Total Synthesis of (+)-Iresin

Article abstract of DOI:10.1021/acs.joc.5b00365

The first asymmetric total synthesis of (+)-iresin (4), an historically important ent-Drimane sesquiterpene lactone, was realized from aldehyde 3 via cyclic orthoester 6 in 5 steps. Notable transformations in this synthesis include a tandem trifluoroperacetic acid (TFPAA)-mediated Baeyer-Villiger oxidation-olefin epoxidation-epoxy ester cyclization, regioselective Burgess dehydration, and regioselective Fétizon oxidative lactonization. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b00365

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Note
Total Synthesis of (+)-Iresin
Bian-Lin Wang, Hai-Tao Gao, and Wei-Dong Z. Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00365 • Publication Date (Web): 23 Apr 2015
Downloaded from http://pubs.acs.org on April 25, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Total Synthesis of (+)ꢀIresin †
9
BianꢀLin Wang, a HaiꢀTao Gao, a and WeiꢀDong Z. Lia, b, *
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, P. R. China
bInnovative Drug Research Centre, Chongqing University, Chongqing 401331, P. R.
China
Eꢀmail: wdli@cqu.edu.cn
* Fax / Phone: 0086ꢀ(0)23ꢀ65678459
ABSTRACT: The first asymmetric total synthesis of (+)ꢀiresin (4), a historically
important entꢀDrimane sesquiterpene lactone, was realized from aldehyde 3 via cyclic
orthoester 6 in 5 steps. Notable transformations in this synthesis include a tandem
trifluoroperacetic acid (TFPAA)ꢀmediated Baeyer−Villiger oxidation−olefin
epoxidation−epoxy ester cyclization, regioselective Burgess dehydration, and
regioselective Fétizon oxidative lactonization.
Keywords: Homoiodo allylsilane, (+)ꢀIresin, Burgess reagent, Fétizon reagent, Total
synthesis
† In memory of Carl Djerassi
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 16
1
2
3
4
5
6
7
8
9
Drimane (known also as Iresane) sesquiterpenoids constitute a group of widely
occurring terpene natural products possessing a characteristic bicyclofarnesol skeleton
(Figure 1).1 Thus, the Drimane was once regarded as the missing biogenetic link
between the lower and higher terpenoids.2 Oxygenated Drimane sesquiterpenoids
exhibit a wide range of significant biological activities,1, 3 such as antifeedant,
insecticidal, and cytotoxic, have stimulated a great deal of attention on synthetic
development.4 (+)ꢀIresin (4), a unique entꢀDrimane sesquiterpene lactone, was first
isolated by Djerassi and coꢀworkers5 in 1954 from the Mexican herb plant Iresine
celosioides (known as “herb of the mayas”) and characterized6 in 1958 by extensive
chemical, spectroscopic methods, and Xꢀray crystallographic study as the tricyclic
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
dihydroxy lactone 4. Full NMR spectroscopic assignments of 4 appeared in 2005.7
The sole documented classical synthetic study on 4 by Pelletier and Prabhakar8 in
1968 led to the total synthesis of isoiresin in a racemic form.
O
HO
O
I
CHO
PMBO
O
ref. 9
SiR3
HO
HO
O
O
2
3
( )-Andrographolide (1)
this work
OH
O
O
HO
HO
Drimane
( )-Drimenol
(+)-Iresin (4)
Figure 1. Structure of (+)ꢀiresin and previous total synthesis of (−)ꢀandrographolide
(1) from homoiodo allylsilane epoxide 2 via aldehyde intermediate 3
ACS Paragon Plus Environment

Page 3 of 16
The Journal of Organic Chemistry
1
2
In a previous publication of this serial study,9 we have reported the total synthesis
of (−)ꢀandrographolide (1) from an homoiodo allylsilane epoxide 2 by a
conformationally directed biomimetic cationic cyclization to form aldehyde 3 as a
pivotal intermediate (Figure 1). We describe in this Note the first asymmetric total
synthesis of (+)ꢀiresin (4) from the same intermediate 3. The conversion of aldehyde 3
to lactone 4 requires the elaboration of an unsaturated γꢀlactone function which would
be achieved via oxidative cleavage of the formyl carbon and regioselective olefin
formation and subsequent lactonization.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The synthetic route to 4 commenced with aldehyde 3 is outlined in Schemes 1 and
2. To facilitate the Baeyer−Villiger oxidation,10 3 was converted to the corresponding
methyl ketone derivative 5 via a standard methylation−oxidation procedure. After
screening of peroxy acids, freshly prepared trifluoroperacetic acid (TFPAA, ca. 0.2 M)
was found to be the optimal oxidant in the presence of excess Na2HPO4 in CH2Cl2 at
0 °C. Keto olefin 5 was thus transformed to the cyclic orthoester 611 as the major
product (53%), along with the corresponding hydrolytic product monoacetates 7a and
7b (17%).11a, e The stereostructure of 6 was confirmed by a single crystal Xꢀray
diffraction analysis.12 It is worthwhile to note that not only the Baeyer−Villiger
oxygenation of the keto function occurred smoothly, but also the olefin epoxidation
and subsequent epoxideꢀopening−cyclization took place leading to the cyclic
orthoester 6. The acetonide function of 5 was also unexpectedly cleaved under these
reaction conditions. The unusual oneꢀpot formation of cyclic orthoester 6 could be
understood via the intramolecular rearrangement of an epoxy ester intermediate 5a as
depicted in Scheme 1, based on serial mechanistic studies by Giner et al. 11c−e Acidic
hydrolysis of orthoester 6 afforded a product mixture of monoacetates 7a and 7b, 11a, e
which was subjected to acetylation to give the tetrakisꢀacetate 8 in 68% yield from 6
(Scheme 2). Standard dehydration of 8 employing various dehydrating agents (i.e.
MsCl, SOCl2, or POCl3) in the presence of pyridine or Et3N led to, after deacetylation,
regioisomer 10 predominatedly (2.6∼4.1 : 1) in good yield. In contrast, with Burgess’
reagent (3 eq.),13 dehydration of 8 in warm benzene (50 °C) gave, after deacetylation,
the desired regioisomer 9 as the major product (4.8 : 1) in 70% overall yield.14
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 16
1
2
With 9 and 10 in hand, we selected the Fétizon’s reagent15 for the final oxidative
lactonization (Scheme 2). To our delight, oxidation of 9 with freshly prepared Fétizon
reagent in refluxing benzene produced the desired target lactone (+)ꢀiresin (4)
chemoselectively in 78% yield, along with aldehyde 11 in 14% yield. Reduction of 11
with NaBH4 at 0 °C in methanol gave (+)ꢀiresin (4) in 86% yield. Synthetic 4 exhibits
identical spectroscopic data with those of reported (+)ꢀiresin.5, 6 Further structural
confirmation of synthetic 4 was provided by the Xꢀray crystallographic analysis of the
bisꢀparaꢀbromobenzoate derivative 14.6e, 16 Interestingly, oxidation of 10 with excess
Fétizon reagent in refluxing benzene furnished lactone aldehyde 12 chemoselectively
in 91% yield, which was reduced with NaBH4 at 0 °C to give lactone 13 in 92% yield.
The structure of synthetic 13, known as isoiresin,8, 17 was further confirmed by a
single crystal Xꢀray crystallographic analysis.18
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Synthesis of orthoester 6 from aldehyde 3
ACS Paragon Plus Environment

Page 5 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
Scheme 2. Total syntheses of (+)ꢀiresin (4) and (−)ꢀisoiresin (13)
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
In summary, the first asymmetric total syntheses of (+)ꢀiresin (4) and (−)ꢀisoiresin
(13) were achieved from readily accessible aldehyde 3 in 5 and 6 steps, respectively.
Notable transformations include the peroxidation of keto olefin 5 with TFPAA leading
to cyclic orthoester
6
via
a
tandem Baeyer−Villiger oxidation−olefin
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 16
1
2
3
4
5
6
7
8
9
epoxidation−epoxy ester cyclization, regioselective dehydration of 8 with Burgess
reagent, as well as the regioselective Fétizon oxidative γꢀlactonization of 9 and 10.
The biomimetic synthetic approach19 demonstrated here for the entꢀDrimanes would
be equally effective for other Drimane sesquiterpenoids, i.e. starting from
synthetically readily accessible pseudoꢀantipodal intermediate 15.9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General
For product purification by flash column chromatography, silica gel (200~300
mesh) and petroleum ether (bp. 60~90 °C) were used unless otherwise noted. All
solvents were purified and dried by standard techniques, and distilled prior to use.
Other commercially available reagents were used as received without further
purification unless otherwise indicated. All organic extracts were dried over
anhydrous sodium sulfate or magnesium sulfate. All moistureꢀsensitive reactions were
carried out under an atmosphere of nitrogen in glassware that had been flameꢀdried
1
13
under vacuum. H and C NMR spectra were recorded on a 400 MHz spectrometer
with TMS as an internal reference and CDCl3 as solvent, unless otherwise indicated.
IR spectra were recorded on a FTꢀIR spectrometer as liquid film or KBr pellet. HRMS
were acquired on a FTꢀICR spectrometer. Melting points were measured on a hot
stage and were uncorrected.
1-((4aR,6aS,7R,10aS,10bR)-3,3,6a,10b-tetramethyl-8-methylenedecahydro-1H
-naphtho[2,1-d][1,3]dioxin-7-yl)propan-2-one (5). To a stirred solution of aldedyde
(1.20 g, 3.92 mmol) in dry Et2O (20 mL) was added 2.5 ml of CH3Li (1.6 M in
ACS Paragon Plus Environment

Page 7 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
diethylether, 4.0 mmol) dropwise at 0 °C under N2. After being stirred for 10 min, the
reaction mixture was quenched with water (2.0 mL). The ethereal layer was washed
with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was
used in the next step without further purification. DMSO (610 mg, 7.81 mmol) in
CH2Cl2 (4.0 mL) was added dropwise to a solution of oxalic dichloride (0.33 mL,
3.87 mmol) in CH2Cl2 (4.0 mL) at −78 °C under N2. After stirring for 15 min, the
solution of crude alcohol in CH2Cl2 (6.0 mL) was added via syringe, and the reaction
was stirred an additional 1 h at −78 °C. Et3N (2.2 mL, 15.7 mmol) was added, and the
reaction was stirred for 10 min at −78 °C. The bath was removed, the resulting
mixture was stirred for 20 min at room temperature. The mixture was partitioned
between H2O (15 mL) and CH2Cl2 (30 mL), and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2 × 15 mL), and the combined organic
layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified by flash silica gel column chromatography (petroleum
ether/EtOAc = 8:1) to give compound 5 (1.15 g, 92% from 3) as a colorless oil: Rf =
0.51 (petroleum ether/EtOAc = 8:1); [α]2D0 +20 (c 1.0, CHCl3); IR (film): νmax 3078,
2936, 2891, 1717, 1644, 1374, 1227, 1095, 885 cm–1; 1H NMR (400 MHz, CDCl3): δ
4.77 (s, 1H), 4.37 (s, 1H), 3.97 (d, J = 11.6 Hz, 1H), 3.50 (dd, J = 8.4, 4.0 Hz, 1H),
3.18 (d, J = 11.6 Hz, 1H), 2.68 (dd, J = 17.2, 10.4 Hz, 1H), 2.45−2.38 (m, 3H), 2.17
(s, 3H), 2.08 (td, J = 12.0, 4.8 Hz, 1H), 2.02−1.96 (m, 1H), 1.81−1.71 (m, 2H), 1.58
(ddd, J = 23.6, 7.6, 5.6 Hz, 1H), 1.41 (s, 3H), 1.37 (s, 3H), 1.35−1.26 (m, 3H), 1.21 (s,
3H), 0.91 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 208.3, 148.3, 107.2, 99.0,
76.4, 63.9, 52.0, 51.1, 40.1, 37.8, 37.7, 37.3, 34.4, 30.1, 27.2, 26.1, 25.3, 25.0, 23.0,
16.5 ppm; HRMS (ESI): calcd For C20H33O3 [M+H]+ 321.2424; found 321.2428.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3S,5aR,7aS,8R,9R,11aR,11bR)-8-(hydroxymethyl)-3,8,11a-trimethyldecahydr
o-1H-3,5a-epoxynaphtho[1,2-e][1,3]dioxepin-9-ol (6). To a stirred solution of 50 %
aq H2O2 (112 mg, 1.65 mmol) in CH2Cl2 (8.0 mL) was added TFAA (0.28 mL, 1.99
mmol) at 0 ºC. After being stirred for 25 min, powdered Na2HPO4 (1.13 g, 7.96 mmol)
was added to the mixture, then the solution of 5 (106 mg, 0.33 mmol) in CH2Cl2 (2.0
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 16
1
2
3
4
5
6
7
8
9
ml) was added dropwise over 5 min. After stirring for 25 min at 0 °C, the reaction
mixture was quenched with 5 mL of saturated aqueous Na2S2O3. The resulting
mixture was extracted with ethyl acetate (3 × 30 mL), and the combined organic
extracts were washed with water and brine, dried over anhydrous Na2SO4. The solvent
was evaporated under reduced pressure, and the residue was purified by silica gel
column chromatography eluting with 1:2 petroleum ether/EtOAc to give 6 as white
solids (55 mg, 53%) and the mixture of monoacetate products (7a and 7b, 19 mg,
17%). Compound 6: Rf = 0.39 (petroleum ether/EtOAc = 1 : 2); mp 118−121 °C; [α]D20
+6 (c 1, CHCl3); IR (KBr): νmax 3365, 2938, 2886, 1463, 1402, 1301, 1134, 863 cm–1;
1H NMR (400 MHz, CDCl3): δ 4.26 (d, J = 11.2 Hz, 1H), 4.03 (dd, J = 12.4, 5.6 Hz,
1H), 3.87 (d, J = 7.2 Hz, 1H), 3.82 (d, J = 12.4 Hz, 1H), 3.43−3.35 (m, 3H), 2.82 (d, J
= 7.6 Hz, 1H), 2.73 (s, 1H), 1.92−1.84 (m, 3H), 1.78−1.67 (m, 2H), 1.62 (dd, J = 12.8,
3.2 Hz, 1H), 1.58−1.49 (m, 1H), 1.55 (s, 3H), 1.26 (s, 3H), 1.14 (s, 3H), 0.94−0.89 (m,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ 119.7, 80.3, 79.8, 74.8, 63.9, 58.7, 53.7,
50.2, 42.4, 37.4, 36.9, 33.6, 27.2, 22.7, 22.3, 18.5, 16.7 ppm; HRMS (ESI): calcd For
C17H28O5 [M+H]+ 313.2010; found 313.2003. Xꢀray crystallographic data of 6:
C17H28O5, triclinic, space group: P1, a = 6.108 (2) Å, b = 7.159 (3) Å, c = 20.206 (7)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Å,
α
= 97.983(18)°, β = 91.80 (2)°, γ = 111.632(18)°, Z = 1, dcalcd = 1.281 g/cm3, R1(I >
2σ(I)) = 0.0451, wR2 = 0.1065. Compound 7a: 1H NMR (400 MHz, CD3OD): δ 4.15
(d, J = 11.2 Hz, 1H), 4.06 (d, J = 11.2 Hz, 1H), 3.95 (d, J = 10.8 Hz, 1H), 3.91 (dd, J
= 12.0, 4.0 Hz, 1H), 3.76 (dd, J = 11.6, 2.8 Hz, 1H), 3.40−3.34 (m, 2H), 2.05 (s, 3H,
CH3CO), 1.95 (d, J = 12.8 Hz, 1H), 1.85−1.70 (m, 3H), 1.65−1.63 (m, 2H), 1.54−1.49
13
(m, 1H), 1.21 (s, 3H), 1.45−1.37 (m, 2H), 1.06 (s, 3H), 0.97 (t, J = 7.2 Hz, 1H); C
NMR (100 MHz, CD3OD): δ 173.0, 81.2, 74.6, 71.8, 65.2, 59.5, 56.5, 56.4, 43.8, 39.0,
1
38.7, 38.3, 28.4, 23.6, 21.0, 19.0, 17.8 ppm. Compound 7b: H NMR (400 MHz,
CD3OD): δ 4.25−4.24 (m, 2H), 4.14 (d, J = 11.2 Hz, 1H), 3.43 (d, J = 10.8 Hz, 1H),
3.40−3.34 (m, 2H), 3.20 (d, J = 10.8 Hz, 1H), 2.01 (s, 3H, CH3CO), 1.89 (dt, J = 13.2,
3.2 Hz, 1H), 1.82−1.79 (m, 1H), 1.73−1.63 (m, 6H), 1.40 (t, J = 3.6 Hz, 1H), 1.22 (s,
4H), 0.98 (s, 3H); 13C NMR (100 MHz, CD3OD): δ 173.1, 81.1, 74.7, 69.8, 65.2, 63.0,
56.5, 53.6, 43.8, 39.0, 38.6, 38.1, 28.3, 23.5, 21.3, 19.0, 17.4 ppm.
ACS Paragon Plus Environment

Page 9 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
((1R,2R,4aS,5R,6R,8aR)-6-acetoxy-2-hydroxy-5,8a-dimethyldecahydronaphth
alene-1,2,5-triyl)tris(methylene) triacetate (8). To a stirred solution of 6 (260 mg,
0.83 mmol) in THF (4.0 mL) were added 6 N aq HCl (2.0 ml). After 30 min, the
reaction mixture was diluted with water (5.0 ml) and extracted with ethyl acetate (4 ×
20 mL). The combined organic extracts were washed with water and brine, dried over
Na2SO4, and concentrated in vacuo to give solid mixture of monoacetate products 7a
and 7b. To a solution of products 7a and 7b in pyridine (2.0 ml) was added Ac2O
(0.50 mL, 5.3 mmol) and DMAP (9 mg, 0.074 mmol). After stirring overnight at room
temperature, the reaction mixture was extracted with ethyl acetate, then washed with
saturated NaHCO3 solution, water and brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash silica gel column chromatography
(petroleum ether/EtOAc = 3:1) to give compound 8 (257 mg, 68% from 6, 80% from
mixture of 7a and 7b) as a colorless oil. Compound 8: Rf = 0.50 (petroleum
ether/EtOAc = 1 : 1); [α]2D0 –27 (c 1.0, CHCl3); IR (film): νmax 3498, 2949, 1738, 1441,
1372, 1246, 1037, 985 cm–1; 1H NMR (400 MHz, CDCl3): δ 4.59 (dd, J = 9.6, 7.2 Hz,
1H), 4.36 (d, J = 12.0 Hz, 1H), 4.28 (d, J = 4.0 Hz, 2H), 4.17 (d, J = 12.0 Hz, 1H),
3.98 (d, J = 11.2 Hz, 1H), 3.95 (d, J = 11.6 Hz, 1H), 2.09 (s, 3H), 2.06 (s, 3H), 2.04 (s,
3H), 2.03 (s, 3H), 1.97 (d, J = 13.2 Hz, 1H), 1.85−1.80 (m, 2H), 1.76−1.69 (m, 4H),
1.49−1.41(m, 1H), 1.34−1.25 (m, 2H), 1.07 (d, J = 12.0 Hz, 1H), 1.04 (s, 3H), 1.03 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ 170.9, 170.9, 170.6, 170.5, 79.7, 72.6, 70.9,
65.0, 61.3, 55.1, 53.3, 41.1, 37.6, 37.5, 23.3, 22.7, 21.2, 21.1, 20.9, 18.1, 16.2 ppm;
HRMS (ESI): calcd For C23H40NO9 [M+NH4]+ 474.2698; found 474.2704.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
((1S,4aS,5R,6R,8aR)-6-hydroxy-5,8a-dimethyl-1,4,4a,5,6,7,8,8a-octahydronap
hthalene-1,2,5-triyl)trimethanol
(9)
and
((4aS,5R,6R,8aR)-6-hydroxy-5,8a-dimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthale
ne-1,2,5-triyl)trimethanol (10). Compound 8 (250 mg, 0.55 mmol) in 2 ml of
benzene was added dropwise to a solution of Burgess reagent (390 mg, 1.64 mmol,
Burgess reagent was prepared according to the literature methods13d) in 3 mL of
benzene at 50 °C under N2. After being stirred for 1 h at 50 °C, the reaction mixture
was diluted with water (5.0 ml) and extracted with diethyl ether (3 × 10 mL). The
combined organic layers was washed with water and brine , dried over Na2SO4, and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 16
1
2
3
4
5
6
7
8
9
concentrated in vacuo to give a liquid residue. The residue was dissolved in dry
CH3OH (5.0 mL) and NaOCH3 (148 mg, 2.74 mmol) was added. The reaction
mixture was stirred for 3 h, then filtered through a pad of Celite, eluting with
CHCl3/CH3OH (10 : 1). The resulting filtrate was concentrated under reduced
pressure and purified by flash silica gel column chromatography CHCl3/CH3OH (25 :
1) to give 86 mg (58%) of 9 as white solids and 18 mg (12%) of 10 as white
amorphous solids. Compound 9: Rf = 0.46 (CHCl3/CH3OH = 10 : 1); mp 160−162 °C;
[α]2D0 –3 (c 1.0, CH3OH); IR (KBr): νmax 3327, 2930, 2858, 1707, 1448, 1363, 1024,
994 cm–1 ; 1H NMR (400 MHz, CD3OD): δ 5.77 (t, J = 2.4 Hz, 1H), 4.23 (d, J = 12.8
Hz, 1H), 4.19 (d, J = 11.2 Hz, 1H), 3.95 (d, J = 12.8 Hz, 1H), 3.83 (dd, J = 11.2 , 2.4
Hz, 1H), 3.62 (dd, J = 10.8, 7.2 Hz, 1H), 3.48 (d, J = 11.2 Hz, 1H), 3.39 (dd, J = 11.2,
4.4 Hz, 1H), 2.19−2.05 (m, 3H), 1.96 (t, J = 14.8 Hz, 1H), 1.82−1.74 (m, 2H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1.38−1.29 (m, 2H), 1.20 (s, 3H), 0.79 (s, 3H) ppm; C NMR (100 MHz, CD3OD): δ
138.7, 126.3, 81.4, 66.8, 65.0, 61.3, 55.9, 51.7, 43.1, 38.8, 36.5, 28.8, 24.4, 23.3, 16.1
ppm; HRMS (ESI): calcd For C15H26O4Na [M+Na]+ 293.1723; found 293.1727.
Compound 10: Rf = 0.55 (CHCl3/CH3OH = 10 : 1); [α]2D0 –81 (c 1.2, CH3OH); IR
1
(film): νmax 3340, 2937, 2858, 1700, 1448, 1359, 1017 cm–1 ; H NMR (400 MHz,
CD3OD): δ 4.20 (d, J = 12.0 Hz, 2.0H), 4.13 (d, J = 11.2 Hz, 1H), 4.02 (d, J = 11.6
Hz, 1H), 3.94 (d, J = 12.4 Hz, 1H), 3.41 (d, J = 11.2 Hz, 1H), 3.36 (dd, J = 10.8, 5.6
Hz, 1H), 2.35 (dd, J = 18.0, 5.6 Hz, 1H), 2.12 (ddd, J = 18.4, 11.6, 7.2 Hz, 1H),
1.95−1.77 (m, 4H), 1.51−1.42 (m, 2H), 1.22 (s, 3H), 1.23−1.21 (m, 1H), 1.00 (s, 3 H)
ppm; 13C NMR (100 MHz, CD3OD): δ 144.3, 136.8, 81.1, 65.2, 63.2, 57.6, 52.9, 43.7,
39.0, 35.5, 31.2, 28.9, 23.4, 21.6, 20.1 ppm; HRMS (ESI): calcd For C15H30NO4
[M+NH4]+ 288.2169; found 288.2173.
Synthesis of (+)-Iresin (4). A mixture of 9 (57 mg, 0.21 mmol), silver
carbonate−Celite (0.57 g/mmol, 600 mg, 1.05 mmol, Fétizon reagent was prepared
according to the literature methods15d) in 3 mL of benzene was heated to refluxed for
5 h, cooled and filtered through a pad of Celite (ethyl acetate). The solvent was
removed in vacuo and the residue was then purified by silica gel column
ACS Paragon Plus Environment

Page 11 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
chromatography (petroleum ether/EtOAc = 1 : 1) to give (+)ꢀIresin 1 (44 mg, 78%) as
colorless crystals and aldehyde 11 (8 mg, 14%) as a white solid. NaBH4 (2 mg, 0.052
mmol) at 0 °C was added to a solution of aldehyde in CH3OH (1 mL). After stirring
for 10 min at 0 °C, the reaction mixture was diluted with water (3.0 mL) and extracted
with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with 1 N
aq HCl, water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by flash silica gel column chromatography (petroleum
ether/EtOAc = 1:1) to give iresin (7 mg, 86% from 11) as white solids. Iresin (4): Rf =
0.47 (AcOEt); mp 139−142 °C, (Lit.5 mp 140−142 °C); [α]D20 +20 (c 1.0, CHCl3),
(Lit.5 [α]2D8 +21); IR (film): νmax 3383, 2931, 2870, 1755, 1687, 1423, 1221, 1028,
964 cm–1; 1H NMR (400 MHz, CDCl3): δ 6.86 (ddd，J = 3.6, 3.6, 3.6 Hz, 1H), 4.40
(dd, J = 9.2, 9.2 Hz, 1H), 4.26 (d, J = 10.4 Hz, 1H), 4.02 (dd, J = 9.2, 9.2 Hz, 1H),
3.54−3.49 (m, 2H), 3.12 (dd, J = 8.8, 2.0 Hz, 1H), 3.00 (d, J = 4.4 Hz, 1H), 2.83−2.77
(m, 1H), 2.51(dddd, J = 20.0, 4.8, 4.0, 4.0 Hz, 1H), 2.18−2.10 (m, 1H), 1. 89−1.79 (m,
2H), 1.68 (ddd, J = 13.6, 3.6, 3.6 Hz, 1H), 1.50 (dd, J = 12.0, 5.2 Hz, 1H), 1.35 (ddd,
J = 13.6, 13.6, 4.0 Hz, 1H), 1.28 (s, 3H), 0.77 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 169.8, 135.8, 127.0, 80.4, 67.2, 63.3, 50.6, 50.0, 42.1, 37.1, 33.7, 27.3, 24.6,
22.1, 14.3 ppm; HRMS (ESI): calcd For C15H23O4 [M+H]+ 267.1591; found
267.1585. Aldehyde 11: Rf = 0.64 (AcOEt); mp 145−147 °C; [α]2D0 +35 (c 0.6, CHCl3);
1H NMR (400 MHz, CDCl3): δ 10.00 (d, J = 1.2 Hz, 1H), 6.86 (d, J = 3.2 Hz, 1H),
4.44 (dd, J = 8.8, 8.8 Hz, 1H), 4.03 (dd, J = 8.8, 8.8 Hz, 1H), 3.37 (br d, J = 7.6 Hz,
1H), 2.85−2.80 (m, 2H), 2.67 (dddd, J = 20.4, 5.2, 4.0, 4.0 Hz, 1H), 2.49−2.45 (m,
1H), 1.97−1.94 (m, 2H), 1.75 (ddd, J = 13.6, 4.4, 4.4 Hz, 1H), 1.66 (dd, J = 11.6, 6.0
Hz, 1H), 1.42−1.35 (m, 1H), 1.34 (s, 3H), 0.74 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 206.4, 169.5, 134.6, 127.1, 76.9, 67.2, 51.9, 50.6, 49.4, 37.3, 34.2, 27.7,
24.5, 19.6, 13.6 ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of (−)-isoiresin (13). Lactonization of 10 to aldehyde 12 (91% yield)
was carried out by a procedure analogous to that of 9. Compound 12: white solids; Rf
= 0.57 (AcOEt); mp 151−154 °C; [α]2D0 –67 (c 1.0, CHCl3); H NMR (400 MHz,
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 16
1
2
3
4
5
6
7
8
9
CDCl3): δ 9.83 (d, J = 2.4 Hz, 1H), 4.77−4.65 (m, 2H), 3.29 (br s, 1H), 3.16 (d, J =
10.0 Hz, 1H), 2.52−2.47 (m, 1H), 2.29−2.15 (m, 2H), 2.07−1.95 (m, 2H), 1.86−1.80
(m, 1H), 1.76 (ddd, J = 13.2, 3.6, 3.6 Hz, 1H), 1.55 (dd, J = 12.8, 4.4 Hz, 1H),1.47 (d,
J = 12.0 Hz, 1H), 1.37 (s, 3H), 1.09 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
206.9, 173.7, 167.9, 124.1, 77.0, 68.3, 52.5, 51.5, 36.4, 34.0, 27.8, 21.5, 20.1, 19.2,
18.2 ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reduction of aldehyde 12 to isoiresin (13) (92% yield) was carried out by a
procedure analogous to that of aldehyde 11. Isoiresin (13): colorless crystals; Rf =
0.46 (AcOEt); mp 217−220 °C; [α]2D0 –62 (c 1.0, CHCl3); IR (KBr): νmax 3303, 2924,
1
2853, 1736, 1670, 1643, 1430, 1384, 1196, 1011, 989 cm–1; H NMR (400 MHz,
CDCl3): δ 4.76−4.62 (m, 2H), 4.23 (dd, J = 11.2, 2.0 Hz, 1H), 3.54−3.49 (m, 1H),
3.41 (t, J = 9.6 Hz, 1H), 2.72 (dd, J = 8.8, 2.4 Hz, 1H), 2.61 (d, J = 4.0 Hz, 1H), 2.43
(dt, J = 18.0, 2.8 Hz, 1H), 2.17−2.10 (m, 1H), 2.03−1.86 (m, 3H), 1.73 (ddd, J = 12.8,
13
3.2, 3.2 Hz, 1H), 1.53−1.45 (m, 2H), 1.31 (s, 3H), 1.14 (s, 3H) ppm; C NMR (100
MHz, CDCl3): δ 174.0, 169.2, 123.8, 80.1, 68.1, 63.8, 51.0, 42.9, 36.0, 33.8, 27.5,
22.6, 21.7, 21.5, 18.1 ppm; HRMS (ESI): calcd For C15H23O4 [M+H]+ 267.1591;
found 267.1586. Xꢀray crystallographic data of 13: C15H22O4, orthorhombic, space
group: C2221, a = 6.580 (6) Å, b = 12.892 (15) Å, c = 32.76 (3) Å, Z = 8, dcalcd
1.359 g/cm3, R1(I > 2σ(I)) = 0.0357, wR2 = 0.0836.
=
Preparation of bis-(4-Br)benzoate derivative 14 of (+)ꢀiresin (4). To a stirred
solution of (+)ꢀiresin (4) (43 mg, 0.16 mmol) in dry pyridine (2 mL) was added
pꢀbromobenzoyl chloride (177 mg, 0.81 mmol) and DMAP (2 mg, 0.016 mmol) at
room temperature. When the consumption of iresin was complete (monitored by TLC),
the reaction mixture was extracted with ethyl acetate, then washed with saturated
NaHCO3 solution, water and brine, dried over Na2SO4, and concentrated to give light
yellow solid residue, which after purification by flash column chromatography on
silica gel (benzene/EtOAc = 30:1) afforded 14 (97 mg, 95%) as colorless crystals. Rf
= 0.30 (petroleum ether/EtOAc = 1 : 2); mp 208−211 °C, (Lit.6e mp 211.5−212 °C);
[α]2D0 –50 (c 1.6, CHCl3); IR (KBr): νmax 3014, 2890, 1760, 1741, 1689, 1590, 1480,
ACS Paragon Plus Environment

Page 13 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1291, 1012, 846 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.81−7.78 (m, 4H), 7.53 (d, J =
8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 3.2 Hz, 1H), 4.96 (dd, J = 9.6, 6.4
Hz, 1H), 4.87 (d, J = 12.0 Hz, 1H), 4.59 (d, J = 11.6 Hz, 1H), 4.45 (dd, J = 9.2, 9.2 Hz,
1H), 4.08 (dd, J = 9.2, 9.2 Hz, 1H), 2.92−2.87 (m, 1H), 2.63 (dd, J = 20.0, 4.4 Hz,
1H), 2.53−2.45 (m, 1H), 1.96−1.91 (m, 2H), 1.81−1.75 (m, 2H), 1.60−1.52 (m, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1.23 (s, 3H), 0.92 (s, 3H) ppm; C NMR (100 MHz, CDCl3): δ 169.4, 165.8, 165.3,
135.1, 131.9, 131.6, 131.1, 130.9, 128.8, 128.7, 128.4, 128.3, 127.0, 80.2, 66.9, 64.1,
50.3, 50.2, 41.7, 36.9, 33.9, 25.1, 23.7, 22.1, 13.8 ppm; HRMS (ESI): calcd For
C29H29Br2O6 [M+H]+ 633.0305; found 633.0309. Xꢀray crystallographic data of 16:6e
C29H28Br2O6, monoclinic, space group: P21, a = 6.2860 (12) Å, b = 7.3672 (15) Å, c =
28.272 (6) Å, β = 92.047 (13)°, Z = 2, dcalcd = 1.605 g/cm3, R1(I > 2σ(I)) = 0.0530,
wR2 = 0.1339.
ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation (21132006) for financial
support. The Cheung Kong Scholars program and the scholars program of Chongqing
University are gratefully acknowledged.
ASSOCIATED CONTENT
Supporting Information: 1H and 13C NMR spectra for all compounds 4−6, 7a, 7b,
8−14, and Xꢀray crystallographic data for compounds 6, 13, 14, CIF files for
compounds 6, 13, 14. This material is available free of charge via the Internet at
http://pubs.acs.org.
REFERENCES
1. For excellent reviews on the occurrence, biological activity and synthesis of
Drimane sesquiterpenoids, see: (a) Jansen, B. J. M.; de Groot, Ae. Nat. Prod. Rep.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 16
1
2
3
4
5
6
2004, 21, 449−477. (b) Jansen, B. J. M.; de Groot, A. Nat. Prod. Rep. 1991, 8,
309−318.
7
8
9
2. (a) Ruzicka, L. Experientia 1953, 9, 357−367. (b) Parker, W.; Roberts, J. S.;
Ramage, R. Quarterly Rev., Chem. Soc. 1967, 331−363. (c) Rücker, G. Angew.
Chem., Int. Ed. 1973, 12, 793−806.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. For selected recent reports: (a) Xu, D.; Sheng, Y.; Zhou, Z.ꢀY.; Liu, R.; Leng, Y.;
Liu, J.ꢀK. Chem. Pharm. Bull. 2009, 57, 433−435. (b) Stierle, D. B.; Stierle, A. A.;
Girtsman, T.; McIntyre, K.; Nichols, J. J. Nat. Prod. 2012, 75, 262−266. (c) Felix,
S.; Sandjo, L. P.; Opatz, T.; Erkel, G. Beilstein J. Org. Chem. 2013, 9, 2866−2876.
(d) Felix, S.; Sandjo, L. P.; Opatz, T.; Erkel, G. Bioorg. Med. Chem. 2014, 22,
2912−2918.
4. For an eariler review, see: (a) Jansen, B. J. M.; de Groot, A. Nat. Prod. Rep. 1991,
8, 319−337. For selected recent reports: (b) Suzuki, Y.; Nishimaki, R.; Ishikawa,
M.; Murata, T.; Takao, K.ꢀi.; Tadano, K.ꢀi. J. Org. Chem. 2000, 65, 8595−8607.
(c) Justicia, J.; Oltra, J. E.; Barrero, A. F.; Guadano, A.; GonzalezꢀColoma, A.;
Cuerva, J. M. Eur. J. Org. Chem. 2005, 712−718. (d) D’Acunto, M.; Monica, C.
D.; Izzo, I.; De Petrocellis, L.; Di Marzo, V.; Spinella, A. Tetrahedron 2010, 66,
9785−9789. (e) Shi, H.; Fang, L.; Tan, C.; Shi, L.; Zhang, W.; Li, C.ꢀC.; Luo, L.;
Yang, Z. J. Am. Chem. Soc. 2011, 133, 14944−14947.
5. Djerassi, C.; Sengupta, P; Herran, J.; Walls, F. J. Am. Chem. Soc. 1954, 76,
2966−2968.
6. (a) Djerassi, C; Rittel, W.; Nussbaum, A. L.; Donovan, F. W.; Herran, J. J. Am.
Chem. Soc. 1954, 76, 6410−6411. (b) Djerassi, C.; Rittel, W. J. Am. Chem. Soc.
1957, 79, 3528−3534. (c) Djerassi, C.; Donovan, F. W.; Burstein, S.; Mauli, R. J.
Am. Chem. Soc. 1958, 80, 1972−1977. (d) Djerassi, C.; Burstein, S. J. Am. Chem.
Soc. 1958, 80, 2593. (e) Rossmann, M. G.; Lipscomb, W. N. Tetrahedron 1958, 4,
275−293. (f) Rossmann, M. G.; Lipscomb, W. N. J. Am. Chem. Soc. 1958, 80,
2592−2593. (g) Djerassi, C.; Burstein, S. Tetrahedron 1959, 7, 37−46.
ACS Paragon Plus Environment

Page 15 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7. Rios, M. Y.; Berber, L. A. Magn. Reson. Chem. 2005, 43, 339−342.
8. Pelletier, S. W.; Prabhakar, S. J. Am. Chem. Soc. 1968, 90, 5318−5320.
9. Gao, H.ꢀT.; Wang, B.ꢀL.; Li, W.ꢀD. Z. Tetrahedron 2014, 70, 9436−9448.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10. (a) Krow, G. T. Org. React. 1993, 43, 251−798. (b) Villamizar, J.; Plata, F.;
Canudas, N.; Tropper, E.; Fuentes, J.; Orcajo, A. Synth. Commun. 2006, 36,
311−320. (c) Chauvet, F.; CosteꢀManière, I; Martres, P.; Perfetti, P.; Waegell, B.;
Zahra, J.ꢀP. Tetrahedron Lett. 1996, 37, 3695−3696. (d) Ochiai, M.; Yoshimura,
A.; Miyamoto, K.; Hayashi, S.; Nakanishi, W. J. Am. Chem. Soc. 2010, 132,
9236−9239.
11. For examples on cyclic orhtoester formation, see: (a) Giner, J.ꢀL.; Ferris, W. V.,
Jr.; Mullins, J. J. J. Org. Chem. 2002, 67, 4856−4859. (b) Giner, J.ꢀL.; Faraldos, J.
A. J. Org. Chem. 2002, 67, 2717−2720. For mechanistic studies on the epoxy
ester−orthoester rearrangement, see: (c) Giner, J.ꢀL.; Li, X.ꢀY.; Mullins, J. J. J.
Org. Chem. 2003, 68, 10079−10086. (d) Giner, J.ꢀL. J. Org. Chem. 2005, 70,
721−724. (e) Giner, J.ꢀL.; Faraldos, J. A. Helv. Chim. Acta 2003, 86, 3613−3622.
(f) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.; Couladouros, E. A.;
Sorensen, E. J. J. Am. Chem. Soc. 1995, 117, 624−633.
12. For detailed Xꢀray crystallographic data, see Supporting Information. CCDC
1013827 contains the supplementary crystallographic data for compound 6. These
data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
13. (a) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744−4745. (b)
Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem. 1973, 38, 26−31.
(c) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94, 6135−6141. (d)
Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. Williams, W. M. Org. Synth.
1987, 6, 788−791. (e) Lamberth, C. J. Prakt. Chem. 2000, 342, 518−522.
14. The ratio of regioisomers was determined by 1H NMR spectroscopic analysis of a
crude product mixture of 9a and 10a:
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 16
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15. (a) Fétizon, M.; Golfier, M.; Louis, J.ꢀM. J. Chem. Soc., Chem. Commun. 1969,
1118−1119. (b) Fétizon, M.; Golfier, M.; Mourgues, P. Tetrahedron Lett. 1972,
43, 4445−4448. (c) Kakis, F. J.; Fétizon, M.; Douchkine, N.; Golfier, M.;
Mourgues, P.; Prange, T. J. Org. Chem. 1974, 39, 523−533. (d) Balogh, V.;
Fétizon, M.; Golfier, M. J. Org. Chem. 1971, 36, 1339−1341. (e) Heathcock, C.
H.; Stafford, J. A.; Clark, D. L. J. Org. Chem. 1992, 57, 2575−2585.
16. For detailed Xꢀray crystallographic data, see Supporting Information. CCDC
1013829 contains the supplementary crystallographic data for compound 13.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
17. Crabbe, P.; Burstein, S.; Djerassi, C. Bull. Soc. Chim. Belg. 1958, 67, 632−641.
18. For detailed Xꢀray crystallographic data, see Supporting Information. CCDC
1013828 contains the supplementary crystallographic data for compound 14.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
19. For earlier biomimetic approaches to the bicyclofarnesol skeleton, see: (a) van
Tamelen, E. E.; Hessler, E. J. J. Chem. Soc., Chem. Commun. 1966, 411−413. (b)
van Tamelen, E. E.; Coates, R. M. J. Chem. Soc., Chem. Commun. 1966,
413−415.
ACS Paragon Plus Environment