Stereoselective construction of quaternary chiral centers using Ti(III)-mediated opening of 2,3-epoxy alcohols: Studies directed toward the synthesis of penifulvins

Article abstract of DOI:10.1016/j.tetlet.2010.06.076

A trisubstituted α,β-unsaturated ester moiety was suitably placed in a molecule also bearing an epoxy alcohol moiety at its other end to intramolecularly trap the intermediate radical, which was formed when the molecule was treated with Cp₂Ti(I

Full text of DOI:10.1016/j.tetlet.2010.06.076

Tetrahedron Letters 51 (2010) 4425–4428
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective construction of quaternary chiral centers
using Ti(III)-mediated opening of 2,3-epoxy alcohols: studies directed
toward the synthesis of penifulvins q
b
b
a
Tushar Kanti Chakraborty a, , Amit Kumar Chattopadhyay , Rajarshi Samanta , Ravi Sankar Ampapathi
*
a Central Drug Research Institute, CSIR, Lucknow 226 001, India
b Indian Institute of Chemical Technology, CSIR, 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 trisubstituted
a,b-unsaturated ester moiety was suitably placed in a molecule also bearing an epoxy
Received 21 May 2010
Revised 14 June 2010
Accepted 15 June 2010
Available online 18 June 2010
alcohol moiety at its other end to intramolecularly trap the intermediate radical, which was formed when
the molecule was treated with Cp2Ti(III)Cl to regio- and stereoselectively open its epoxy ring, giving rise
to a quaternary chiral center. The method was subsequently used in an attempt to construct the bicyclic
core framework of potent insecticides penifulvins.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Penifulvin
Ti(III)-mediated epoxide opening
Radical cyclization
Quaternary chiral center
In our previous studies, we have shown that Ti(III)-mediated
opening of chiral 2,3-epoxy alcohols1 followed by intramolecular
trapping of the resultant intermediate radicals by a suitably placed
electron-deficient double bond leads to the formation of highly
functionalized carbocycles,2 oxacycles,3 and azacycles4 as shown
in Scheme 1.
with epoxy alcohol 3 in hand, the stage was set to implement
the crucial Ti(III)-mediated epoxide opening followed by cycliza-
tion. Indeed, on exposure to the Cp2Ti(III)Cl reagent, generated
in situ from Cp2TiCl2 and Zn dust and freshly fused ZnCl2,9 com-
pound 3 underwent epoxide opening at ‘C2 position’ from the
hydroxy side1 and gave rise to a radical intermediate that was
In the present Letter, we extend our work further to the synthesis
of substituted ring systems, shown in Scheme 2, by using trisubsti-
tuted double bond in epoxy alcohol 3 to trap the intermediate
radical, generated on treatment with Cp2Ti(III)Cl, giving rise to ster-
eoselective construction of quaternary chiral center in the carbocy-
clic ring of 4. The method developed herein was subsequently
applied in our ongoing studies directed toward the syntheses of no-
vel antiinsectan sesquiterpenoid penifulvins A–E.5,6
H
X
n
X
n
CO2R'
R
CO2R'
R
Cp2TiCl, THF
O
H
2
HO
OP
OP
1
X = CH2, O, NTs; n = 1,2
[P = H, protective group; R = H, alkyl; R' = Me, Et]
Synthesis of 3 started with the mono protection of 1,4-butane
diol 5 (Scheme 3). Oxidation and vinyl Grignard addition furnished
Scheme 1. Stereoselective syntheses of highly substituted carbo-, oxa-, and
azacycles using Ti(III)-mediated opening of 2,3-epoxy alcohols.
the allylic alcohol
6 which after a protection–deprotection
sequence gave the alcohol 7. Carbinol 8 was obtained from com-
pound 7 in two steps.
Oxidation and subsequent Horner–Wadsworth–Emmons olef-
ination7 of the resulting methyl ketone gave the E-olefin 9 as a
major product. Deprotection of 9 was followed by Sharpless kinetic
resolution8 to provide the chiral epoxy alcohol 3 (ee >92%). Now
CO Et
2
Me
CO Et
2
OH
Cp TiCl, THF
2
Me
O
H
HO
OH
3
4
q
CDRI Communication No. 7940.
Scheme 2. Stereoselective synthesis of highly substituted cyclopentane ring
system with a quaternary chiral center using Ti(III)-mediated opening of 2,3-epoxy
alcohol.
* Corresponding author. Tel.: +91 522 2623286; fax: +91 522 2623405/3938.
E-mail address: chakraborty@cdri.res.in (T.K. Chakraborty).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.076

4426
T. K. Chakraborty et al. / Tetrahedron Letters 51 (2010) 4425–4428
R1
a, b
e, f
c, d
PMBO
O
HO
OH
2
OH
6
5
Penifulvins
R2
O
A (12): R1, R2, R3, R4 = H
H
H
OH
O
B (13): R1 = OH, R2, R3, R4 = H
C (14): R1 = H, R2 = OH, R3, R4 = H
D (15): R1, R2, R3 = H, R4 = OH
E (16): R1, R2 = H, R3 = OH, R4 = H
HO
g, h,
2
Me
R4
OTBS
O
R3
8
7
OTBS
k
O
EtO C
2
O
i, j
OEt
3
O
Olefination
H
Me
H
OP
H
OTBS
Me
9
O
OH
Me
H
Hydroboration
H
H
CO Me
2
O
O
l
17
Penifulvin A (12)
4
+
O
O
O
O
O
H
HO
OEt
CO2Et
OEt
OP
H
11
H
H
10
O
OH
Cp2TiCl
Scheme 3. Synthesis of 4; Reagents and conditions: (a) NaH, PMBBr, TBAI, THF, 0 °C
to rt, 12 h, 60%; (b) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 to 0 °C, 1 h, (ii)
vinylmagnesium bromide, THF, 0 °C, 15 min, 75% yield in two steps; (c) TBDMSCl,
Et3N, DMAP, CH2Cl2, 0 °C to rt, 12 h, 95%; (d) DDQ, CHCl3:buffer (pH 7): 20:1, rt, 1 h,
85%; (e) SO3-Py, Et3N, CH2Cl2–DMSO (1:1.6), 0 °C, 30 min; (f) CH3MgI, Et2O, 0 °C,
10 min, 75% yield in two steps; (g) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0 °C
to rt, 9 h, 88%; (h) (EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C to rt, 24 h, 75%; (i) TBAF, THF,
0 °C, 3 h, 78%; (j) Ti(OiPr)4, L(+)-DIPT, TBHP, MS (4 Å), CH2Cl2, ꢁ20 °C, 48 h, 35%; (k)
Cp2TiCl2, Zn, ZnCl2, THF, ꢁ20 °C to rt, 18 h, 65% (based on recovered starting
material); (l) 2,2-dimethoxypropane, CH2Cl2, CSA, rt, 24 h, 85%.
OH
O
18
OH
19
20
Scheme 4. Structures of penifulvins and retrosynthetic analysis of penifulvin A
(12).
O
O
O
S
S
c, d
a, b
O
O
23
21
22
OMe
H
H
H
H
4
2
EtO2C
3
9
O5
g, h
Me
6
e, f
OH
O7
H
OH
H
Me
8
H
24
CO2Et
H
25
Me
Figure 1. Important NOEs that were used to establish the relative stereo positions
of H6, H7, and Me(9) of 11.
j
i
O
20
OH
+
26
intramolecularly trapped by the trisubstituted a,b-unsaturated es-
ter moiety leading to the formation of the substituted cyclopen-
tane ring 4 as the major product along with the six-membered
lactone 10 in about 65% yield (based on 15% recovered starting
material). Small amounts of some unidentified products, less polar
than the starting material, were also formed. The inseparable mix-
ture of 4 and 10 (1:1) was treated with 2,2-dimethoxypropane un-
der acid-catalyzed conditions to give a single product 11 in 85%
yield.10
CO2Et
OH
OH
H
27
Scheme 5. Synthesis of 27; Reagents and conditions: (a) LDA, TMSCl, THF, 0 °C, 2 h;
(b) mesityl oxide, TiCl4, CH2Cl2, ꢁ78 °C, 1 h, 56% (in two-steps); (c) CH2(CH2–S–
TMS)2, ZnI2, ether, rt, 10 h, 54%; (d) Mg, TiCl4, THF, CH2Cl2, 0 °C, 2 h, 62%; (e) SeO2,
TBHP, tBuOH, 50 °C, 12 h, 39%; (f) AgNO3, EtOH–H2O, 50 °C, 30 min, 90%; (g) ethyl
ethynyl ether, n-BuLi, THF, ꢁ78 °C, 4 h, 72%; (h) AuCl3, CH2Cl2–EtOH, rt, 15 min,
91%; (i) m-CPBA, CH2Cl2, 0 °C, 2 h, 85%; (j) Cp2TiCl2, Zn, ZnCl2, THF, rt, 14 h, 82%.
The stereochemistry of 11 was determined by using the 1H and
2D NOESY experiments. Some of the important NOEs are shown in
3
Figure 1. J6–7 of about ꢀ5 Hz and NOEs between H6–H4(down)
and H7–H4(down) suggest that H6 and H7 protons are having a
dihedral angle of ꢀ30°, which are in axial, equatorial disposition
at C6 and C7 of the six-membered skewed chair conformation.
Also, NOEs between H7–Me(9), H6–Me(9), and H4(down)–Me(9)
suggest that H7 and Me(9) are cis fused.
in which four rings share a central quaternary carbon. Additionally
there are two (except penifulvin D, having three) more quaternary
carbons, a c- and d-lactone sharing the acylal center and a total of
To demonstrate the practical applicability of the method, it was
applied in our ongoing studies directed toward the synthesis of
penifulvins. Penifulvins A–E (12–16, Scheme 4) were isolated from
an organic extract of cultures of Penicillium griseofulvum
NRRL35584 and showed potent antifungal and antiinsectan activi-
ties in preliminary assays against the fall armywarm.5,6 The overall
structure of penifulvins has dioxa[5.5.5.6]fenestrance ring system
five (except penifulvin E, having six) stereo centers congested on a
15 carbon skeleton. The biological activities and challenging struc-
tures of penifulvins have attracted the attention of synthetic
chemists.11
Due to the very few methods available for the construction of
functionalized quaternary centers12 and the presence of several
such centers in penifulvins, we felt that the method we have in

T. K. Chakraborty et al. / Tetrahedron Letters 51 (2010) 4425–4428
4427
minor Z-isomer 26 could be separated easily at this stage through
silica gel column chromatography. The E geometry of 20 was
confirmed from NOE experiment. 1H NOE study showed that irra-
diation of the olefinic singlet signal at d 5.59 caused no enhance-
ment of the proton signal at d 2.18 corresponding to allylic
methyl. Similarly on irradiation of allylic methyl singlet signal at
d 2.18, there was no enhancement of proton signal at d 5.59 corre-
sponding to olefinic proton. On the other hand, irradiation of the
olefinic singlet signal at d 5.6 enhanced the peak of allylic CH2
quatrate at d 2.1 to prove the E geometry of 20. To carry out the
crucial radical-mediated cyclization reaction, the epoxy alcohol
20 was treated with Cp2TiCl1 (generated in situ using Cp2TiCl2,
ZnCl2, and activated Zn powder) in THF at ꢁ20 °C, then allowed
to come to room temperature and stirred for another 12 h. This
metal-mediated radical cyclization gave 2719 in 82% yield.
The relative stereochemistry of the newly generated centre was
confirmed by NOESY experiment. NOESY spectrum of 27 showed a
strong dipolar coupling between C8–H and 10-CH3 indicating that
they are in the same side of the cyclic ring. Similarly NOE cross
peaks between C8–H/C11–H, 10-CH3/C11–H proved that C11–H also
to be in the same side of the bicyclic ring. Stereochemistry of C6–H
center was fixed from the NOE between C6–H/C9–H (Fig. 2).
The Ti(III)-mediated ring closure reaction of 20 was expected to
provide the desired compound 19 in the same way as 3 was trans-
formed into 4 carrying the CH2OH and CH2CO2Et substituents in cis
orientations in the newly formed five-membered ring. But the for-
mation of the unwanted isomer 2719, contrary to our expectation,
has now given us a challenge to find a way out to access the right
intermediate 19 in order to complete the total synthesis of
penifulvins.
12
13
EtO2C
H
4
H
5
3
9
2
H
8
7
6
1
H
11
HO
10
CH3
HO
H
H
Figure 2. Important NOEs that were used to establish the relative stereochemist-
ries in 27.
hand to build chiral quaternary centers using Ti(III)-mediated ring
opening of 2,3-epoxy alcohols could be tested for its practical
applicability in assembling the core bicylic ring system of these
molecules.
Retrosynthetic analysis of one of the penifulvins, penifulvin A
(12) is illustrated in Scheme 4. We envisaged that compound 12
could have been derived from intermediates 17–19 via functional
groups manipulations. The bicylic core of 19 could be obtained
from epoxy alcohol 20 via Cp2TiCl-mediated radical cyclization.
We commenced our synthesis fromcommerciallyavailable start-
ing material cyclopentanone 21 as shown in Scheme 5. The first step
involved a crucial Michael addition reaction13 in which cyclopenta-
none 21 was first converted to the corresponding TMS enol ether
derivative using LDA and TMSCl in THF at ꢁ78 °C. The TMS-enol
ether intermediate, without purification and characterization, was
mixed with mesityl oxide in CH2Cl2 and the mixture was added
dropwise to a TiCl4 solution in CH2Cl2 at ꢁ78 °C to give 22 in 56%
yield. Next our objective was to protect selectively one of the
carbonyl groups of 22. We achieved it by treating 22 with 1,3-prop-
anedithiobis(trimethylsilane) and ZnI2 in diethyl ether at room tem-
perature.14 A variety of reagents and conditions, such as (CH2OH)2,
PTSA, benzene; CH2(CH2OH)2, PTSA, benzene; (CH2OTMS)2, TMSOTf,
CH2Cl2; CH2(CH2SH)2, BF3ꢂEt2O, and CH2Cl2 were used but none of
them were found to be effective except the above-mentioned
condition.
Acknowledgments
The authors wish to thank DST, New Delhi for the Ramanna Fel-
lowship (SR/S1/RFOC-06/2006; T.K.C.) and CSIR, New Delhi for re-
search fellowships (A.K.C. and R.S.).
References and notes
The resulting mono-keto compound was then subjected to one
carbon olefination. Several reagents and conditions such as Ph3P+-
CH3Iꢁ, n-BuLi, THF; Ph3P+CH3Iꢁ, KOtBu, diethyl ether; Cp2TiMe2,
and toluene were used but none of them gave the desired product.
Finally the transformation was successfully carried out using Mg
and TiCl4 in CH2Cl2–THF solvent mixture at 0 °C to afford 23 in 62%
1. (a) Chakraborty, T. K.; Dutta, S. J. Chem. Soc., Perkin Trans. 1 1997, 1257–1259;
(b) Chakraborty, T. K.; Das, S. Tetrahedron Lett. 2002, 43, 2313–2315.
2. Chakraborty, T. K.; Samanta, R.; Das, S. J. Org. Chem. 2006, 71, 3321–3324.
3. Chakraborty, T. K.; Samanta, R.; Ravikumar, K. Tetrahedron Lett. 2007, 48, 6389–
6392.
4. Chakraborty, T. K.; Samanta, R.; Roy, S.; Sridhar, B. Tetrahedron Lett. 2009, 50,
3306–3310.
5. Shim, S. H.; Gloer, J. B.; Wicklow, D. T. J. Nat. Prod. 2006, 69, 1601–1605.
6. Shim, S. H.; Swenson, D. C.; Gloer, J. B.; Dowd, P. F.; Wicklow, D. T. Org. Lett.
2006, 8, 1225–1228.
7. (a) Horner, L.; Hoffman, H.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499–
2505; (b) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733–1738; Cf.: (c) Wadsworth, W. S., Jr. In Organic Reactions; Wiley: New
York, 1977; Vol. 25. pp 73–254.
8. Gao, Y.; Klunder, J. M.; Hanson, R. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J.
Am. Chem. Soc. 1987, 109, 5765–5780.
t
yield.15 Allylic oxidation of 23 using SeO2 and TBHP in BuOH at
50 °C gave the desired allylic alcohol in 39% yield.16 Extensive
decomposition of the starting material was observed when other
reagents and conditions such as SeO2, H2O2, dioxane; SeO2, H2O2,
tBuOH; and SeO2, AcOH–H2O were used. The relative stereochemis-
try of the newly generated center carrying the –OH group was
established latter by NOESY spectroscopy. Next, to deprotect the
dithiane moiety, the allylic alcohol intermediate was treated with
AgNO3 in EtOH at 50 °C to give 24 in 90% yield.17
Our next objective was to carry out two carbon olefination reac-
tion. A variety of reagents such as (MeO)2P(O)CO2Me, (CF3CH2O)2-
P(O)CO2Me, and Ph3PCH2CO2Me were used but Mayer–Schuster
rearrangement18 was found to be effective. First the carbonyl com-
pound 24 was treated with lithiated ethyl ethynyl ether in THF at
ꢁ78 °C followed by Mayer–Schuster rearrangement, using anhy-
drous AuCl3 in CH2Cl2–EtOH solvent system at room temperature
to afford 25, as an inseparable mixture of E and Z olefins (3.4:1),
in 61% yield in two steps. Then this inseparable mixture of com-
pounds was treated with m-CPBA in CH2Cl2 at 0 °C to give the E
olefinic epoxy compound 20 (single diasteromer) in 65% yield.
The stereochemistry of the epoxy ring was not determined as its
opening with Ti(III) was expected to lead to a radical center. The
9. (a) Green, M. L. H.; Lucas, C. R. J. Chem. Soc., Dalton Trans. 1972, 1000–1003; (b)
Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110, 8561–8562; For
reviews on Cp2TiCl see: (c) Barrero, A. F.; Quílez del Moral, J.; Sánchez, E. M.;
Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627–1641; (d) Daasbjerg, K.; Svith, H.;
Grimme, S.; Gerenkamp, M.; Mück-Lichtenfeld, C.; Gansäuer, A.; Barchuk, A.
Top. Curr. Chem. 2006, 263, 39–69; (e) Gansäuer, A.; Rinker, B. Tetrahedron 2002,
58, 7017–7026; (f) Gansäuer, A.; Bluhm, H. Chem. Rev. 2000, 100, 2771–2788.
10. Spectral data of compound 11: Rf = 0.6 (SiO2, 25% EtOAc in petroleum ether);
½
a 2D8
ꢃ
+15.3 (c 0.063, CHCl3); 1H NMR (CDCl3, 400 MHz): d 1.1 (Me9), 1.32 and
1.44 (acetonide methyls), 1.36 (m, H40), 1.43 (m, H7), 1.75 (m, H4), 2.02 (m,
3
3
H50), 2.12 (m, H5), 2.47 (d, J2–2 = 14.7 Hz, H2), 2.79 (d, J2–2 = 14.7 Hz, H20),
0
0
3
3
3
3.64 (s, 3H), 3.80 (dd, J8–8 = 12.5 Hz, J7–8 = 3.2 Hz, H80), 4.06 (dd, J8–
0
0
= 12.5 Hz, J7–8 = 5.4 Hz, H8), 4.43 (dt, J = 1.4, 6.1 Hz, H6); 13C NMR (CDCl3,
3
80
100 MHz): d 173.3, 97.2, 72.4, 57.9, 51.0, 48.3, 47.8, 41.0, 36.7, 31.1, 30.1, 28.7,
26.2; IR (KBr): 2983, 2859, 1727, 1427, 1178 cmꢁ1; MS (ESI): m/z 265 (20)
[M+Na]+.
11. (a) Gaich, T.; Mulzer, J. J. Am. Chem. Soc. 2009, 131, 452–453; (b) Gaich, T.;
Mulzer, J. Org. Lett. 2009, 12, 272–275.
12. Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969–5994.

4428
T. K. Chakraborty et al. / Tetrahedron Letters 51 (2010) 4425–4428
13. Narasaka, K.; Soai, K.; Aolawa, Y.; Mukaiyama, T. Bull. Chem. Soc. Jpn 1976, 49,
779–783.
14. Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. J. Am. Chem. Soc. 1977,
99, 5009–5017.
15. Yan, T.-H.; Tsai, C.-C.; Chien, C.-T.; Cho, C.-C.; Huang, P.-C. Org. Lett. 2004, 6,
4961–4963.
16. Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526–5528.
17. Reece, C. A.; Rodin, J. O.; Briwnlee, R. G.; Duncan, W. G.; Silverstein, R. M.
Tetrahedron 1968, 24, 4249–4256.
Cp2TiCl generated in situ. The reaction mixture was warmed up to room
temperature over a period of 1 h and stirring was continued for additional 12 h.
The reaction was then quenched with saturated NH4Cl solution (5 mL) and
filtered through Celite. The filtrate was diluted with EtOAc (100 mL), washed
with water (20 mL), brine (20 mL), and dried over anhydrous Na2SO4. The
organic extract was concentrated in vacuo and chromatographed on silica gel
with EtOAc–petroleum ether (1:4) as eluant to afford 27 (659 mg, 82%) as
colorless oil. Rf = 0.3 (SiO2, 25% EtOAc in petroleum ether); 1H NMR (CDCl3,
400 MHz): d 4.40 (t, J = 8.1 Hz, 1H), 4.31 (q, J = 7.3 Hz, 2H), 3.94 (d, J = 12.5 Hz,
1H), 3.82 (d, J = 12.5 Hz, 1H), 3.51 (br s, 1H), 2.86 (d, J = 14.7 Hz, 1H), 2.59 (d,
J = 14.7 Hz, 1H), 2.36–2.16 (m, 2H), 1.87 (d, J = 13.9 Hz, 1H), 1.83 (d, J = 2.1 Hz,
1H), 1.78–1.67 (m, 2H), 1.64 (br s, 1H), 1.63 (d, J = 13.9 Hz, 1H), 1.56–1.46 (m,
1H), 1.29 (s, 3H), 1.26 (t, J = 7.3 Hz, 3H), 1.04 (s, 3H), 0.87 (s, 3H); 13C NMR
(CDCl3, 100 MHz): d 174.4, 78.2, 65.9, 63.1, 60.4, 56.8, 55.5, 44.4, 37.5, 34.0,
33.9, 28.7, 24.2, 21.4, 14.2; IR (neat): 3435, 2959, 1733, 1717, 1457, 1370,
1217 cmꢁ1; MS (ESI): m/z 285.7 (100) [M+H]+.
18. (a) Mayer, K. H.; Schuster, K. Chem. Ber. 1992, 55, 819–823; (b) Engel, D. A.;
Dudley, G. B. Org. Lett. 2006, 8, 4027–4029.
19. Synthesis of compound 27: To a stirred solution of ZnCl2 (1.07 g, 8.51 mmol) in
THF (60 mL) were added activated Zn dust (1.11 g, 17.02 mmol) and Cp2TiCl2
(2.1 g, 8.51 mmol) sequentially at room temperature. The stirring was
continued for another 1 h and cooled to ꢁ20 °C. Then compound 20 (800 mg,
2.83 mmol) in THF (10 mL) was added drop by drop to the stirred solution of