Synthetic studies towards bioactive frondosins: rapid framework access and diversity creation

Article abstract of DOI:10.1016/j.tetlet.2009.07.021

A very concise and diversity-oriented approach to rapidly access frondosin-related frameworks from commercially available building blocks is outlined.

Full text of DOI:10.1016/j.tetlet.2009.07.021

Tetrahedron Letters 50 (2009) 5263–5266
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies towards bioactive frondosins: rapid framework access
and diversity creation
*
Goverdhan Mehta , Nachiket S. Likhite
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A very concise and diversity-oriented approach to rapidly access frondosin-related frameworks from
commercially available building blocks is outlined.
Received 31 May 2009
Revised 23 June 2009
Accepted 3 July 2009
Available online 9 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Freyer and co-workers reported the isolation and structure
determination of five novel meroterpenoids from the marine
sponge Dysidea frondosa collected from the Pacific island, Pohnpei
in the Federated States of Micronesia.1 A bioassay-guided effort
yielded frondosins A-E 1–5, possessing novel carbon skeleta that
emanated through a mixed biosynthetic pathway. The structures
of 1–5 were derived through extensive two-dimensional NMR
studies.1 Besides their unusual molecular architecture, frondosins
1–5 exhibited promising bioactivity profiles. In particular, frondo-
sins inhibited binding of interleukin-8 (IL-8) to its receptor and
also protein kinase C in low micromolar range. Among the frondo-
sins, the simplest member frondosin 1 was found to be the most
3.2
l
M, respectively.1 The IC50 value of 1 against PKC-
M. Subsequently, researchers at the
a was even
more promising at 1.8
l
National Cancer Institute (NCI) reported the isolation of antipodal
frondosins A and D from another sponge, Euryspongia sp.,2 and ob-
served that these natural products exhibited HIV-inhibitory activ-
ity in anti-HIV assays.2
Since IL-8, a chemoattractant peptide for neutrophils, is impli-
cated in acute and chronic inflammatory disorders, tumour pro-
gression and metastasis,3 the promising bioactivity of frondosins
1–5 against this target has stimulated a great deal of interest and
activity towards their synthesis.
Several research groups have developed and successfully imple-
mented impressive synthetic strategies towards bioactive frondo-
sins.4–9 We have also accomplished the total synthesis of
frondosins A and B.10 However, recognizing the importance and
promise of frondosins in general, and of frondosin A in particular,
we decided to embark on a second-generation approach for the ra-
pid acquisition of the oxyarylated bicyclo[5.4.0]undecane-based
AB-ring core. The mandate of the present study was to enable cre-
ation of diversity around the frondosin scaffold, particularly with
regard to the arene and the seven-membered B-ring, rather than
achieve a particular target. In this Letter, we disclose a very concise
and practical synthesis of the frondosin core that enables ready ac-
cess to interesting functional variants and diversified structures.
Claisen–Schmidt condensation between cyclohexanone and the
dimethyl ether of gentisic aldehyde 6a led to the arylidene 7a and
further exhaustive methylation furnished the gem-dimethylated
product 8a,10 Scheme 1. Hosomi–Sakurai addition of allyltrimeth-
active with IC50 values against IL-8R
a
and IL-8Rb of 3.4 and
OH
HO
14
D
D
17
18
HO
C
O
10
1
A11
B
8
A
B
5
4
1: Frondosin A
2: Frondosin B
O
OR
O
O
OH
ylsilane to 8a in the presence of TiCl4 was stereoselective to furnish
11
*
*
9a as a single 10S ,11R -diastereomer (frondosin numbering).
The origin of stereoselectivity in this addition could possibly be
attributed to the intermediacy of a tight arene
p-stabilized tita-
4: Frondosin D (R = H)
5: Frondosin E (R = Me)
3: Frondosin C
nium enolate (see Scheme 1), which facilitates protonation from
the more open arene-bearing face. In a similar fashion, aldehydes
6b,c furnished 7b,c and were further gem-dimethylated to 8b,c,
respectively. Hosomi–Sakurai allylation of 8b,c led to 9b,c with
* Corresponding author. Tel.: +91 8023600367; fax: +91 8023600283.
E-mail address: gm@orgchem.iisc.ernet.in (G. Mehta).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.021

5264
G. Mehta, N. S. Likhite / Tetrahedron Letters 50 (2009) 5263–5266
R2
R2
R2
OMe
OMe
OMe
R1
R
R3
b
R1
R
R3
R1
R
R3
MeO
MeO
MeO
H
H
H
a
+
CHO
6a-c
a
+
O
OH
OH
O
O
O
9a
11
12
a: R = R3 = OMe, R1 = R2 = H
b: R = R2 = R3 = OMe, R1 = H
c: R = R2 = R3 = OMe, R1 = Br
7a-c
8a-c
c
b
c
OMe
OMe
OMe
R2
R2
R1
R1
R
R3
R3
MeO
MeO
MeO
H
H
H
d
R
H
OH
OH
Cl
Cl
O
Ti
OH
OH
OH
Cl
O
15
13
14
9a-c
Scheme 3. Reagents and conditions: (a) zinc dust, allyl bromide, THF, sonication,
10–15 °C, 15 min, 96%; (b) Grubbs’ 1st generation catalyst, C6H6, rt, 8 h, 98%; (c)
Grubbs’ 1st generation catalyst, C6H6, reflux, 2 h, 85%; (d) OsO4, 50% aq 4-
methylmorpholine N-oxide, acetone–water (4:1), rt, 12 h, 95%.
Scheme 1. Reagents and conditions: (a) 1.0 M aq NaOH, 12 h, 70% (7a, 7c), 80%
(7b); (b) tBuOK, MeI, toluene, 0 °C to rt, 3–4 h, 85% (8a), 80% (8b), 50% (8c); (c) (i)
TiCl4, À78 °C, CH2Cl2, 30 min, (ii) allyltrimethylsilane, À30 °C, 3–4 h, 98% (9a, 9b),
65% (9c).
OMe
OMe
OMe
a
excellent diastereocontrol, Scheme 1. The involvement of an elec-
tron-rich arene-stabilized titanium enolate species in the diaste-
reoselection was further supported by the fact that when the
Hosomi–Sakurai reaction was performed in the presence of iodine
MeO
MeO
MeO
H
H
H
+
instead of TiCl4, according to a recently reported protocol,12 a 1:1
O
11
*
*
*
*
OH
OH
diastereomeric mixture of 10S , 11R -9a and 10S ,11S -10 was
obtained, Scheme 2. Thus, the observed diastereoselection leading
to 9a–c appears to be a consequence of a subtle, but interesting
long-range interaction between the electron-rich arene ring and
the Ti-enolate.
10
16
17
c
b
OMe
OMe
Barbier-type addition of allyl bromide to 9a in the presence of
zinc led to a readily separable diastereomeric mixture (1:1) of 11
and 12 to set-up the contemplated RCM protocol. Indeed, exposure
of tertiary alcohols 11 and 12 to Grubbs’ I catalyst smoothly led to
oxyarylated bicyclo[5.4.0]undecanes 13 and 14, respectively.11
OsO4-Mediated dihydroxylation of 13 led to a crystalline triol 15
whose X-ray crystal structure secured the stereochemical assign-
ment of its precursors 13, 11 and 9a and by extrapolation of 12
and 14, Scheme 3.13 Access to the frondosin core could also be
achieved from the 10S ,11S -isomer 10 through Barbier addition
to give diastereomeric tertiary alcohols 16 and 17 and RCM medi-
ated by Grubbs’ I catalyst furnished bicyclic compounds 18 and 19,
respectively, Scheme 4.11 The stereostructures of these were se-
cured through single crystal X-ray structure determination of 18.13
In a similar manner, 9b and 9c were subjected to Barbier reac-
tion with allyl bromide in the presence of zinc; quite unexpectedly,
the additions were stereoselective furnishing 20 and 21, respec-
tively, Scheme 5. A single crystal X-ray structure determination13
of 21 settled the stereochemical issues. Both dienes 20 and 21
MeO
MeO
H
H
OH
OH
ORTEP
18
19
Scheme 4. Reagents and conditions: (a) zinc dust, allyl bromide, THF, sonication,
10–15 °C, 15 min, 86%; (b) Grubbs’ 1st generation catalyst, C6H6, reflux, 2 h, 65%; (c)
Grubbs’ 1st generation catalyst, C6H6, reflux, 1 h, 88%.
*
*
MeO
MeO
OMe
OMe
OMe
OMe
a
R
R
R
MeO
MeO
MeO
H
H
H
b
O
OH
OH
20 (R = H)
21 (R = Br)
22 (R = H)
23 (R = Br)
9b (R = H)
9c (R = Br)
OMe
OMe
+
OMe
a
Scheme 5. Reagents and conditions: (a) zinc dust, allyl bromide, THF, sonication,
10–15 °C, 15 min, 74% based on recovered starting material (20), 64% based on
recovered starting material (21); (b) Grubbs’ 1st generation catalyst, C6H6, reflux, 2–
4 h, 99% (22), 65% (23).
MeO
MeO
MeO
H
H
O
O
O
underwent smooth and efficient RCM reaction on exposure to
Grubbs’ I catalyst to furnish bicyclic compounds 22 and 23, respec-
tively, Scheme 5.11 This sequence enabled a rapid five-step access
to the basic bicyclic core of frondosins with functional variation
10
8a
9a
Scheme 2. Reagents and conditions: (a) allyltrimethylsilane, cat. I2, CH2Cl2, 0 °C to
rt, 5 h, 88%.

G. Mehta, N. S. Likhite / Tetrahedron Letters 50 (2009) 5263–5266
5265
OMe
OMe
OMe
OMe
OMe
OMe
MeO
H
MeO
MeO
H
MeO
MeO
MeO
H
H
H
a
b
a
b
O
O
OH
OH
OH
14
32
33
13 (β -OH)
14 (α -OH)
24
25
c
OMe
OMe
OMe
d
c
OMe
OMe
OH
OH
MeO
MeO
MeO
OH
O
e
d
MeO
MeO
H
H
O
O
OH
36
34
35
O
ORTEP of 26
27
26
Scheme 8. Reagents and conditions: (a) tBuOK, DMSO, rt, 12 h, 60% based on
recovered starting material; (b) SOCl2, pyridine, À40 °C, 15 min, 80%; (c) OsO4, 50%
aq 4-methylmorpholine N-oxide, acetone–water (4:1), rt, 12 h, 60%; (d) DMP,
CH2Cl2, 0 °C to rt, 5 h, 78%; (e) CF3COOH, CH2Cl2, 0 °C, 30 min, 53%.
Scheme 6. Reagents and conditions: (a) SOCl2, pyridine, À40 °C, 15 min, 72–75%;
(b) 1O2, TPP, CH2Cl2, rt, 8 h, quant.; (c) (i) zinc dust, AcOH, CH2Cl2, rt, 24 h, 92%; (ii)
MnO2, CH2Cl2, rt, 5 h, quant.; (d) PDC, tBuOOH, CH2Cl2, 0 °C to rt, 2 h, 20% or Cr(CO)6,
tBuOOH, MeCN, reflux, 2 h, 30%.
cascade of cyclopropylcarbinyl–cyclobutyl cation rearrangements,
Scheme 7. On the other hand, tertiary alcohol 18 on exposure to
BF3ÁOEt2 furnished the homoconjugated diene 30, which could be
partially reduced to furnish the frondosin prototype structure 31,
Scheme 7.
at the arene moiety from commercial starting materials and set the
stage to explore further creation of diversity on the seven-mem-
bered ring of the bicyclic framework.
Towards this end, bicyclic tertiary alcohols 13 and 14, on expo-
sure to classical dehydration conditions, furnished smoothly cyclo-
heptadiene derivative 24, Scheme 6.
Oxyfunctionalization of 24 was achieved through singlet oxy-
gen-mediated photooxygenation to furnish stereoselectively endo-
peroxide 25 through addition from the upper face, Scheme 6.
Reductive peroxide cleavage of 25 to the 1,4-enediol and MnO2
oxidation furnished a crystalline hemiketal 26, the stereostructure
of which was elucidated through single crystal X-ray structure
determination. In an alternate oxyfunctionalization approach,
diene 24 was subjected to direct allylic oxidation with either
PDC/tBuOOH or Cr(CO)6/tBuOOH,14 which interestingly led to the
transposed cycloheptadienone 27, Scheme 6.11
In the context of further amplifying the substitution on the se-
ven-membered ring, it was observed that the double bond in 14
could be relocated to give 3211 through exposure to a base, Scheme
8. Further, controlled dehydration in 32 furnished the cyclohepta-
diene 33. Regioselective OsO4-mediated dihydroxylation of 33 led
to 34, which could be oxidized to the a
-hydroxyketone 35.11 Expo-
sure of 34 to acid led to the tricyclic dihydrofuran derivative 36,
Scheme 8.11
In summary, we have delineated a concise route to the core
structure of bioactive frondosins that is amenable to ready diversi-
fication of the arene moiety and enables functionalization of all the
positions on the seven-membered ring.
It is interesting to note that the dehydration of bicyclic tertiary
alcohols in Lewis acid medium takes a somewhat different course.
For example, compound 14 on exposure to BF3-etherate led to the
cyclopropane-bearing tricycle 28 (stereostructure established
through 2D NMR studies)11 via the possible intermediacy of cyclo-
propylcarbinyl cation 29 and a 1,3-cyclopropane shift involving a
Acknowledgements
NSL thanks CSIR for the award of a research fellowship. X-ray
data were collected at the CCD facility at IISc. We thank Mr. Saikat
Sen for crystal structure determination and Dr. C. S. Ananda Kumar
for help with some experiments. GM is thankful to CSIR for the
award of a Bhatnagar Fellowship and to CBU of JNCASR, Bangalore,
for supporting this research.
OMe
OMe
OMe
References and notes
MeO
MeO
MeO
H
H
a
1. Patil, A. D.; Freyer, A. J.; Killmer, L.; Offen, P.; Carte, B.; Jurewicz, A. J.; Johnson,
R. K. Tetrahedron 1997, 53, 5047–5060.
2. Hallock, Y. F.; Cardellina, J. H., II; Boyd, M. R. Nat. Prod. Lett. 1998, 11, 153–160.
3. (a) Seitz, M.; Dewald, B.; Gerber, N.; Baggiolini, M. J. Clin. Invest. 1991, 87, 463–
469; (b) Miller, E. J.; Cohen, A. B.; Nagao, D.; Griffith, R. J.; Maunder, R. J.;
Martin, T. R.; Weiner-Kronish, J. P.; Sticherling, M.; Christophers, E.; Matthay,
M. A. Am. Rev. Respir. Dis. 1992, 146, 427–432; (c) Brat, D. J.; Bellail, A. C.; Van
Meir, E. G. Neurooncology 2005, 7, 122–133; (d) Zhu, Y. M.; Webster, S. J.;
Flower, D.; Woll, P. J. Br. J. Cancer 2004, 91, 1970–1976.
OH
14
29
28
OMe
OMe
OMe
4. (a) Inoue, M.; Frontier, A. J.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2000, 39,
761–764; (b) Inoue, M.; Carson, M. W.; Frontier, A. J.; Danishefsky, S. J. J. Am.
Chem. Soc. 2001, 123, 1878–1889.
MeO
MeO
MeO
H
b
c
5. (a) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 1569–1572; (b)
Hughes, C. C.; Trauner, D. Tetrahedron 2004, 60, 9675–9686.
6. (a) Kerr, D. J.; Willis, A. C.; Flynn, B. L. Org. Lett. 2004, 6, 457–460; (b) Masters,
K.-S.; Flynn, B. L. J. Org. Chem. 2008, 73, 8081–8084.
OH
18
30
31
7. (a) Li, X.; Ovaska, T. V. Org. Lett. 2007, 9, 3837–3840; (b) Li, X.; Kyne, R. E.;
Ovaska, T. V. Tetrahedron 2007, 63, 1899–1906; (c) Li, X.; Keon, A. E.; Sullivan, J.
A.; Ovaska, T. V. Org. Lett. 2008, 10, 3287–3290.
Scheme 7. Reagents and conditions: (a) cat. BF3ÁOEt2, CH2Cl2, 0 °C, 15 min, 58%; (b)
cat. BF3ÁOEt2, CH2Cl2, 0 °C, 15 min, 82%; (c) 10% Pd–C, H2, EtOAc, rt, 5 min, quant.

5266
G. Mehta, N. S. Likhite / Tetrahedron Letters 50 (2009) 5263–5266
8. Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem. Soc. 2007, 129, 11781–11790.
9. Oslon, J. P.; Davies, H. M. L. Org. Lett. 2008, 10, 573–576.
0.98 (m, 2H), 1.01 (s, 3H), 0.99 (s, 3H); 13C NMR (75 MHz, CDCl3): d 153.39,
150.10, 138.82, 134.87, 131.40, 117.88, 111.89, 111.74, 56.59, 55.58, 41.01,
39.05, 37.14, 37.03, 30.53, 27.27, 25.41, 24.18, 21.99, 21.94 [2C]; HRMS (ES): m/z
calcd for C21H30O3 (M+Na)+: 353.2093, found: 353.2086; 35 IR (neat): mmax
10. Mehta, G.; Likhite, N. S. Tetrahedron Lett. 2008, 49, 7113–7116.
11. All new compounds reported here are racemic and characterized on the basis of
spectroscopic data (IR, 1H, 13C NMR and mass). Spectral data of some key
3433, 2929, 2861, 1698, 1492, 1464, 1224 cmÀ1 1H NMR (300 MHz, CDCl3): d
;
compounds follows: 9a IR (neat): mmax 2932, 1705, 1503, 1460 cmÀ1
;
1H NMR
6.96 (s, 1H), 6.85 (s, 2H), 4.79 (s, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 2.70–2.65 (m, 2H),
2.32–1.98 (m, 4H), 1.81–1.46 (m, 6H), 1.09 (s, 3H), 1.02 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 209.01, 153.80, 151.40, 144.16, 132.04, 130.79, 114.42,
114.31, 113.35, 83.43, 56.17, 55.58, 53.41, 41.19, 39.31, 36.76, 28.06 [2C], 27.70,
26.98, 19.67; HRMS (ES): m/z calcd for C21H28O4 (M+Na)+: 367.1885, found:
(300 MHz, CDCl3): d 6.77 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 3.0 Hz, 1H), 6.61 (d,
J = 2.7 Hz, 1H), 5.66–5.52 (m, 1H), 4.89–4.77 (m, 2H), 3.76 (s, 3H), 3.75 (s, 3H),
3.48–3.40 (m, 1H), 3.03–2.94 (m, 1H), 2.47–2.28 (m, 2H), 1.76–1.72 (m, 2H),
1.55–1.49 (m, 4H), 1.23 (s, 3H), 1.08 (s, 3H); 13C NMR (75 MHz, CDCl3): d 216.84,
153.42, 152.48, 137.32, 132.57, 116.22, 115.15, 111.68, 110.53, 56.09, 55.55,
50.18, 46.20, 42.74, 37.99, 33.81, 25.53, 24.51 [2C], 21.84; HRMS (ES): m/z calcd
for C20H28O3 (M+Na)+: 339.1936, found: 339.1933; 10 IR (neat): mmax 2934,
367.1874; 36 IR (neat): m ;
max 2926, 1582, 1495, 1462, 1219, 1048 cmÀ1 1H NMR
(300 MHz, CDCl3): d 6.85–6.76 (m, 3H), 5.05 (s, 1H), 3.78 (s, 3H), 3.77 (s, 3H),
2.58–2.52 (m, 1H), 2.08–1.96 (m, 2H), 1.69–1.39 (m, 6H), 1.35–1.20 (m, 2H),
1.17–1.11 (m, 1H), 0.98 (s, 3H), 0.93 (s, 3H); 13C NMR (75 MHz, CDCl3): d 153.20
[2C], 137.96, 130.17, 124.31, 116.69, 112.52, 112.48, 89.83, 81.75, 56.19, 55.66,
37.13, 36.16, 25.05, 24.53, 24.25 [2C], 23.09, 20.31, 17.75; HRMS (ES): m/z calcd
for C21H28O3 (M+Na)+: 351.1936, found: 351.1948.
1710, 1642, 1592, 1500, 1460 cmÀ1 1H NMR (300 MHz, CDCl3): d 6.77 (d,
;
J = 8.7 Hz, 1H), 6.69 (dd, J = 8.4, 2.7 Hz, 1H), 6.65 (d, J = 3.3 Hz, 1H), 5.70–5.59
(m, 1H), 5.00–4.86 (m, 2H), 3.75 (s, 6H), 2.95–2.85 (m, 1H), 2.43–2.32 (m, 2H),
2.06–1.99 (m, 1H), 1.78–1.36 (m, 6H), 1.15 (s, 3H), 1.03 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 215.74, 153.12, 151.59, 137.17, 133.41, 115.61, 115.22,
111.28, 110.02, 55.95, 55.58, 49.31, 45.61, 41.61, 35.38, 33.13, 29.25, 25.67,
25.28, 21.58; HRMS (ES): m/z calcd for C20H28O3 (M+Na)+: 339.1936, found:
12. Yadav, J. S.; Reddy, B. V. S.; Sadasiv, K.; Satheesh, G. Tetrahedron Lett. 2002, 43,
9695–9697.
13. X-ray data were collected at 293 K on a SMART CCD–BRUKER diffractometer
339.1920; 13 IR (neat):
m
max 3573, 2934, 1499, 1465 cmÀ1
;
1H NMR (300 MHz,
with graphite monochromated MoKa radiation (k = 0.71073 Å). Structures
CDCl3): d 6.84 (d, J = 3.0 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.68 (dd, J = 9.0, 3.0 Hz,
1H), 5.93–5.86 (m, 1H), 5.56–5.50 (m, 1H), 3.75 (s, 6H), 3.08–2.96 (m, 2H), 2.75
(s, 1H), 2.69 (br s, 1 H), 2.47 (dd, J = 17.5, 7.6 Hz, 1H), 2.19–2.12 (m, 1H), 1.96
(dd, J = 16.4, 7.4 Hz, 1H), 1.57–1.52 (m, 1H), 1.37–1.25 (m, 5H), 1.06 (s, 3H), 0.95
(s, 3H); 13C NMR (75 MHz, CDCl3): d 153.68, 150.93, 137.67, 132.66, 126.17,
114.37, 111.93, 110.68, 78.13, 56.20, 55.62, 47.52, 39.73, 37.68, 34.96, 31.91,
29.99, 25.63, 23.36, 20.99 [2C]; HRMS (ES): m/z calcd for C21H30O3 (M+Na)+:
353.2093, found: 353.2088; 14 IR (neat): mmax 3563, 2932, 1613, 1499,
were solved by direct methods (SIR92). Refinement was by full-matrix least-
squares procedures on F2 using SHELXL-97. Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre. Compound 15:
CCDC 697875, C21H32O5, MW = 364.47, crystal system: triclinic, space group:
ꢀ
P1, cell parameters: a = 8.0132 (55) Å, b = 11.3339 (78) Å, c = 12.1107 (83) Å,
a
= 66.434 (10)°, b = 83.514 (11)°,
c
= 88.146 (11)°, V = 1001.62 (51) Å3, Z = 2,
q
calcd = 1.21 g cmÀ3
,
F(0 0 0) = 396.0,
l
= 0.085 mmÀ1
,
number of l.s.
r(I) and 0.090 for
parameters = 251, R1 = 0.061 for 2474 reflections with I > 2
1463 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 6.77 (d, J = 8.7 Hz, 1H), 6.73 (d,
all 3402 data, wR2 = 0.116, GOF = 1.135 for all data. An ORTEP diagram of 15,
J = 3.0 Hz, 1H), 6.67 (dd, J = 8.8, 3.0 Hz, 1H), 6.18–6.11 (m, 1H), 5.76–5.67 (m,
1H), 3.78 (s, 3H), 3.76 (s, 3H), 2.98 (br s, 1H), 2.62–2.40 (m, 3H), 2.11–2.04 (m,
2H), 1.90 (s, 1H), 1.75–1.65 (m, 1H), 1.34–1.15 (m, 3H), 1.05–0.97 (m, 2H), 1.02
(s, 3H), 0.99 (s, 3H); 13C NMR (75 MHz, CDCl3): d 153.72, 151.02, 137.50, 135.17,
127.91, 111.71 [2C], 109.85, 73.94, 56.18, 55.56, 38.72, 37.27, 35.26, 34.03 [2C],
27.91, 25.27, 22.73, 21.92, [2C]; HRMS (ES): m/z calcd for C21H30O3 (M+Na)+:
353.2093, found: 353.2073; 18 mp: 127–128 °C; IR (neat): mmax 3434, 2929,
drawn at 30% ellipsoid probability, is shown below.
1615, 1494, 1461 cmÀ1 1H NMR (300 MHz, CDCl3): d 6.76 (d, J = 8.7 Hz, 1H),
;
6.67 (dd, J = 8.7, 3.0 Hz, 1H), 6.62 (d, J = 3.0 Hz, 1H), 6.02–5.96 (m, 1H), 5.63–
5.57 (m, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 2.91–2.81 (m, 1H), 2.65–2.50 (m, 2H),
2.40 (s, 1H), 2.35–2.29 (m, 1H), 2.18 (dd, J = 17.6, 7.4 Hz, 1H), 1.79–1.69 (m, 1H),
1.54–1.41 (m, 2H), 1.26–1.16 (m, 2H), 1.08–0.99 (m, 1H), 0.96 (s, 3H), 0.94 (s,
3H), 0.96–0.94 (m, 1H); 13C NMR (75 MHz, CDCl3): d 153.28, 150.89, 135.81,
134.10, 126.53, 115.80, 111.12, 110.09, 77.62, 56.13, 55.61, 42.54, 39.51, 38.97,
36.79, 33.56, 30.83, 25.08, 22.69, 22.41, 22.34; HRMS (ES): m/z calcd for
C21H30O3 (M+Na)+: 353.2093, found: 353.2079; 19 IR (neat): mmax 3558, 2934,
1592, 1493, 1467 cmÀ1 1H NMR (300 MHz, CDCl3): d 6.81–6.67 (m, 3H), 5.92–
;
5.83 (m, 1H), 5.58–5.50 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 2.67–2.61 (m, 2H),
2.43 (dd, J = 16.8, 8.1 Hz, 1H), 2.22 (s, 1H), 2.17–2.02 (m, 2H), 1.48–1.26 (m, 6H),
0.99 (s, 3H), 0.98 (s, 3H); 13C NMR (75 MHz, CDCl3): d 153.29, 150.43, 137.14,
131.15, 126.78, 114.96, 111.04, 109.62, 76.29, 55.94, 55.65, 46.47, 40.13, 38.31,
32.89, 32.01, 27.94, 25.63, 23.27, 21.96, 21.86; HRMS (ES): m/z calcd for
C21H30O3 (M+Na)+: 353.2093, found: 353.2117; 22 IR (neat): mmax 3564, 3416,
Compound 18: CCDC 697874, C21H30O3, MW = 330.45, crystal system: triclinic,
space group: P1, cell parameters: a = 7.3108 (70) Å, b = 9.3827 (88) Å,
ꢀ
c = 13.6878 (13) Å,
V = 898.98 (45)
= 0.080 mmÀ1
reflections with I > 2
a
= 89.473 (16)°, b = 81.928 (15)°,
c
= 75.333 (15)°,
F(0 0 0) = 360.0,
Å3, calcd = 1.22 g cmÀ3
Z = 2,
q
,
l
,
number of l.s. parameters = 222, R1 = 0.041 for 2806
(I) and 0.047 for all 3255 data, wR2 = 0.107,
2931, 1508, 1204, 1036 cmÀ1 1H NMR (300 MHz, CDCl3): d 6.65 (s, 1H), 6.49 (s,
;
r
GOF = 1.037 for all data; Compound 21: CCDC 733793; C24H35BrO4,
MW = 467.4, crystal system: monoclinic, space group: P21/n, cell parameters:
a = 17.0258 (49) Å, b = 7.4381 (20) Å, c = 19.0945 (56) Å, b = 104.623 (6)°,
1H), 6.15–6.14 (m, 1H), 5.74–5.67 (m, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.78 (s, 3H),
2.91 (br s, 1H), 2.66 (br s, 1H), 2.58 (dd, J = 14.1, 8.4 Hz, 1H), 2.48–2.41 (m, 1H),
2.12–2.04 (m, 2H), 1.74–1.64 (m, 2H), 1.35–1.23 (m, 2H), 1.20–1.05 (m, 1H),
1.02 (s, 3H), 1.00 (s, 3H), 1.02–0.91 (m, 2H); 13C NMR (75 MHz, CDCl3): d 150.88,
147.42, 143.33, 135.27, 127.83, 111.92, 111.87, 98.25, 74.07, 56.88, 56.70,
56.11, 49.07, 38.77, 37.34, 35.46, 34.10, 28.06, 25.28 [2C], 22.81, 21.99; HRMS
(ES): m/z calcd for C22H32O4 (M+Na)+: 383.2198, found: 383.2198; 23 IR (neat):
V = 2339.79
= 1.783 mmÀ1
reflections with I > 2
(40)
number of l.s. parameters = 268, R1 = 0.061 for 1949
(I) and 0.176 for all 4321 data, wR2 = 0.076,
Å3,
Z = 4,
q
calcd = 1.33 g cmÀ3
,
F(0 0 0) = 983.9,
l
,
r
GOF = 0.891 for all data. An ORTEP diagram of 21, drawn at 30% ellipsoid
probability, is shown below.
m
max 3493, 2928, 1512, 1203, 1033 cmÀ1 1H NMR (300 MHz, CDCl3): d 6.65 (s,
;
1H), 6.20–6.13 (m, 1H), 5.79–5.72 (m, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H),
2.93 (br s, 1H), 2.64–2.57 (m, 1H), 2.47–2.41 (m, 1H), 2.10–2.03 (m, 2H), 1.80 (s,
1H), 1.75–1.63 (m, 1H), 1.43–1.23 (m, 4H), 1.13–1.08 (m, 1H), 1.03 (s, 3H), 1.02
(s, 3H); 13C NMR (75 MHz, CDCl3): d 150.40, 148.56, 145.37, 137.29, 134.82,
128.45, 113.70, 109.88, 73.56, 61.18, 60.58, 56.75, 49.38, 38.90, 37.32, 36.19,
34.05, 28.67, 26.94, 25.27, 22.78, 21.91; HRMS (ES): m/z calcd for C22H31BrO4
(M+Na)+: 461.1303, found: 461.1313; 27 IR (neat):
1461 cmÀ1
m
max 2934, 1653, 1612, 1496,
;
1H NMR (300 MHz, CDCl3): d 6.82–6.72 (m, 3H), 6.43 (dd, J = 11.1,
6.6 Hz, 1H), 6.19–6.14 (m, 2H), 4.04 (t, J = 6.9 Hz, 1H), 3.81 (s, 3H), 3.72 (s, 3H),
3.16–3.08 (m, 1H), 1.73–1.68 (m, 2H), 1.46–1.36 (m, 2H), 1.27–1.20 (m, 2H),
1.17 (s, 3H), 1.08 (s, 3H); 13C NMR (75 MHz, CDCl3): d 194.29, 168.14, 153.47,
151.08, 143.33, 133.25, 131.38, 124.79, 115.33, 112.01, 111.59, 55.90, 55.61,
44.14, 43.35, 41.85, 40.01, 34.47, 29.99, 27.39, 21.93; HRMS (ES): m/z calcd for
C21H26O3 (M+Na)+: 349.1780, found: 349.1797; 28 IR (neat): mmax 2927, 1697,
1506, 1489, 1455, 1219, 1053 cmÀ1 1H NMR (300 MHz, CDCl3): d 6.84 (d,
;
Compound 26: CCDC 733792; C21H28O4, MW = 360.5, crystal system: triclinic,
space group: P1, cell parameters: a = 10.4326 (43) Å, b = 12.4180 (50) Å,
J = 3.3 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.69 (dd, J = 9.0, 3.0 Hz, 1H), 3.79 (s, 3H),
3.75 (s, 3H), 3.35 (t, J = 4.9 Hz, 1H), 2.14–2.05 (m, 1H), 1.75–1.45 (m, 7H), 1.22 (s,
3H), 1.16 (s, 3H), 0.93–0.84 (m, 3H), 0.17 (d, J = 3.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d 153.36, 151.76, 139.09, 134.22, 129.70, 114.60, 111.23, 110.89, 56.06,
55.47, 39.77, 37.42, 34.76, 31.59, 30.18, 28.96, 28.70, 19.74, 18.28, 10.65, 7.83;
MS (ES): m/z 335 (M+Na)+; 32 IR (neat): mmax 3488, 2933, 1496, 1461, 1214,
ꢀ
c = 16.2569 (66) Å,
a
= 91.438 (8)°, b = 101.948 (8)°,
c
l
= 93.388 (7)°, V = 2055.38
(14) Å3, Z = 4, calcd = 1.16 g cmÀ3, F(0 0 0) = 775.9,
q
= 0.082 mmÀ1, number of
l.s. parameters = 479, R1 = 0.129 for 4799 reflections with I > 2
r(I) and 0.167
for all 7181 data, wR2 = 0.374, GOF = 1.432 for all data.
14. (a) Schultz, A. G.; Taveras, A. G.; Harrington, R. E. Tetrahedron Lett. 1988, 29,
3907–3910; (b) Pearson, A. J.; Chen, Y.-S.; Hsu, S.-Y.; Ray, T. Tetrahedron Lett.
1984, 25, 1235–1238.
1049 cmÀ1 1H NMR (300 MHz, CDCl3): d 6.81–6.71 (m, 2H), 6.55 (d, J = 2.7 Hz,
;
1H), 5.57–5.55 (m, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.28 (d, J = 12.6 Hz, 1H), 2.46–
2.22 (m, 3H), 1.79–1.57 (m, 5H), 1.44–1.35 (m, 2H), 1.17–1.11 (m, 1H), 1.08–