Model studies towards paecilomycine A-C: Exploring scaffold diversity through a key intramolecular Pauson-Khand reaction

Article abstract of DOI:10.1016/j.tetlet.2011.01.131

A diversity generative approach to bioactive and structurally complex natural products paecilomycine A-C, involving an intramolecular Pauson-Khand reaction as a key step is delineated.

Full text of DOI:10.1016/j.tetlet.2011.01.131

Tetrahedron Letters 52 (2011) 1663–1666
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Model studies towards paecilomycine A–C: exploring scaffold diversity
through a key intramolecular Pauson–Khand reaction
Goverdhan Mehta a, , Ramesh Samineni a,b, Pabbaraja Srihari b
⇑
a School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
b Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A diversity generative approach to bioactive and structurally complex natural products paecilomycine A–
C, involving an intramolecular Pauson–Khand reaction as a key step is delineated.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 1 January 2011
Revised 22 January 2011
Accepted 27 January 2011
Available online 1 February 2011
Keywords:
Stereoselective Luche reduction
TBS migration
Oxa-Michael addition
Intramolecular Pauson–Khand reaction
H
H
10
7
10
7
Neurodegenerative disorders (Alzheimer’s, Huntington’s and
Parkinson’s diseases) are characterized by a net loss of neurons
and neuronal connectivity from specific regions of the central
nervous system (CNS) and constitute a major public health con-
cern particularly in the context of the aging world popula-
tion.1a–d While natural neurotrophins like nerve growth factor
(NGF), neurotrophins (NT-3,4,5) and brain derived neurotrophic
factor (BDNF) embodying polypeptidyl architecture have been
implicated in the growth, survival and repair of neurons, their
poor pharmacokinetic profile (like inability to cross the blood–
brain barrier), short in vivo half life and propensity to proteolytic
degradation render them and their synthetic peptide analogs less
attractive for therapeutic/clinical development. On the other
hand, small molecule natural products (SMNPs) exhibiting neuro-
trophic activity are emerging as promising non-peptidyl candi-
dates for total and diverted synthesis and for the exploration of
chemical diversity space around their frameworks.2,3 Thus, syn-
thesis of diverse neurotrophically active SMNPs has drawn con-
siderable attention in the past few years as an arena of creative
endeavors in organic synthesis. Our group4 has also been inter-
ested in the synthesis of SMNPs that harbor complex architecture
and exhibit promising neurotrophic activity, particularly with the
potential for promoting neurite outgrowth.
13
O
14
O
14
OH
O
16
16
9
9
13
OH
11
6
11
6
8
12
8
12
R
5 O 2
3
5
2
4
15
15
4
OH
3
O
Paecilomycine A (1) : R = H
Paecilomycine B (2) : R = OH
Paecilomycine C (3)
In 2004, Oshima and co-workers reported the isolation of some
novel trichothecane based sesquiterpenoids, paecilomycine A (1), B
(2) and C (3) from Paecilomyces tenuipes (Isaria japonica), a popular
entomopathogenic fungus used in folk medicine and health foods
in the East Asia (China, Korea and Japan). The structures of 1–3
were determined on the basis of incisive analyses of their spectral
data, particularly the incisive 2D NMR studies and their absolute
configuration was determined using the MPA ester protocol.5 This
study also reported5 that paecilomycine A 1 significantly enhanced
neurite outgrowth in rat PC-12 neurons in previously conditioned
human glial cells, at 10 nm concentration. Quite remarkably, the
potency of 1 in enhancing the expression levels of neurotrophic
factors was 1000 times higher than of another promising neurotro-
phic natural product scabronine G.5 The novel bioactivity profile of
1 and the novel, complex tetracyclic framework present in 1–3
with attendant stereochemical and functional intricacies make
paecilomycine A–C attractive targets of total synthesis and chemi-
⇑
cal analoging. An inaugural racemic total synthesis of paecilomy-
Corresponding author. Tel.: +91 4023010785; fax: +91 4023012460.
E-mail addresses: gmsc@uohyd.ernet.in, gm@orgchem.iisc.ernet.in (G. Mehta).
6
cine A was accomplished by Min and Danishefsky
in 2007
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.131

1664
G. Mehta et al. / Tetrahedron Letters 52 (2011) 1663–1666
wherein an intramolecular Pauson–Khand reaction (PKR) served as
the key step. Herein, we report model studies directed towards
paecilomycine A–C employing a tactical variant of the intramolec-
ular Pauson–Khand reaction,6,7 wherein the C2–C12 olefinic bond
eventuates in a strategically favorable position, providing a rapid
and flexible framework access for diversity creation.
In pursuit of model synthetic studies towards paecilomycine A–
C 1–3, our initial focus was on setting-up the key intramolecular
PKR (2+2+1 cycloaddition) protocol in a precursor like 4 to furnish
the core tricyclic scaffold 5, Scheme 1. To access a precursor like 4,
ethyl 4-methyl-2-oxocyclohex-3-enecarboxylate 6, readily obtain-
able from commercially available ethyl acetoacetate (EAA) and
methyl vinyl ketone (MVK),8a,b served as a suitable starting point.
Hydroxymethylation of the b-keto ester moiety in 6 was smooth
and afforded primary alcohol 7, which was protected as its TBS
ether 8.9 The quaternary carbon center installed in 8 corresponded
to C6 of the paecilomycine, and the chemo-differentiated and stra-
tegically positioned side arms present in it were well poised for
generating stereo-diversity (vide infra). The carbonyl group in the
TBS enone 8 was reduced under Luche conditions10 to stereoselec-
tively furnish the allylic alcohol 9, Scheme 2. The observed stere-
oselectivity in the formation of 9 can be explained through the
hydride attack from the less hindered b-face, opposite to the bulky
TBS group.
The allylic alcohol 9 could be propargylated in the presence of
sodium hydride to furnish two propargyl ethers (7:3), viz. the ex-
pected 10a and the unexpected 10b in which the TBS group migra-
tion had occurred.11 The stereostructure of 10b and by
extrapolation of 10a was settled through single crystal X-ray struc-
ture determination on a derivative prepared from 10b.12 The ester
group in the major product 10a was elaborated to set-up the req-
uisite intramolecular PKR and generate the C6–C11 trans ring junc-
tion stereochemistry present in the paecilomycine scaffold. DIBAL-
H reduction in 10a afforded the primary alcohol 11, which was oxi-
dized to an aldehyde using IBX in DMSO and further Wittig olefin-
ation with the ylide generated from methyltriphenylphosphonium
iodide afforded the enyne 12. After a few trials, the intramolecular
Pauson–Khand reaction7 in 12 could be optimized to consistently
furnish tricyclic enone 13 as a single diastereoisomer, albeit in
modest yield, Scheme 3. Interestingly, the vinyl arm in 12, during
the PKR, positioned it self to eventuate in 5b-H disposition in a
stereoselective manner. Deprotection of the TBS group in enone
13 using aq HF in acetonitrile13 or TBAF in THF led to the intramo-
lecular oxa-Michael product 14, representing the core tetracyclic
structure present in paecilomycine C (3) and its structure was se-
cured through a single crystal X-ray structure determination.12
Towards further diversification in the context of paecilomycine
1–3, enone 13 was subjected to nucleophilic epoxidation with
hydrogen peroxide and sodium hydroxide14 to stereoselectively
furnish epoxide 15, Scheme 3. TBS deprotection in 15 with aqueous
HF in acetonitrile delivered the tetracyclic ether 17 through pri-
mary hydroxyl group mediated intramolecular epoxide ring open-
H
H
O
H
O
Pauson-Khand
reaction
RO
RO
O
4
5
C
O
Scheme 1. Intramolecular Pauson–Khand reaction.
O
O
O
O
a,b
c
CO2Et
CO2Et
CO2Et
RO
R = H (7)
MVK
EAA
6
d
R = TBS (8)
e
H
H
H
OTBS
CO2Et
O
OH
f
ing to furnish
a a-hydroxy ketone functionality on the
+
paecilomycine scaffold. In another diversionary foray, epoxide 15
was reductively cleaved with in situ generated15 ‘PhSeH’ to deliver
a very labile b-hydroxy-ketone 16, reminiscent of the tertiary C12
hydroxyl group present in paecilomycine A along with the dehy-
drated product 13.
In order to generate stereo-diversity on the paecilomycine core,
the TBS group in propargylated 10a was deprotected to 18 and oxi-
dation of the primary hydroxyl group to the aldehyde and Wittig
methylenation furnished the PKR precursor 19, Scheme 4. The ester
CO2Et
CO2Et
O
TBSO
10 a
TBSO
10 b
9
Scheme 2. Reagents and conditions: (a) NaOMe (cat.), MeOH, 15 h, 0 °C to rt, 85%;
(b) H2SO4, cat. H2O, À10 to À5 °C for 30 min and then at rt for 1.5 h, 35%; (c) KHCO3,
aq HCHO (37–41% w/v), EtOH, 86%; (d) TBSCl, imidazole,CH2Cl2, 3 h, 89%; (e)
CeCl3Á7H2O, NaBH4, MeOH, À15 °C, 15 min, 88%; (f) NaH, HMPA, THF, TBAI,
propargyl bromide, À20 °C, 3 h, 79% (10a:10b in 7:3 ratio).
H
H
H
H
O
O
H
O
O
H
a
c
b
f
10 a
O
TBSO
OH
TBSO
TBSO
11
12
13
14
O
O
d
H
H
H
O
H
O
H
O
H
e
f
f
OH
O
14
OH
O
TBSO
TBSO
16
O
15
O
17
O
Scheme 3. Reagents and conditions: (a) DIBAL-H, 0 °C, 1 h, CH2Cl2, 96%; (b) (i) IBX, DMSO, THF, rt, 2 h, (ii) tBuOK, PPh3CH2I, THF, 0 °C, 15 min, 69% in two steps; (c) (i)
Co2(CO)8, CH2Cl2, 1 h, (ii) NMO, CH2Cl2, CO gas, 4 h, 34%; (d) H2O2, 6 N NaOH, MeOH, 0 °C, 2 h, 85%, (e) (PhSe)2, NaBH4, EtOH, 10 min, rt, 15% (16) and 75% (13); (f) aq HF,
acetonitrile (5:95), rt, 6 h, 70–76% or TBAF, THF, rt, 8–10 h, 65–75%.

G. Mehta et al. / Tetrahedron Letters 52 (2011) 1663–1666
1665
H
determination12 revealed its stereochemistry and of its precursor
22a with C5 b-H. This led to the formulation of the other diastereo-
mer 22b with C5 a-H. Both the TBS enones 22a and 22b were fur-
H
H
O
O
O
a
b
ther elaborated to create paecilomycine A like functionality with
the installation of the C12 tertiary hydroxyl group. Nucleophilic
epoxidation of 22a furnished a single epoxide 24 and ‘PhSeH’ med-
iated reductive epoxide opening to 25 and further TBS deprotection
led to 26, Scheme 5. Likewise 22b was transformed to the epoxide
27 and further reductive cleavage to 28 and deprotection delivered
the diastereomeric hydroxyl-ketone 29, Scheme 5.
In conclusion, we have described a concise approach involving
intramolecular PKR protocol as the key step to access paecilomy-
cine A–C scaffold and explored the framework and functional
group diversity space around it. These model studies also set the
stage for exploring the installation of the key C14 methyl group
within the context of our overall strategy to complete the total
synthesis of paecilomycine natural products and such endeavors
are currently underway.
EtO2C
EtO2C
EtO2C
OTBS
OH
10 a
18
19
c
H
H
H
O
O
H
O
H
e
+
RO
TBSO
22 b
TBSO
22 a
O
O
R = H (20)
d
R = TBS (21)
Scheme 4. Reagents and conditions: (a) TBAF, THF, rt, 4 h, 93%; (b) (i) IBX, THF,
DMSO, rt, 4 h, (ii) tBuOK, PPh3CH2I, THF, 0 °C, 15 min (64% in two steps); (c) DIBAL-
H, CH2Cl2, 0 °C, 1 h, 95%; (d) TBSCl, imidazole, CH2Cl2, 0 °C to rt, 91%; (e) (i)
Co2(CO)8, THF, rt, 1 h, (ii) TMANOÁ2H2O, THF, À10 °C to rt, 3 h, 22a:22b in 1.5:1
ratio, 75%.
Acknowledgments
This research was carried out under the Indo-French joint labo-
ratory initiative. R.S. thanks CSIR for the award of a Research fel-
lowship. G.M. wishes to thank Eli Lilly and Jubilant Bhartia
Foundations for the research support and the Government of India
for the award of National Research Professorship. We acknowledge
the help of Dr. Saikat Sen in solving the X-ray crystal structures at
the CCD facility of the University of Hyderabad.
H
H
O
H
O
H
a
b
22 a
O
HO
TBSO
O
O
23
24
References and notes
c
1. (a) Dawbarn, D.; Allen, S. J. Neuropathol. Appl. Neurobiol. 2003, 29, 211–230; (b)
Kirik, D.; Georgiveska, B.; Björklund, A. Nat. Neurosci. 2004, 7, 105–110; (c)
Finkbeiner, S. Nat. Med. 2010, 16, 1227–1232; (d) Abdipranoto, A.; Wu, S.;
Stayte, S.; Vissel, B. CNS Neurol. Disord.: Drug Targets 2008, 7, 187–210.
2. For selected examples from the seminal work on the isolation and structure
determination of neurotrophic SMNPs, see: (a) Huang, J.-m.; Yokoyama, R.;
Yang, C.-s.; Fukuyama, Y. Tetrahedron Lett. 2000, 41, 6111–6114; (b) Huang, J.-
m.; Yokoyama, R.; Yang, C.-s.; Fukuyama, Y. J. Nat. Prod. 2001, 64, 428–431; (c)
Huang, J.-M.; Yokoyama, R.; Yang, C.-S.; Fukuyama, Y. J. Nat. Prod. 2002, 65,
527–531.
H
O
H
OH
RO
O
R = TBS (25)
R = H (26)
3. (a) Wilson, R. M.; Danishefsky, S. J. Acc. Chem. Res. 2006, 39, 539–549; (b)
Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2007, 72, 4293–4305.
4. For related work from our group, see: (a) Mehta, G.; Singh, S. R. Tetrahedron
Lett. 2005, 46, 2079–2082; (b) Mehta, G.; Singh, S. R. Angew. Chem., Int. Ed. 2006,
45, 953–955; (c) Mehta, G.; Shinde, H. M. Tetrahedron Lett. 2007, 48, 8297–
8300; (d) Mehta, G.; Maity, P. Tetrahedron Lett. 2007, 48, 8865–8868; (e) Mehta,
G.; Bhat, B. A. Tetrahedron Lett. 2009, 50, 2474–2477.
d
H
H
O
O
H
b
c
5. Kikuchi, H.; Miyagawa, Y.; Sahashi, Y.; Inatomi, S.; Haganuma, A.; Nakahata, N.;
Oshima, Y. Tetrahedron Lett. 2004, 45, 6225–6228.
22 b
H
OH
O
6. Min, S.-J.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 2199–2202.
7. For some reviews on Pauson–Khand reaction see: (a) Brummnod, K. M.; Kent, J.
L. Tetrahedron 2000, 56, 3263–3283; (b) Gibson, S. E.; Stevenazzi, A. Angew.
Chem., Int. Ed. 2003, 42, 1800–1810.
8. (a) Begbie, A. L.; Golding, B. T. J. Chem. Soc., Perkin Trans. 1 1972, 602–605; (b)
McAndrew, B. A. J. Chem. Soc., Perkin Trans. 1 1979, 1837–1846.
TBSO
RO
O
O
R = TBS (28)
R = H (29)
27
d
9. All new compounds reported here are racemic and were characterized on the
basis of spectroscopic data (IR, 1H, 13C, mass, HRMS). Spectral data for some of
Scheme 5. Reagents and conditions: (a) TBAF, THF, rt, 3 h, 69%; (b) H2O2, 6 N NaOH,
MeOH, 0 °C, 2–3 h, 82–85%; (c) (PhSe)2, NaBH4, EtOH, rt, 10 min, 75–82%; (d) aq HF,
acetonitrile (5:95), 14 h, 75–79%.
the key compounds are as follows: Compound 12: IR (neat)
mmax = 2955, 2929,
2857, 2117, 1638, 1463, 1256, 1178, 1080 cmÀ1 1H NMR (500 MHz, CDCl3)
;
d = 5.66 (dd, J = 18, 11 Hz, 1H), 5.51 (br s, 1H), 4.98–4.93 (m, 2H), 4.16 (dd,
J = 16, 2 Hz, 1H), 4.10 (dd, J = 16, 2Hz, 1H), 3.80 (d, J = 4 Hz. 1H), 3.59 (d, J = 10
Hz, 1H), 3.35 (d, J = 10 Hz, 1H), 2.24 (t, J = 2 Hz, 1H), 1.91–1.79 (m, 2H), 1.68–
1.62 (m, 1H), 1.60 (s, 3H), 1.30–1.21 (m, 1H), 0.82 (s, 9H), À0.05 (s, 3H), À0.06
(s, 3H) ppm; 13C NMR (75 MHz, CDCl3) d = 141.7, 139.0, 120.3, 113.6, 80.8, 75.4,
73.7, 66.6, 56.6, 44.5, 27.5, 26.1 (3C), 24.7, 23.6, 18.4, À5.2, À5.3; MS (ESI) m/z
343 (M+Na)+; HRMS (ESI) m/z calcd for C19H32O2SiNa (M+Na)+ 343.2069, found
group in 19 was now reduced and the resulting primary hydroxyl
group was protected as the TBS derivative 21 and this maneuver
set-up the C6–C11 ring junction in unnatural cis disposition. Exe-
cution of the intramolecular PKR protocol on 21 was significantly
more productive in terms of yield but furnished a diastereomeric
mixture of enones 22a and 22b (1.5:1), Scheme 4. The significantly
improved yield of PKR reaction in 21 is perhaps due to the spatial
proximity of the cis-disposed alkene and alkyne bearing side arms
as well as to the optimized reaction conditions. TBS deprotection in
22a afforded crystalline 23 and its single crystal X-ray structure
343.2076. Compound 13: IR (neat)
mmax = 2926, 2853, 1736, 1641, 1464, 1252,
1078, cmÀ1 1H NMR (300 MHz, CDCl3) d = 6.01(br s, 1H), 5.22 (br s, 1H), 4.70
;
(d, J = 14 Hz, 1H), 4.33 (d, J = 14 Hz, 1H), 4.02 (br s, 1H), 3.60 (d, J = 11 Hz, 1H),
3.44 (d, J = 11 Hz, 1H), 3.08 (d, J = 19 Hz, 1H), 2.73 (br s, 1H), 2.35 (dd, J = 19, 7
Hz, 1H), 2.16–1.85 (m, 3H), 1.68 (s, 3H), 1.40–1.24 (m. 1H), 0.83 (s, 9H), À0.04
(s, 3H), À0.06 (s, 3H); 13C NMR (75 MHz, CDCl3) d = 209.0, 174.9, 137.8, 128.7,
120.4, 81.6, 67.7, 60.0, 50.7, 41.8, 36.6, 27.6, 27.5 (3C), 25.7, 22.8, 17.9, À5.9,
À6.1; MS (ESI) m/z 371 (M+Na)+; HRMS (ESI) m/z calcd for C20H32O3SiNa
(M+Na)+ 371.2018, found 371.2022. Compound 14: mp 124–126 °C, IR (neat)

1666
G. Mehta et al. / Tetrahedron Letters 52 (2011) 1663–1666
m
max = 2954, 2919, 2856, 1741, 1669, 1444, 1295, 1224, 1063 cmÀ1
;
1H NMR
2.43 (m, 1H), 2.38–2.26 (m, 2H), 2.07–2.04 (m, 2H), 1.80–1.76 (m, 1H), 1.73 (s,
3H); 13C NMR (75 MHz, CDCl3) d = 212.9, 141.2, 118.8, 73.7, 71.5, 71.0, 62.6,
49.6, 46.2, 40.6, 36.6, 28.0, 24.8, 23.2; MS (ESI) m/z 275 (M+Na)+; HRMS (ESI) m/
z calcd for C14H20O4Na (M+Na)+ 275.1259, found 275.1264.
(300 MHz, CDCl3) d = 5.30 (br s, 1H), 4.22 (d, J = 8 Hz, 1H), 4.07 (br s, 1H), 3.97
(d, J = 11 Hz, 1H), 3.73 (d, J = 11 Hz, 1H), 3.66 (d, J = 8 Hz, 1H), 2.47 (d, J = 18 Hz,
1H), 2.34–2.14 (m, 4H), 1.98–1.63 (m, 3H), 1.70 (s, 3H), 1.68–1.58 (m. 1H); 13
C
NMR (75 MHz, CDCl3) d = 212.8, 136.0, 122.0, 86.2, 80.2, 72.6, 52.5, 47.4, 44.1,
36.9, 29.8, 28.2, 25.7, 23.2; MS (ESI) m/z 257 (M + Na)+; HRMS (ESI) m/z calcd
for C14H18O3Na (M+Na)+ 257.1153, found 257.1160. Compound 17: mp 161–
10. Luche, J. L. J. Am. Chem. Soc 1978, 100, 2226–2227.
11. For examples of silyl group migration, see: (a) Icheln, D.; Gehrcke, B.; Piprek, Y.;
Mischnick, P.; König, W. A.; Dessoy, M. A.; Morel, A. F. Carbohydr. Res. 1996, 280,
237–250; (b) Yamazaki, T.; lchige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073–
4076; (c) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic
Synthesis; Wiley Interscience: New Jersey, 2007. pp 166–170.
162 °C, IR (neat) m ;
max = 3501, 2955, 2862, 1742, 1438, 1220, 1182, 1063 cmÀ1
1H NMR (300 MHz, CDCl3) d = 5.30 (br s, 1H), 4.21 (d, J = 8 Hz, 1H), 4.04 (br s,
1H), 3.96 (d, J = 11 Hz, 1H), 3.89 (d, J = 11 Hz, 1H), 3.86 (s, 1H), 3.55 (d, J = 8 Hz,
1H), 2.60–2.42 (m, 2H), 2.17 (dd, J = 17, 8 Hz, 1H), 1.99–1.74 (m, 3H) 1.70 (s,
3H), 1.69–1.62 (m. 1H); 13C NMR (75 MHz, CDCl3) d = 215.7, 136.6, 121.3, 86.7,
79.7, 75.1, 71.7, 70.2, 49.8, 47.4, 35.3, 28.0, 25.5, 22.9; MS (ESI) m/z 273
(M+Na)+; HRMS (ESI) m/z calcd for C14H18O4Na (M+Na)+ 273.102, found
12. Single crystal X-ray diffraction data were collected on a Bruker AXS SMART
APEX CCD diffractometer at 291 K using graphite monochromated MoK
radiation (k = 0.7107 Å). The data were reduced by SAINTPLUS an empirical
absorption correction was applied using the package SADABS and XPREP was used
to determine the space group. The crystal structures were solved by direct
methods using SIR92 and refined by full-matrix least-squares method on F2
using SHELXL97. Crystal data for 3,5-dinitrobenzoate derived from 10b:
a
;
273.1113. Compound 21: IR (neat)
mmax = 2898, 2857, 2117, 1636, 1463, 1256,
1093 cmÀ1 1H NMR (500 MHz, CDCl3) d = 6.01 (dd, J = 18, 11 Hz, 1H), 5.55 (br s,
;
1H), 5.13 (dd, J = 17, 2 Hz, 1H), 5.09 (dd, J = 18, 2 Hz, 1H), 4.22 (d, J = 3 Hz, 2H),
4.16 (br s, 1H), 3.64 (d, J = 10 Hz, 1H), 3.32 (d, J = 10 Hz, 1H), 2.39–2.36 (m, 1H),
2.04–2.01 (m, 1H), 1.86–1.80 (m, 2H), 1.67 (s, 3H), 1.66–1.61 (m, 1H), 0.90 (s,
9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) d = 138.8, 136.8, 121.6, 114.4, 80.7,
75.4, 73.5, 66.3, 57.1, 44.8, 27.4, 27.0, 25.9 (3C), 23.0, 18.2, À5.50, À5.51; MS
(ESI) m/z 343 (M+Na)+; HRMS (ESI) m/z calcd for C19H32O2SiNa (M+Na)+
C
21H22N2O9, M = 446.41, monoclinic, P21/n, a = 7.6684(12), b = 9.2015(15),
c = 31.838(5) Å, b = 93.400(3)°, V = 2242.5(6) Å3, calcd = 1.322 g/cm3,
Z
=
4,
q
16356 reflections measured, 4178 unique (Rint = 0.0621), R1 = 0.0725 and
wR2 = 0.1603 for 2412 observed reflections, CCDC 806206 (an ORTEP diagram
of the 3,5-dinitrobenzoate drawn at 30% ellipsoidal probability is shown
below).
343.2069, found 343.2054. Compound 22a: IR(neat)
mmax = 2935, 2856, 1704,
1629, 1443, 1253, 1167, 1112, 1085 cmÀ1 1H NMR (300 MHz, CDCl3) d = 5.91
;
(br s, 1H), 5.54 (d, J = 5 Hz, 1H), 4.61 (d, J = 13 Hz, 1H), 4.20 (d, J = 13 Hz, 1H),
3.88 (d, J = 6 Hz, 1H), 3.50 (d, J = 10 Hz, 1H), 3.39 (d, J = 6 Hz, 1H), 3.38 (d, J = 10
Hz, 1H), 2.48–2.30 (m, 2H), 2.09–1.83 (m, 2H), 1.70 (s, 3H), 1.66–1.57 (m. 1H),
1.41–1.32 (m. 1H), 0.89 (s, 9H), 0.01 (s, 6H); 13C NMR (75 MHz, CDCl3)
d = 209.1, 175.7, 140.4, 126.8, 118.8, 73.3, 66.1, 65.5, 44.5, 42.8, 36.2, 27.3, 25.8
(3C), 23.1, 18.2, 17.9, À5.5, À5.6; MS (ESI) m/z 371 (M+Na)+; HRMS (ESI) m/z
calcd for C20H32O3SiNa (M+Na)+ 371.2198, found 371.2022. Compound 22b:
mp 129-131 °C; IR (neat)
mmax = 2927, 2854, 1734, 1674, 1463, 1380, 1249,
1114 cmÀ1 1H NMR (300 MHz, CDCl3) d = 5.87 (br s, 1H), 5.43 (br s, 1H), 4.40
;
(dd, J = 21, 14 Hz, 2H), 4.20–4.15 (m, 1H), 3.49 (d, J = 18 Hz, 1H), 3.46 (d, J = 18
Hz, 1H), 3.13 (d, J = 7 Hz, 1H), 2.55 (dd, J = 19, 3 Hz, 1H), 2.27 (dd, J = 19, 7 Hz,
1H), 2.05–1.98 (m, 2H), 1.83–1.72 (m, 1H), 1.75 (s, 3H), 1.67–1.60 (m, 1H), 0.86
(s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz, CDCl3) d = 207.7, 181.5,
139.4, 129.0, 122.5, 73.6, 67.5, 65.9, 44.4, 39.0, 37.4, 26.8, 26.5, 25.8 (3C), 23.0,
18.2, À5.5 (2C); MS (ESI) m/z 371 (M+Na)+; HRMS (ESI) m/z calcd for
Crystal data for 14: C14H18O3, M = 234.28, monoclinic, P21, a = 8.543(3),
b = 6.330(2),
q
c = 11.100(4) Å,
b = 94.043(6)°,
V = 598.8(4) Å3,
Z = 2,
calcd = 1.299 g/cm3, 4466 reflections measured, 1215 unique (Rint = 0.0318),
C
20H32O3SiNa (M+Na)+ 371.2198, found 371.2063. Compound 26: mp 143–
R1 = 0.0496 and wR2 = 0.1181 for 1086 observed reflections, CCDC 806208.
Crystal data for 23: C14H18O3, M = 234.28, orthorhombic, Pna21, a = 12.667(2),
145 °C, IR (neat) m ;
max = 3448, 2923, 2853, 1717, 1463, 1376, 1274, 1085 cmÀ1
1H NMR (300 MHz, CDCl3) d = 5.52 (d, J = 4 Hz, 1H), 3.90 (d, J = 11 Hz, 1H), 3.74
(d, J = 5 Hz, 1H), 3.52 (d, J = 11 Hz, 1H), 3.46 (d, J = 11 Hz, 1H), 3.38 (d, J = 11 Hz,
1H), 2.80–2.60 (m, 3H), 2.48 (d, J = 18 Hz, 1H), 2.22 (d, J = 18 Hz, 1H), 2.09–1.89
(m, 2H) 1.70 (s, 3H), 1.66–1.56 (m. 1H), 1.43–1.32 (m, 1H); 13C NMR (75 MHz,
CDCl3) d = 218.2, 139.0, 119.3, 74.9, 73.7, 72.1, 65.5, 48.5, 46.6, 40.2, 39.0, 27.5,
23.0, 21.0; MS (ESI) m/z 275 (M+Na)+; HRMS (ESI) m/z calcd for C14H20O4Na
b = 15.795(3), c = 6.0485(10) Å, V = 1210.1(3) Å3, Z = 4,
q
calcd = 1.286 g/cm3,
8694 reflections measured, 2248 unique (Rint = 0.0434), R1 = 0.0553 and
wR2 = 0.1189 for 1978 unique reflections, CCDC 806207.
13. Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.; Roberts, S. M.
Tetrahedron Lett. 1979, 20, 3981–3982.
14. Miyashita, M.; Suzuki, T.; Yoshikoshi, A. J. Am. Chem. Soc. 1989, 111, 3728–
3734.
(M+Na)+ 275.1259, found 275.1255. 29: mp 137–139 °C, IR (neat)
m
max = 3433,
2928, 2851, 1731, 1666, 1384, 1270, 1172, 1073,cmÀ1
;
1H NMR (300 MHz,
15. Miyashita, M.; Suzuki, T.; Hoshino, M.; Yoshikoshi, A. Tetrahedron 1997, 53,
12469–12486.
CDCl3) d = 5.53 (dd, J = 5, 1 Hz, 1H), 3.89 (s, 1H), 3.75 (d, J = 11 Hz, 1H), 3.57–
3.47 (m, 3H), 3.11 (d, J = 11 Hz, 1H), 2.72–2.67 (m, 1H), 2.55–2.45 (m,1H), 2.47–