A biomimetic total synthesis of allomicrophyllone: Protective Diels-Alder reaction as a stratagem

Article abstract of DOI:10.1016/j.tetlet.2010.10.063

A biomimetic total synthesis of bioactive tetracyclic natural product allomicrophyllone has been achieved in which a protective Diels-Alder reaction employing a disposable sacrificial 1,3-diene directs the regioselectivity of the subsequent Diels-Alder re

Full text of DOI:10.1016/j.tetlet.2010.10.063

Tetrahedron Letters 51 (2010) 6590–6593
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A biomimetic total synthesis of allomicrophyllone: protective Diels–Alder
reaction as a stratagem
⇑
Goverdhan Mehta , Tabrez Babu Khan
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A biomimetic total synthesis of bioactive tetracyclic natural product allomicrophyllone has been achieved
in which a protective Diels–Alder reaction employing a disposable sacrificial 1,3-diene directs the regi-
oselectivity of the subsequent Diels–Alder reaction.
Received 17 September 2010
Revised 7 October 2010
Accepted 7 October 2010
Available online 21 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Ehretia microphylla Lamk. (syn. Carmona retusa Vahl. Masam) is
an important medicinal plant in the Philippines and finds extensive
use in traditional medical practices for the treatment of ailments
ranging from coughs to dysentery.1 From the aerial parts of the
plant, isolation of triterpenes (ursolic acid and bauerenol), poly-
phenols (rosmarinic acid) and flavonoid glycosides (astragalin
and nicotoflorin) has been reported.2 A more recent3 bioassay
guided investigation of the aerial parts of the plants has led to
the isolation of five closely related dimeric prenyl-benzoquinones
namely microphyllone 1,2a dehydromicrophyllone 2, hydroxymi-
crophyllone 3, allomicrophyllone 4 and cyclomicrophyllone 5.
Among these novel natural products, microphyllone 1 and allomi-
of acremine G 9 towards allomicrophyllone 4 met with regioselec-
tivity hurdles which could be overcome through a tactical inter-
vention involving a protective Diels–Alder reaction to facilitate
the requisite biomimetic Diels–Alder reaction. In this Letter we dis-
close the successful application of the protective D–A tactic to-
wards the first total synthesis of allomicrophyllone 4.
OH
O
OH
O
OH
O
HO
HO
HO
O
O
O
crophyllone 4 exhibited impressive inhibitory activity (IC50 33
lM
and IC50 36 M, respectively) on exocytosis of rat basophils caused
l
OH
by antigen-induced stimulation, indicating their role as antiallergic
agents. During the structure elucidation of microphyllones 1–5,
Yamamura et al.3 proposed an interesting Diels–Alder cycloaddi-
tion based scheme for their biosynthesis involving two representa-
tive monomeric units, the dienophilic benzoquinone 6 and the
diene 7a (Scheme 1). Broadly, an enzyme mediated C–C oxidative
coupling in the putative Diels–Alder adduct 8 would lead to
hydroxymicrophyllone 3 (path ‘a’), while a C–O coupling in 8
would eventuate in allomicrophyllone 4 (path ‘b’) (Scheme 1).
Quite surprisingly, synthetic endeavours towards any of the micro-
phyllones 1–5 have not yet appeared in the literature despite their
interesting biosynthetic origin and promising antiallergic3 and hair
growth stimulant and promoter4 bioactivity.
microphyllone 1
dehydromicrophyllone 2 hydroxymicrophyllone 3
O
O
O
OH
O
O
O
O
HO
HO
O
HO
OH
OH
allomicrophyllone 4
cyclomicrophyllone 5
acremine G 9
To execute the biomimetic Diels–Alder cycloaddition strategy
towards allomicrophyllone 4, synthesis of the two key monomeric
units, the prenylated quinone 6 and prenylated diene 7a, was
undertaken along classical routes from readily available starting
materials.
Gentisaldehyde 10, obtained commercially, was routinely sub-
jected to Wittig-Horner olefination to furnish the cinnamate ester
11. Addition of excess methyllithium to 11 and periodate mediated
oxidation of the quinol moiety in the resulting tertiary alcohol 12
led to the desired benzoquinone 6 (Scheme 2).
Recently, we5 and others6 have reported the total synthesis of a
natural product acremine
G
9,7 having close structural
resemblance to allomicrophyllone 4, following a biogenetic-type
Diels–Alder approach.8 Seemingly straightforward adaptation of
the successful biomimetic Diels–Alder strategy5,6 in the context
⇑
Corresponding author. Tel.: +91 4023010785; fax: +91 4023012460.
E-mail addresses: gmsc@uohyd.ernet.in, gm@orgchem.iisc.ernet.in (G. Mehta).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.063

G. Mehta, T. B. Khan / Tetrahedron Letters 51 (2010) 6590–6593
6591
OH
O
oxidative C-C
coupling
O
HO
H
O
'a'
O
O
b
a
3
4
OH
Diels-Alder
reaction
+
HO
HO
O
O
O
oxidative C-O
coupling
'b'
OH
OH
OH
6
OH
HO
7a
O
8
OH
Scheme 1. Proposed biosynthetic pathways for 3 and 4.
OH
OH
CO2Me
CO2Me
a
TBSO
HO
a
O
O
OH
OH
11
OTBS
OH
10
11
13
MeO
b
b
OH
O
OH
c
c
TBSO
TBSO
OH
O
OTBS
OTBS
6
HO
12
HO
7b
14
Scheme 2. Reagents and conditions: (a) Ph3P@CHCO2Me, C6H6, reflux, 2 h, 88%; (b)
MeLi, THF, ꢁ30 °C, 1 h, 55% (based on the recovered starting material); (c) NaIO4,
MeOH/H2O (2:1), 0 °C to rt, 1 h, 83%.
Scheme 3. Reagents and conditions: (a) TBSCl, imidazole, DMAP, DMF, 80 °C, 12 h,
90%; (b) MeLi, THF, ꢁ78 °C, 30 min, 90%; (c) MsCl, Et3N, DMAP, CH2Cl2, 0 °C to rt, 1 h,
80%.
The cinnamate ester 11 also served as the precursor for the
prenylated diene component 7a. Protection of the phenolic hydro-
xyl groups in 11 as the TBS derivative 13 and addition of excess
methyllithium led to the tertiary alcohol 12 (Scheme 3). Dehydra-
tion in 14 was smooth and furnished the required TBS protected
diene 7b.
Me
O
R'
O
Me
a
+
OTBS
R
O
O
TBSO
6
With the prenylated benzoquinone 6 and the partner diene 7b
in hand, we explored the cycloaddition between them. In conso-
nance with our recent observation,5 the D–A reaction between 6
and 7b was dramatically accelerated by the commonly used chro-
matographic silica gel (100–200 mesh) and the reaction was over
in ꢀ5 min under ambient conditions. However, the reaction turned
out to be regioselective and deviant with only the unsubstituted
benzoquinone double bond participating and undergoing concom-
itant oxidation to furnish quinones 15a,b which were clearly
unserviceable for further elaboration, Scheme 4. This necessitated
devising a tactic that would subdue the reactivity of the unsubsti-
tuted quinone double bond and facilitate cycloaddition at the pre-
nyl bearing double bond, thereby reversing the regioselectivity of
the D–A reaction. Among the various options available, a dispos-
able thiophenyl substitution on the unsubstituted double bond of
6 appeared to be a viable tactic as this moiety is known10 to alter
the regioselectivity of Diels–Alder reaction and could be dispensed
with at an appropriate stage of the synthesis.
7b
15a,b
OH
OH
TBSO
TBSO
15a, R =
15b,
R' = H
OTBS
R' =
R = H
OTBS
Scheme 4. Reagents and conditions: (a) silica gel, rt, 5 min, 58% (based on the
recovered 7b).
nones 16 (Scheme 5). Reactions of thiophenylated quinones 16
with the diene 7b in the presence of silica gel indeed reversed
the quinone double bond regioselectivity and two [4+2]-adducts
179 and 189 (2:1 ratio) were obtained with complete stereoselec-
tivity (Scheme 5). Regioisomeric nature and endo-stereochemistry
of adducts 17 and 18 were deduced from 2D NMR data (HMBC,
HMQC) and particularly on the basis of nOe between the benzylic
methine proton and the olefinic proton on the neighbouring
bridgehead prenyl group. The stereochemical outcome of the
D–A reaction between 7b and 16 leading exclusively to 17 and
Thus, exposure of benzoquinone 6 to methanolic thiophenol
furnished a mixture of regioisomeric thiophenyl substituted qui-

6592
G. Mehta, T. B. Khan / Tetrahedron Letters 51 (2010) 6590–6593
O
O
O
O
H
H
SPh
+
TBSO
a
O
O
16
21
OTBS
6
OH
OH
OH
7b
b
a
O
O
H
H
SPh
O
O
O
O
nOe
nOe
H
H
H
H
H
H
H
+
nOe
TBSO
SPh
nOe
TBSO
H
+
H
O
H
O
H
H
TBSO
TBSO
OH
O
OH
OTBS
OTBS
OH
OH
17
18
OTBS
OTBS
22
b
c
ref. 5,6
ref. 5,6
23
O
e
c
ref. 5,6
O
SPh
O
O
O
H
O
H
HO
HO
SPh
O
O
O
HO
TBSO
OH
OH
H
O
20
19
OH
O
OH
Scheme 5. Reagents and conditions: (a) silica gel, rt, 5–6 h, 60% (overall, based on
the recovered 7b, 17 = 41% and 18 = 19%); (b) anhydrous KF, 30% HBr in glacial
AcOH, DMF, O2, rt, 36 h, 60%; (c) anhydrous KF, 30% HBr in glacial AcOH, DMF, O2, rt,
36 h, 54%.
OTBS
24
25
d
ref. 5,6
f
O
O
18 appears to be substantially influenced by the presence of the re-
mote thiophenyl group on the quinone moiety. Such regio- and ste-
reochemical effects have been previously observed and well
documented in the D–A reactions of dienes with related sulfinyl-
1,4-benzoquinones.11,12
O
O
HO
HO
O
The stage was now set to orchestrate the one-pot radical med-
iated intramolecular oxidative coupling reaction, recently discov-
ered by Stratakis and co-workers6 and extended by us,5 in 17
and 18, involving successive desilylation, epimerization and cycli-
zation. Both, 17 and 18 on exposure to in situ generated HF under
oxygen blanket led to thiophenylated allomicrophyllone deriva-
tives 199 and 20,9 respectively (Scheme 5). Structure of 19 was se-
cured by X-ray structure determination13 and confirmed the
presence of the allomicrophyllone framework. Reductive desulph-
urisation in 19 and 20 was expected to deliver the natural product
allomicrophyllone 5. However, various protocols to reductively re-
move thiophenyl group in 19/20 proved unsuccessful and we were
forced to change track.
OH
OH
4
26
Scheme 6. Reagents and conditions: (a) MeOH, 0 °C, 30 min, 95%; (b) 7b, silica gel,
rt, 72 h, 67% (overall, based on the recovered 7b, 22 = 51% and 23 = 16%); (c)
anhydrous KF, 30% HBr in glacial AcOH, DMF, O2, rt, 72 h, 58%; (d) diphenylether,
sealed tube, 200 °C, 6 h, 50%; (e) diphenylether, sealed tube, 175 °C, 1 h, 50%; (f)
anhydrous KF, 30% HBr in glacial AcOH, DMF, O2, rt, 72 h, 25%.
moiety to deliver allomicrophyllone 49 which was found to be
spectroscopically (1H & 13C NMR) identical with the natural
product.
Since the exo-adduct 22 was readily available, we elaborated it
into an epimer of allomicrophyllone. It turned out that the exo-ad-
duct 22 was amenable to retro-[4+2] reaction at this stage to deli-
ver 25 in moderate yield. Exposure of 25 to in situ generated HF led
to one-pot successive desilylation, epimerization and cyclization to
furnish epi-allomicrophyllone 269 (Scheme 6).
In short, we have accomplished a total synthesis of the dimeric
natural product allomicrophyllone following a biomimetic Diels–
Alder reaction between rapidly assembled monomeric diene and
dienophilic units. The desired D–A reaction was preceded by a pro-
tective Diels–Alder reaction with a disposable sacrificial cyclo-
pentadiene to ensure the requisite regioselectivity.
At this stage, we considered the possibility of a protective D–A
reaction to precede the desired D–A reaction to block the more
reactive unsubstituted double bond of the benzoquinone
6
employing cyclopentadiene (CP) as the sacrificial diene. Indeed,
D–A reaction of 6 with CP was smooth and furnished a single
endo-adduct 219 in a regio- and stereoselective manner. Silica-gel
mediated D–A reaction between 21 and the diene 7b led to two
[4+2]-adducts exo-229 and endo-239 in a ratio of 3:1, respectively
(Scheme 6). Clearly, the altered stereoelectronic environment in
the endo-adduct 21 profoundly impacted the stereoselectivity of
the D–A reaction with 7b and the exo-adduct 22 was formed as
the major product.12 In the context of the target allomicrophyllone
4, it was the endo-adduct 23 that was serviceable and further one-
pot cyclization with in situ generated HF as described by Stratakis
and co-workers6 led to the hexacyclic 24 embodying the allomicro-
phyllone moiety (Scheme 6). Retro-[4+2] reaction on 24 under
static thermal activation disengaged the sacrificial cyclopentadiene
Acknowledgements
T.B.K. thanks UGC for support through Dr. D.S. Kothari post-doc-
toral fellowship. G.M. wishes to thank CSIR, Eli Lilly and Jubilant
Bhartia Foundation for research support. The experimental work

G. Mehta, T. B. Khan / Tetrahedron Letters 51 (2010) 6590–6593
6593
–OH), 1.55 (d, J = 9 Hz, 1H), 1.44 (d, J = 9 Hz, 1H), 1.38 (s, 6H) ppm; 13C NMR
(100 MHz, CDCl3) d = 199.60, 198.73, 147.50, 147.27, 135.53, 135.09, 135.08,
118.58, 71.32, 49.08, 48.92, 48.88, 48.84, 48.56, 29.48 (2C) ppm; HRMS (ES) m/z
calcd for C16H18O3Na (M+Na)+: 281.1154; found: 281.1161; Compound 22 IR
1H
ꢀ
;
described here and the X-ray data collection were carried out at
IISc, Bangalore and we thank Mr. Saikat Sen for solving the crystal
structure.
(thin film) mmax ¼ 3500, 2930, 1703, 1486, 1248, 1200, 913, 839, 780 cmꢁ1
NMR (400 MHz, CDCl3) d = 6.57 (d, J = 8 Hz, 1H), 6.52 (dd, J = 3, 8 Hz, 1H), 6.35
(d, J = 3 Hz, 1H), 5.91 (dd, J = 3, 6 Hz, 1H), 5.83 (dd, J = 3, 6 Hz, 1H), 5.39 (d,
J = 5 Hz, 1H), 4.95 (s, 2H), 4.64 (d, J = 5 Hz, 1H), 3.47 (br s, 1H), 3.38 (br s,1H),
3.33 (dd, J = 4, 10 Hz, 1H), 3.28 (dd, J = 4, 10 Hz, 1H), 3.03 (dd, J = 8, 10 Hz, 1H),
2.50 (dd, J = 10, 18 Hz, 1H), 2.41 (dd, J = 8, 18 Hz, 1H), 1.78 (s, 3H), 1.45 (d,
J = 9 Hz, 1H), 1.31 (d, J = 9 Hz, 1H), 1.06 (s, 9H), 1.04 (s, 3H), 0.95 (s, 9H), 0.84 (s,
3H), 0.21 (s, 3H), 0.20 (s, 3H), 0.15 (s, 3H), 0.14 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) d = 210.67, 210.35, 149.64, 147.87, 140.06, 136.95, 136.05, 132.34,
130.89, 125.78, 123.65, 121.90, 120.11, 118.71, 70.30, 56.82, 51.55, 50.08,
48.57, 48.24, 46.86, 44.67, 38.85, 30.19, 29.20, 28.44, 25.93 (3C), 25.76 (3C),
23.13, 18.29, 18.28, ꢁ3.96, ꢁ4.38, ꢁ4.40, ꢁ4.61 ppm; HRMS (ES) m/z calcd for
Supplementary data
Supplementary data associated with (cystallographic details for
compound 19) this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.10.063.
References and notes
C
39H58Si2O5Na (M+Na)+: 685.3721; found: 685.3722; Compound 23 IR (thin
1. Quisumbing, E. Medicinal Plants of Philippines; Katha Publishing: Philippines,
1978. p 711.
2. (a) Agarwal, S. K.; Rastogi, R. P.; van Koningsveld, H.; Goubitz, K.; Olthof, G. T.
Tetrahedron 1980, 36, 1435–1440; (b) Rimando, A. M.; Inoshiri, S.; Otsuka, H.;
Kohda, H.; Yamasaki, K.; Padolina, W. G.; Torres, L.; Quintana, E. G.; Cantoria, M.
C. Shoyakugaku Zasshi 1987, 41, 242–247.
3. Yamamura, S.; Simpol, L. R.; Ozawa, K.; Ohtani, K.; Otsuka, H.; Kasai, R.;
Yamasaki, K.; Padolina, W. G. Phytochemistry 1995, 39, 105–110.
4. Hide, M.; Ohtani, K.; Koike, T.; Morihara, N. PCT Int. Appl. WO 2003022231 A1
20030320, 2003.
5. Mehta, G.; Khan, T. B.; Sunil Kumar, Y. C. Tetrahedron Lett. 2010, 51, 5116–5119.
6. Arkoudis, E.; Lykakis, I. N.; Gryparis, C.; Stratakis, M. Org. Lett. 2009, 11, 2988–
2991.
film) mmax ¼ 3460, 2929, 1698, 1487, 1249, 915, 839, 780 cmꢁ1
;
1H NMR
ꢀ
(400 MHz, CDCl3) d = 6.58 (s, 2H), 6.54 (s, 1H), 6.17 (dd, J = 3, 6 Hz, 1H), 5.96
(dd, J = 3, 6 Hz, 1H), 5.64 (d, J = 16 Hz, 1H), 5.57 (d, J = 16 Hz, 1H), 5.24 (br s, 1H),
4.0 (br s, 1H), 3.33 (br s, 1H), 3.06 (br s,1H), 2.76 (d, J = 18 Hz, 1H), 2.34 (dd,
J = 4, 10 Hz, 1H), 2.15 (d, J = 6 Hz, 1H), 2.04 (dd, J = 4, 10 Hz, 1H), 1.77 (s, 3H),
1.66–1.50 (m, 3H), 1.33 (s, 3H), 1.28 (s, 3H), 1.00 (s, 9H), 0.98 (s, 9H), 0.22 (s,
3H), 0.21 (s, 3H), 0.20 (s, 3H), 0.12 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d = 209.67, 209.24, 149.07, 148.31, 138.14, 137.00, 134.55, 133.88, 130.20,
129.48, 124.32, 121.39, 119.45, 118.66, 70.92, 57.07, 52.34, 51.15, 49.59, 49.35,
48.17, 47.67, 38.78, 30.04, 29.68, 26.07 (3C), 25.75 (3C), 24.57, 23.64, 18.31,
18.26, ꢁ3.98, ꢁ4.28, ꢁ4.39, ꢁ4.41 ppm; HRMS (ES) m/z calcd for C39H58Si2O5Na
(M+Na)+: 685.3721; found: 685.3721; allomicrophyllone (4) IR (thin film)
ꢀ
mmax ¼ 3420, 2928, 1684, 1522, 1205, 1017 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
7. Arnone, A.; Nasini, G.; Panzeri, W.; Vajna de Pava, O.; Malpezzi, L. J. Nat. Prod.
2008, 71, 146–149.
d = 6.84 (d, J = 10 Hz, 1H), 6.61 (d, J = 8 Hz, 1H), 6.57 (d, J = 3 Hz, 1H), 6.52 (dd,
J = 3, 8 Hz, 1H), 6.50 (d, J = 10 Hz, 1H), 5.76 (d, J = 16 Hz, 1H), 5.67 (d, J = 16 Hz,
1H), 5.64 (d, J = 6 Hz, 1H), 4.61 (br s, –OH), 3.77 (d, J = 6 Hz, 1H), 2.73 (d,
J = 19 Hz, 1H), 2.50 (d, J = 19 Hz, 1H), 1.69 (s, 3H), 1.22 (s, 6H) ppm; 13C NMR
(100 MHz, CDCl3) d = 195.64, 192.97, 149.82, 144.91, 143.20, 139.18, 138.44,
131.65, 127.55, 122.40, 121.88, 117.45, 114.75, 114.22, 80.57, 70.85, 54.70,
38.96, 36.07, 29.68, 29.66, 22.51 ppm; HRMS (ES) m/z calcd for C22H22O5Na
(M+Na)+: 389.1365; found: 389.1361; epi-allomicrophyllone (26) IR (thin film)
ꢀ
8. For selected recent examples of biomimetic/bioinspired Diels–Alder reaction in
natural product synthesis, see: (a) Heckrodt, T. J.; Mulzer, J. J. Am. Chem. Soc.
2003, 125, 4680–4681; (b) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.;
Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393–5407; (c) Mehta, G.; Pan, S. C.
Org. Lett. 2004, 6, 3985–3988; (d) Mehta, G.; Ramesh, S. S. Tetrahedron Lett.
2004, 45, 1985–1987; (e) Dong, S.; Zhu, J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2008,
130, 2738–2739; (f) Mehta, G.; Roy, S. Tetrahedron Lett. 2008, 49, 1458–1460;
(g) Arkoudis, E.; Stratakis, M. J. Org. Chem. 2008, 73, 4484–4490.
9. All new compounds reported here are racemic and characterized on the basis of
spectroscopic data (IR, 1H, 13C NMR and mass). Spectral data for some of the
mmax ¼ 3373, 2970, 1691, 1608, 1493, 1205, 895 cmꢁ1
;
1H NMR (400 MHz,
CDCl3) d = 6.99 (d, J = 8 Hz, 1H), 6.88 (d, J = 10 Hz, 1H), 6.64 (d, J = 10 Hz, 1H),
6.61 (dd, J = 3, 8 Hz, 1H), 6.42 (d, J = 3 Hz, 1H), 6.29 (d, J = 16 Hz, 1H), 5.64 (d,
J = 16 Hz, 1H), 5.18 (br s, 1H), 4.44 (br s, –OH), 3.77 (br s, 1H), 2.83 (d, J = 16 Hz,
1H), 2.58 (d, J = 16 Hz, 1H), 1.74 (br s, 3H), 1.32 (s, 3H), 1.30 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3) d = 197.14, 195.33, 150.30, 146.16, 143.30, 140.48,
140.35, 137.60, 125.41, 124.07, 121.82, 119.66, 114.22, 113.14, 85.73, 71.01,
63.69, 49.20, 38.22, 30.03, 29.76, 16.33 ppm; HRMS (ES) m/z calcd for
ꢀ
key compounds follows: Compound 17 IR (neat) mmax ¼ 3447, 2929, 2857, 1690,
1660, 1567, 1488, 1251, 1207, 920 cmꢁ1
;
1H NMR (400 MHz, CDCl3) 7.40–7.31
(m, 3H), 7.19 (d, J = 7 Hz, 2H), 6.55 (dd, J = 3, 8 Hz, 1H), 6.52 (d, J = 8 Hz, 1H),
6.44 (d, J = 3 Hz, 1H), 5.82 (d, J = 16 Hz, 1H), 5.68 (d, J = 16 Hz, 1H), 5.36 (br s,
1H), 5.32 (s, 1H), 4.11 (br s, 1H), 3.00 (d, J = 7 Hz, 1H), 2.94 (d, J = 18 Hz, 1H),
2.01 (dd, J = 7, 18 Hz, 1H), 1.82 (s, 3H), 1.31 (s, 3H), 1.28 (s, 3H), 0.99 (s, 9H),
0.97 (s, 9H), 0.23 (s, 3H), 0.21 (s, 3H), 0.14 (s, 3H), 0.08 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) d = 196.25, 194.38, 155.50, 149.79, 146.75, 138.37, 135.55
(2C), 133.02, 131.81, 129.91, 129.75 (2C), 129.41, 128.96, 127.87, 123.02,
122.16, 119.30, 118.83, 70.81, 56.70, 49.62, 40.45, 29.80, 29.68, 29.65, 26.10
(3C), 25.75 (3C), 23.35, 18.30, 18.19, ꢁ4.04, ꢁ4.20, ꢁ4.36, ꢁ4.43 ppm; HRMS
C
22H22O5Na (M+Na)+: 389.1365; found: 389.1369.
10. Wilgus, H. S., III; Frauenglass, E.; Chiesa, P. P.; Nawn, G. H.; Evans, F. G.; Gates, J.
W., Jr. Can. J. Chem. 1966, 44, 603–609.
11. Carman Carreno, M.; Garcia Ruano, J. L.; Toledo, M. A.; Urbano, A.; Remor, C. Z.;
Stefani, V.; Fisher, J. J. Org. Chem. 1996, 61, 503–509 and related work from the
same group.
12. For a discussion on the stereoelectronic control of Diels–Alder reaction, see: (a)
Mehta, G.; Uma, R. Acc. Chem. Res. 2000, 33, 278–286; (b) Brocksom, T. J.;
Nakamura, J.; Ferreira, M. L.; Brocksom, U. J. Braz. Chem. Soc. 2001, 12, 597–622.
13. Crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre, CCDC-793648. An ORTEP diagram of compound
19 with 30% ellipsoidal probability is shown below.
(ES) m/z calcd for
C
40H56O5SSi2Na (M+Na)+: 727.3285; found: 727.3268;
ꢀ
Compound 18 IR (thin film) mmax ¼ 3482, 2956, 2928, 2857, 2360, 1669, 1487,
1250, 1208, 921, 839 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d = 7.42–7.33 (m, 3H),
7.21 (d, J = 7 Hz, 2H), 6.62 (s, 2H), 6.51 (s, 1H), 5.89 (d, J = 16 Hz, 1H), 5.67 (d,
J = 16 Hz, 1H), 5.42 (s, 1H), 5.39 (br s, 1H), 4.18 (br s, 1H), 2.92 (dd, J = 3, 7 Hz,
1H), 2.76 (d, J = 18 Hz, 1H), 1.98 (dd, J = 7, 18 Hz, 1H), 1.78 (s, 3H), 1.37 (s, 3H),
1.32 (s, 3H), 1.03 (s, 9H), 0.96 (s, 9H), 0.26 (s, 3H), 0.16 (s, 3H), 0.13 (s, 3H), 0.11
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) d = 196.47, 193.94, 158.09, 149.46,
147.46, 139.00, 135.59 (2C), 133.09, 131.22, 130.01, 129.91 (2C), 128.56,
128.19, 127.91, 123.27, 122.06, 119.54, 119.16, 70.80, 57.39, 50.04, 40.70, 29.70
(2C), 29.61, 26.09 (3C), 25.72 (3C), 23.24, 18.40, 18.14, ꢁ3.89, ꢁ4.29, ꢁ4.40,
ꢁ4.44 ppm; HRMS (ES) m/z calcd for
C
40H56O5SSi2Na (M+Na)+: 727.3285;
ꢀ
found: 727.3282; Compound 19 mp 237–238 °C IR (thin film) mmax ¼ 3392,
2924, 1700, 1670, 1557, 1456, 1216, 1194 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d = 7.48–7.43 (m, 5H), 6.67 (d, J = 9 Hz, 1H), 6.54–6.51 (m, 2H), 5.75 (d,
J = 16 Hz, 1H), 5.72 (s, 1H), 5.65 (d, J = 16 Hz, 1H), 5.62 (br s, 1H), 4.70 (br s, –
OH), 3.75 (d, J = 6 Hz, 1H), 2.75 (d, J = 19 Hz, 1H), 2.55 (d, J = 19 Hz, 1H), 1.70 (br
s, 3H), 1.22 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) d = 192.38, 190.37, 157.37,
149.93, 144.84, 142.90, 135.41 (2C), 131.45, 130.52, 130.32 (2C), 127.89,
127.55, 126.94, 122.30, 121.74, 117.39, 114.74, 114.14, 81.08, 70.86, 54.31,
38.94, 36.22, 29.69, 29.65, 22.53 ppm; HRMS (ES) m/z calcd for C28H26O5SNa
+
ꢀ
(M+Na) : 497.1399; found: 497.1999; Compound 20 IR (thin film) mmax ¼ 3445,
1669, 1558, 1473, 1204, 754 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d = 7.48–7.41 (m,
5H), 6.64 (d, J = 9 Hz, 1H), 6.60 (d, J = 3 Hz, 1H), 6.55 (dd, J = 3, 9 Hz, 1H), 5.97 (s,
1H), 5.81 (d, J = 16 Hz, 1H), 5.66 (d, J = 16 Hz, 1H), 5.65 (d, J = 6 Hz, 1H), 4.48 (br
s, –OH), 3.84 (d, J = 6 Hz, 1H), 2.68 (d, J = 19 Hz, 1H), 2.51 (d, J = 19 Hz, 1H), 1.70
(br s, 3H), 1.25 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) d = 192.31, 190.17,
156.58, 149.70, 145.02, 143.43, 135.50 (2C), 131.86, 130.51, 130.32 (2C),
130.03, 127.81, 127.40, 122.52, 121.93, 117.31, 114.80, 114.13, 80.41, 70.92,
55.16, 39.20, 36.51, 29.68 (2C), 22.46 ppm; HRMS (ES) m/z calcd for
C
28H26O5SNa (M+Na)+: 497.1399; found: 497.1377; Compound 21 IR (thin
film) mmax ¼ 3421, 2973, 1654, 1273, 1130, 976 cmꢁ1
;
1H NMR (300 MHz,
ꢀ
CDCl3) d = 6.64 (d, J = 16 Hz, 1H), 6.59 (s, 1H), 6.52 (d, J = 16 Hz, 1H), 6.06 (br s,
2H), 3.54 (br s, 2H), 3.28 (dd, J = 4, 9 Hz, 1H), 3.23 (dd, J = 4, 9 Hz, 1H), 1.67 (br s,