR(film) ν 3385, 3291, 1707, 1270, 1234 cm−1 1H
;
NMR (300 MHz, acetone-d6) δ 7.15 (dd, J = 5.7, 0.8 Hz, 1H,
CH-2), 6.25 (dd, J = 9.7, 2.7 Hz, 1H, CH-4), 6.12 (ddd, J = 9.8,
5.6, 2.2 Hz, 1H, CH-3), 4.82 (d, J = 2.5 Hz, 2H, OCH2), 4.62 (dd,
J = 6.8, 4.7 Hz, 1H, CH-6), 4.54 (m, 1H, CH-5), 2.50 (t, J =
2.5 Hz, 1H, CH); 13C NMR (75 MHz, acetone-d6) δ 167.2
(CvO), 142.5 (CH-4), 136.3 (CH-2), 131.1 (C-1), 123.5 (CH-3),
80.0 (propargyl C), 77.3 (propargyl CH), 72.5 (COH-5), 65.5
(COH-6), 53.4 (OCH2); MS (EI) m/z (%): 194 (7), 176 (28), 138
(47), 121 (100); HRMS (EI) calcd for C10H10O4: 194.0579.
Found: 194.0581; Anal. calcd for C10H10O4: C, 61.85; H, 5.19.
Found: C, 62.08; H, 5.18.
(+)-Ethyl (3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]-
dioxole-4-carboxylate (23).20
(+)-Benzyl (5S,6R)-5,6-dihydroxycyclohexa-1,3-dienecarboxy-
late (18).
23: (73%); colourless oil; Rf = 0.56 [hexanes–EtOAc (1 : 1)];
[α]D20 = +76.2 (c = 1.3, CHCl3) [lit.20 [α]2D3 = +74.6 (c = 4.0,
CHCl3)]; IR (film) ν 3018, 2987, 2936, 1712, 1651, 1425, 1380,
1259, 1155, 1031, 917, 856, 697, 667, 512 cm−1 1H NMR
;
(300 MHz, CDCl3) δ 7.06 (dd, J = 5.6, 0.8 Hz, 1H, CH-5), 6.24
(dd, J = 9.5, 2.8, 1H, CH-6), 6.13 (ddd, J = 9.9, 5.7, 2.1, 1H,
CH-7), 4.62 (d, J = 6.4 Hz, 1H, CH-3a), 4.50 (m, 1H, CH-7a),
4.29 (q, J = 7.2, 2H, OCH2), 1.35 (t, J = 7.2 Hz, 3H, CH3);
13C NMR (75 MHz, CDCl3) δ 166.2 (CvO), 142.3 (CH-6), 130.0
(CH-5), 126.4 (C-4), 121.3 (CH-7), 108.5 (OCO-2), 72.6 (OCH2),
70.4 (CO-7a), 60.5 (CO-3a), 26.2 (CH3), 25.1 (CH3), 14.2 (CH3);
MS (EI) m/z (%): 211 (77), 181 (15), 169 (17), 123 (100), 105
(17), 95 (13), 83 (11), 79 (76), 67 (14), 59 (10), 55 (11), 43 (82),
41 (14); HRMS (EI) 224.1049 = C12H16O4; calcd C11H13O4
[(M − 15)+, CH3]: 211.0970. Found: 211.0969; Anal. calcd for
C12H16O4: C, 64.27; H, 7.19. Found C, 64.52; H, 7.08.
18: (10%); pale yellow oil; Rf = 0.30 [hexanes–EtOAc (1 : 1)];
[α]2D0 = +48.8 (c = 0.2, CHCl3); IR (film) ν 3390, 2959, 1704,
1639, 1575, 1498, 1455, 1395, 1260, 1164, 1104, 1066, 1027,
1
995, 915, 811, 757, 697; H NMR (600 MHz, CDCl3) δ 7.38 (d,
J = 4.5 Hz, 1H, C6H5), 7.35 (m, 4H, C6H5), 7.12 (d, J = 5.6 Hz,
1H, CH-2), 6.23 (dd, J = 9.7, 2.8 Hz, 1H, CH-4), 6.12–6.09 (m,
1H, CH-3), 5.25 (s, 2H, OCH2), 4.62 (m, 1H, CH-6), 4.49 (m,
1H, CH-5); 13C NMR (150 MHz, CDCl3) δ 166.8 (CvO), 138.5
(CH-4), 135.7 (CH-2), 134.3 (benzyl C), 128.7 (C-1), 128.4
(+)-n-Propyl (3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d]-
(benzyl CH), 128.3 (benzyl CH), 128.2 (benzyl CH), 122.8 [1,3]dioxole-4-carboxylate (24).
(CH-3), 68.9 (COH-5), 66.8 (OCH2), 65.2 (COH-6); MS (EI) m/z
(%): 246 (13), 244 (58), 238 (24), 228 (28), 221 (13), 220 (100),
213 (19), 212 (99), 210 (12), 207 (12), 204 (17), 201 (10), 200
(49), 199 (16), 197 (13), 195 (15), 194 (36), 192 (12), 183 (15),
182 (14), 181 (19), 179 (15), 172 (12), 169 (10), 168 (11), 167
(30), 166 (14), 165 (20), 159 (11), 157 (22), 156 (31), 155 (45), 24: (68%); clear colourless oil; Rf = 0.46 [hexanes–EtOAc (4 : 1)];
154 (13), 153 (20), 152 (18), 151 (15); HRMS (EI) 246.0892 = [α]2D0 = +72.6 (c = 1.2, CHCl3); IR (film) ν 2974, 2937, 1713,
C14H14O4; calcd for C14H12O3 [(M − 18)+, H2O]: 228.0786. 1589, 1460, 1379, 1370, 1256, 1160, 1107, 1080, 1052, 1027,
1
Found: 228.0787.
863, 705 cm−1; H NMR (300 MHz, CDCl3) δ 7.16–7.14 (m, 1H,
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CH-5), 6.11 (m, 2H, CH-6/CH-7), 4.95 (d, J = 8.3 Hz, 1H,
(+)-Allyl (3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]-
CH-7a), 4.87 (dd, J = 8.3, 1.4 Hz, 1H, CH-3a), 4.19 (t, J = 6.6 Hz, dioxole-4-carboxylate (27).
2H, OCH2), 1.74 (m, 2H, CH2), 1.46 (s, 3H, CH3), 1.41 (s, 3H,
CH3), 1.00 (t, J = 7.4 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
δ 166.2 (CvO), 133.8 (CH-6), 133.6 (CH-5), 126.4 (C-4), 121.3
(CH-7), 105.5 (OCO-2), 72.6 (CO-7a), 68.2 (CO-3a), 66.4 (OCH2),
26.7 (CH3), 25.0 (CH3), 22.0 (CH2), 10.5 (CH3); MS (EI) m/z (%)
27: (27%); clear colourless oil; Rf = 0.65 [hexanes–EtOAc (4 : 1)];
223 (27), 181 (72), 180 (18), 179 (17), 163 (11), 139 (100), 138
(42), 137 (18), 122 (11), 121 (69), 120 (15), 110 (18), 105 (21), 95
(65), 94 (18), 93 (15), 82 (12), 77 (24), 66 (11), 65 (28), 58 (49);
HRMS (EI) 238.1205 = C13H18O4; calcd C12H15O4 [(M − 15)+,
CH3]: 223.0970. Found: 223.0968.
[α]2D0 = +79.3 (c = 0.2, CHCl3); IR (film) ν 2987, 2935, 1715,
1649, 1589, 1455, 1404, 1371, 1252, 1161, 1109, 1029, 993, 923,
863, 706 cm−1 1H NMR (300 MHz, CDCl3) δ 7.18 (m, 1H,
;
CH-5), 6.12 (m, 2H, CH-6/CH-7), 5.98 (m, 1H, allyl CH), 5.38
(dq, J = 17.4, 1.7 Hz, 1H, allyl CH2), 5.26 (dq, J = 10.6, 1.6 Hz,
1H, allyl CH2), 4.96 (d, J = 8.5 Hz, 1H, CH-3a), 4.88 (dd, J = 8.5,
2.1 Hz, 1H, CH-7a), 4.74 (dt, J = 5.5, 1.5 Hz, 2H, OCH2), 1.46 (s,
3H, CH3), 1.41 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 165.8
(CvO), 134.0 (CH-6), 134.0 (CH-5), 132.2 (allyl CH2), 126.1
(C-4), 121.3 (CH-7), 118.0 (allyl CH), 105.6 (OCO-2), 72.5
(CO-7a), 68.1 (CO-3a), 65.4 (OCH2), 26.7 (CH3), 25.0 (CH3); MS
(EI) m/z (%) 221 (22), 220 (14), 179 (57), 163 (13), 161 (30), 137
(15), 135 (17), 122 (14), 121 (100), 109 (11), 107 (23), 105 (32), 94
(15), 93 (18), 77 (25), 65 (31); HRMS (EI) 236.1049 = C13H16O4;
calcd C12H13O4 [(M − 15)+, CH3]: 221.0814. Found: 221.0810.
(+)-i-Propyl (3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d]-
[1,3]dioxole-4-carboxylate (25).
25: (76%); clear colourless oil; Rf = 0.51 [hexanes–EtOAc (4 : 1)];
[α]2D0 = +94.8 (c = 0.1, CHCl3); IR (film) ν 2983, 2935, 1710,
1589, 1455, 1372, 1261, 1160, 1106, 1027, 927, 862, 803,
706 cm−1 1H NMR (300 MHz, CDCl3) δ 7.12 (m, 1H, CH-5),
;
(+)-Propargyl (3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d]-
6.10 (m, 2H, CH-6/CH-7), 5.16 (hept, J = 6.4, 1H, OCH), 4.94 (d,
J = 8.3 Hz, 1H, CH-3a), 4.87 (dd, J = 8.3, 1.4 Hz, 1H, CH-7a),
1.47 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.31 (d, J = 6.3, 6H, CH3);
13C NMR (75 MHz, CDCl3) δ 165.6 (CvO), 133.7 (CH-6), 133.4
(CH-5), 126.7 (C-4), 121.3 (CH-7), 105.5 (OCO-2), 72.6 (CO-7a),
68.2 (OCH), 68.1 (CO-3a), 26.7 (CH3), 25.0 (CH3), 21.9 (CH3),
21.9 (CH3); MS (EI) m/z (%) 223 (19), 181 (68), 180 (19), 179
(19), 139 (100), 138 (55), 137 (20), 122 (14), 121 (96), 120 (22),
110 (17), 105 (18), 95 (49), 94 (21), 93 (19), 92 (12), 82 (18), 77
(24), 66 (15), 65 (35), 59 (16); HRMS (EI) 238.1205 = C13H18O4;
calcd C12H15O4 [(M − 15)+, CH3]: 223.0970. Found: 223.0966.
[1,3]dioxole-4-carboxylate (28).20
28: (20%); colourless oil; Rf = 0.54 [hexanes–EtOAc (4 : 1)];
[α]D20 = +110.6 (c = 0.2, CHCl3) [lit.20 [α]2D2 = +112.7 (c = 1.3,
CHCl3)]; IR (film) ν 2987, 2935, 1718, 1030 cm−1 1H NMR
;
(300 MHz, CDCl3) δ 7.22 (dd, J = 5.3, 1.1 Hz, 1H, CH-5), 6.14
(m, 2H, CH-6/CH-7), 4.95 (d, J = 8.4 Hz, 1H, CH-3a), 4.89 (dd,
J = 8.4, 2.4 Hz, 1H, CH-7a), 4.84 (dd, J = 2.5, 1.0 Hz, 2H, OCH2),
2.50 (t, J = 2.5 Hz, 1H, propargyl CH), 1.47 (s, 3H, CH3), 1.41 (s,
3H, CH3); 13C NMR (75 MHz, CDCl3) δ 165.3 (CvO), 134.8
(CH-6), 134.4 (CH-5), 125.5 (C-4), 121.2 (CH-7), 105.7 (OCO-2),
77.7 (propargyl C), 74.9 (propargyl CH), 71.8 (CO-7a), 68.0
(CO-3a), 52.3 (OCH2), 26.7 (CH3), 25.0 (CH3); MS (EI) m/z (%)
219 (42), 177 (41), 163 (17), 121 (83), 43 (100); HRMS (EI) calcd
for C12H11O4: 219.0657. Found: 219.0659; Anal. calcd for
C13H14O4: C, 66.66; H, 6.02. Found: C, 66.68; H, 6.08.
(+)-t-Butyl (3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]-
dioxole-4-carboxylate (26).
26: (10%); clear colourless oil; Rf = 0.63 [hexanes–EtOAc (4 : 1)];
[α]2D0 = +81.3 (c = 0.6, CHCl3); IR (film) ν 2981, 2933, 1707,
1589, 1456, 1368, 1275, 1255, 1160, 1109, 1050, 1025, 905, 848,
(+)-Benzyl (3aR,7aS)-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]-
dioxole-4-carboxylate (29).
704 cm−1 1H NMR (300 MHz, CDCl3) δ 7.06 (m, 1H, CH-5),
;
6.08 (m, 2H, CH-6/CH-7), 4.87 (d, J = 8.2 Hz, 1H, CH-3a), 4.85
(d, J = 8.3, 1H, CH-7a), 1.54 (s, 9H, CH3), 1.46 (s, 3H, CH3),
1.41 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 165.4 (CvO),
133.5 (CH-6), 133.1 (CH-5), 127.6 (C-4), 121.3 (CH-7), 105.5
(OCO-2), 81.0 (OC), 72.8 (CO-7a), 68.2 (CO-3a), 28.2 (CH3), 26.7
(CH3), 25.0 (CH3); MS (EI) m/z (%) 181 (25), 179 (14), 139 (46),
138 (40), 121 (46), 95 (19), 94 (21), 93 (13), 77 (14), 65 (24), 29: (70%); clear colourless oil; Rf = 0.53 [hexanes–EtOAc (4 : 1)];
57 (100); HRMS (EI) 252.1361 = C14H20O4; calcd C13H17O4 [α]2D0 = +75.8 (c = 1.5, CHCl3); IR (film) ν 3034, 2987, 2935,
[(M − 15)+, CH3]: 237.1122. Found: 237.1127.
7816 | Org. Biomol. Chem., 2014, 12, 7810–7819
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698 cm−1; 1H NMR (300 MHz, CDCl3): δ 7.39 (m, 5H, C6H5), 7.19 Acetonide 22 19,25d was dissolved in o-xylene and heated to
(m, 1H, CH-5), 6.12 (m, 2H, CH-6/CH-6), 5.28 (s, 2H, OCH2), 4.98 reflux for 24 hours. The solution was concentrated under
(d, J = 8.4 Hz, 1H, CH-3a), 4.88 (dd, J = 8.4, 2.2 Hz, 1H, CH-7a), reduced pressure and purified via flash column chromato-
1.48 (s, 3H, CH3), 1.42 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ graphy [hexanes–EtOAc (6 : 1)] to obtain 34 mg (42%) of 31 as
166.0 (CvO), 136.0 (CH-6), 134.2 (CH-5), 134.1 (C6H5), 128.5 white powdery solid.
(C6H5), 128.2 (C6H5), 128.1 (C6H5), 126.1 (C-4), 121.3 (CH-7),
105.6 (OCO-2), 72.5 (CO-7a), 68.2 (CO-3a), 66.5 (OCH2), 26.7 (pentane); [α]2D0 = +50.3 (c = 0.4, CHCl3); IR (film) ν 2932, 1737,
(CH3), 25.1 (CH3); MS (EI) m/z (%) 105 (15), 91 (100), 77 (14), 65 1436, 1379, 1283, 1262, 1210, 1164, 1060, 882, 804, 742 cm−1
31: Rf = 0.33 [hexanes–EtOAc (3 : 1)]; mp 180–183 °C
;
(25), 58 (11), 52 (15); HRMS (EI) 286.1205 = C17H18O4; calcd 1H NMR (600 MHz, CDCl3) δ 6.45 (d, J = 8.3 Hz, 1H, CH-5),
C11H13O4 [(M − 15)+, CH3]: 271.0965. Found: 271.0966.
6.20 (t, J = 7.2 Hz, 1H, CH-11), 5.40 (t, J = 2.6 Hz, 1H, CH-12),
4.63 (dd, J = 7.2, 1.4 Hz, 1H, CH-6a), 4.40 (dd, J = 7.3, 3.2 Hz,
1H, CH-9a), 4.29 (t, J = 7.6 Hz, 1H, CH-3a), 3.90 (s, 3H, OCH3),
3.79 (s, 3H, OCH3), 3.63 (t, J = 8.2, 1H, CH-10b), 3.37 (m, 1H,
CH-10), 3.11 (dt, J = 7.4, 2.5 Hz, 1H, CH-5a), 1.94 (dd, J = 8.3,
1.9 Hz, 1H, CH-10a), 1.51 (s, 3H, CH3), 1.35 (s, 6H, CH3), 1.30
(s, 3H, CH3); 13C NMR (150 MHz, CDCl3) δ 173.0 (CvO), 171.2
(CvO), 138.8 (CH-5), 129.7 (CH-11), 128.5 (CH-12), 117.8 (C-4),
110.0 (OCO-2), 109.9 (OCO-8), 79.0 (CO-6a), 78.4 (CO-9a), 77.3
(CO-3a), 56.3 (C-6), 52.6 (OCH3), 52.5 (OCH3), 48.9 (CH-5a),
42.6 (CH-10), 38.3 (CH-10a), 27.2 (CH3), 25.4 (CH3), 25.0 (CH3),
24.6 (CH3); MS (EI) m/z (%) 213 (8), 157 (6), 131 (6), 121 (7),
100 (13), 97 (6), 95 (6), 83 (6), 81 (4), 77 (7), 71 (6), 70 (5), 69
(15), 61 (5), 59 (5), 58 (100), 57 (12), 55 (9); HRMS (EI) calcd for
C22H28O8: 420.1784. Found: 420.1801; Anal. calcd for
C22H28O8: C, 62.85; H, 6.71. Found: C, 63.10; H, 6.79.
(+)-(3aS,5aS,6S,6aS,9aS,10R,10aR,10bS)-4,6-Diiodo-2,2,8,8-tetra-
methyl-3a,5a,6,6a,9a,10,10a,10b-octahydro-6,10-ethenonaphtho-
[1,2-d:6,7-d′]bis([1,3]dioxole) (30).
Acetonide 20 29 was dissolved in o-xylene and heated to reflux for
40 hours. The solution was concentrated under reduced pressure
and purified via flash column chromatography [hexanes–EtOAc
(4 : 1)] to obtain 0.19 g (38%) of 2 as a white solid.
30: Rf = 0.39 [hexanes–EtOAc (4 : 1)]; mp 220–224 °C
(EtOAc–pentane); [α]2D0 = +106.5 (c = 1.0, CHCl3); IR (film) ν
2984, 2933, 2898, 1455, 1380, 1280, 1262, 1236, 1225, 1209,
1160, 1082, 1068, 1012 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.89
(d, J = 3.7 Hz, 1H, CH-5), 6.25 (d, J = 8.6 Hz, 1H, CH-11), 5.79
(t, J = 7.3 Hz, 1H, CH-12), 4.49 (d, J = 7.2 Hz, 1H, CH-6a), 4.38
(dd, J = 7.2, 3.6 Hz, 1H, CH-9a), 4.18 (d, J = 4.6 Hz, 1H, CH-3a),
4.15 (d, J = 4.1 Hz, 1H, CH-10b), 2.91 (m, 1H, CH-10), 2.71 (dd,
J = 8.7, 3.6 Hz, 1H, CH-5a), 2.49 (d, J = 9.2 Hz, 1H, CH-10a),
1.47 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.36 (s,
3H, CH3); 13C NMR (150 MHz, CDCl3) δ 140.1 (CH-5), 139.0
(CH-11), 128.7 (CH-12), 109.3 (OCO-2), 108.7 (OCO-8), 103.9
(C-4), 84.7 (CO-6a), 79.1 (CO-9a), 78.6 (CO-3a), 75.2 (CO-10b),
48.3 (C-6), 45.6 (CH-5a), 38.4 (CH-10), 35.2 (CH-10a), 27.9
(CH3), 26.7 (CH3), 25.5 (CH3), 25.1 (CH3); MS (EI) m/z (%) 122
(11), 107 (14), 105 (11), 104 (43), 93 (11), 91 (26), 79 (23), 78
(10), 77 (23), 75 (27), 70 (12), 69 (11), 61 (14), 57 (18), 55 (15),
45 (19), 43 (100), 42 (11), 41 (18), 39 (15); HRMS (EI) calcd for
C18H22O4: 555.9607. Found: 555.9602; Anal. calcd for
C18H22I2O4: C, 38.87; H, 3.99. Found: C, 39.14; H, 4.04.
(+)-(3aR,5aR,6S,6aR,9aS,10R,10aS,10bS)-Diethyl 2,2,8,8-tetra-
methyl-3a,5a,6,6a,9a,10,10a,10b-octahydro-6,10-ethenonaphtho-
[1,2-d:6,7-d′]bis([1,3]dioxole)-4,6-dicarboxylate (32).
A solution of acetonide 23 20 was dissolved in o-xylene and
heated to reflux for 40 hours. The solution was concentrated
under reduced pressure and purified via flash column chrom-
atography [hexanes–EtOAc (4 : 1)] to obtain 0.34 g (68%) of 32
as pale yellow solid.
32: Rf
= 0.24 [hexanes–EtOAc (4 : 1)]; mp 91–93 °C
(pentane); [α]2D0 = +47.8 (c = 1.0, CHCl3); IR (film) ν 2984, 2937,
1721, 1458, 1380, 1262, 1221, 1163, 1072, 1026 cm−1; H NMR
1
(600 MHz, CDCl3) δ 6.43 (d, J = 3.8 Hz, 1H, CH-5), 6.38 (d, J =
8.8 Hz, 1H, CH-11), 6.04 (t, J = 7.0 Hz, 1H, CH-12), 4.60 (d, J =
7.0 Hz, 1H, CH-6a), 4.58 (d, J = 4.8 Hz, 1H, CH-9a), 4.43 (dd, J =
7.0, 3.3 Hz, 1H, CH-3a), 4.37 (q, J = 13.9 Hz, 2H, OCH2), 4.22
(m, 2H, OCH2), 4.16 (dd, J = 4.6, 1.9 Hz, 1H, CH-10b), 3.01 (m,
1H, CH-10), 2.95 (dd, J = 9.0, 3.3 Hz, 1H, CH-5a), 2.32 (d, J =
9.1, 1H, CH-10a), 1.35 (s, 3H, CH3), 1.33 (t, J = 7.1 Hz, 3H,
CH3), 1.29 (s, 3H, CH3), 1.28 (s, 3H, CH3), 1.27 (s, 3H, CH3),
1.26 (s, 3H, CH3); 13C NMR (150 MHz, CDCl3) δ 171.5 (CvO),
165.9 (CvO), 136.5 (CH-5), 131.5 (CH-11), 130.2 (CH-12), 128.8
(C-4), 109.7 (OCO-2), 108.2 (OCO-8), 80.7 (CO-6a), 78.3 (CO-9a),
76.9 (CO-3a), 69.2 (CO-10b), 61.5 (OCH2), 60.7 (OCH2), 53.9
(+)-(3aR,5aR,6S,6aR,9aS,10R,10aS,10bS)-Dimethyl 2,2,8,8-
tetramethyl-3a,5a,6,6a,9a,10,10a,10b-octahydro-6,10-etheno-
naphtho[1,2-d:6,7-d′]bis([1,3]dioxole)-4,6-dicarboxylate (31).
This journal is © The Royal Society of Chemistry 2014
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(C-6), 40.4 (CH-10), 38.6 (CH-5a), 34.9 (CH-10a), 28.1 (CH3),
26.5 (CH3), 25.4 (CH3), 25.1 (CH3), 14.2 (CH3), 14.2 (CH3); MS
(EI) m/z (%) 433 (22), 390 (27), 375 (22), 287 (22), 286 (25), 285
(65), 273 (14), 272 (27), 269 (53), 259 (20), 258 (17), 257 (26),
245 (17), 244 (22), 241 (32), 229 (26), 228 (14), 227 (100), 217
(14), 213 (27); HRMS (EI) 448.2097 = C24H32O8; calcd C23H29O8
[(M − 15)+, CH3]: 433.1857. Found: 433.1857; Anal. calcd for
C24H32O8: C, 64.27; H, 7.19. Found C, 63.99; H, 7.30.
wich, CT, 1993; (m) H. A. J. Carless, Tetrahedron: Asymmetry,
1992, 3, 795; (n) D. A. Widdowson, D. W. Ribbons and
D. D. Thomas, Janssen Chim. Acta, 1990, 8, 3.
4 G. J. Zylstra and D. T. Gibson, J. Biol. Chem., 1989, 264, 14940.
5 M. A. Endoma, V. P. Bui, J. Hansen and T. Hudlicky, Org.
Process Res. Dev., 2002, 6, 525.
6 T. Hudlicky, M. Stabile, D. T. Gibson and G. M. Whited,
Org. Synth., 1999, 76, 77.
7 (a) H. Ziffer, D. M. Jerina, D. T. Gibson and V. M. Bobal,
J. Am. Chem. Soc., 1973, 95, 4048; (b) V. M. Kobal,
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Acknowledgements
The authors are grateful to the following agencies for financial
support of this work: Natural Sciences and Engineering
Research Council of Canada (NSERC) (Idea to Innovation and
Discovery Grants), Canada Research Chair Program, Canada
Foundation for Innovation (CFI), TDC Research, Inc., TDC
8 T. Hudlicky, H. Luna, G. Barbieri and L. D. Kwart, J. Am.
Chem. Soc., 1988, 110, 4735.
9 D. R. Boyd, M. R. J. Dorrity, M. V. Hand, J. F. Malone,
N. D. Sharma, H. Dalton, D. J. Gray and G. N. Sheldrake,
J. Am. Chem. Soc., 1991, 113, 666.
Research Foundation, the Ontario Partnership for Innovation 10 D. R. Boyd, N. D. Sharma, B. Byrne, M. V. Hand,
and Commercialization (OPIC), and The Advanced Biomanu-
facturing Centre (Brock University).
J. F. Malone, G. N. Sheldrake, J. Blacker and H. Dalton,
J. Chem. Soc., Perkin Trans. 1, 1998, 1935.
The authors thank Melissa Di Santo, recipient of an NSERC 11 T. Hudlicky, M. R. Stabile, D. T. Gibson and G. M. Whited,
Undergraduate Student Research Award 2014, for assistance
with this project.
The authors thank Pavlína Horáková, a visiting exchange
Org. Synth., 1999, 76, 77.
12 T. Hudlicky, J. D. Price, F. Rulin and T. Tsunoda, J. Am.
Chem. Soc., 1990, 112, 9439.
student from Palackeho University in Olomouc, Czech Repub- 13 D. R. Boyd, M. V. Hand, N. D. Sharma, J. Chima, H. Dalton
lic for assistance on this project. Her visit was financed in part
by a grant CZ.1.07/2.4.00/31.0130 from European Social Funds.
and G. N. Sheldrake, J. Chem. Soc., Chem. Commun., 1991,
1630.
14 D. R. Boyd, N. D. Sharma, S. A. Barr, H. Dalton, J. Chima,
G. M. Whited and R. Seemayer, J. Am. Chem. Soc., 1994,
116, 1147.
15 T. Hudlicky, J. G. Seoane and T. Pettus, J. Org. Chem., 1989,
54, 4219.
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