Intramolecular asymmetric Pummerer reactions as a key step in the synthesis of bicyclic precursors of anthracyclinones

Article abstract of DOI:10.1016/S0040-4039(99)02025-0

Highly stereoselective Pummerer reactions were observed on reaction of β-hydroxysulfoxides 2a-2d and 2'b with TMSOTf. Sulfenium intermediates are captured intramolecularly by the electrophilic aromatic ring, thus yielding bicyclic structures with a p-tolylsulfenyl group at the benzylic position in a cis arrangement with respect to the hydroxyl group. The stereogenicity transfer seems to be mainly controlled by the hydroxylated chiral carbon. Resulting compounds 3a, 3c and 3d can be used as bicyclic precursors of different anthracyclinones.

Full text of DOI:10.1016/S0040-4039(99)02025-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 261–265
Intramolecular asymmetric Pummerer reactions as a key step in
the synthesis of bicyclic precursors of anthracyclinones†
Jose Luis García Ruano ∗ and Cristina García Paredes
Departamento de Química Orgánica, Universidad Autónoma, Cantoblanco, 28049 Madrid, Spain
Received 30 June 1999; revised 11 October 1999; accepted 26 October 1999
Abstract
Highly stereoselective Pummerer reactions were observed on reaction of β-hydroxysulfoxides 2a–2d and 20b
with TMSOTf. Sulfenium intermediates are captured intramolecularly by the electrophilic aromatic ring, thus
yielding bicyclic structures with a p-tolylsulfenyl group at the benzylic position in a cis arrangement with respect to
the hydroxyl group. The stereogenicity transfer seems to be mainly controlled by the hydroxylated chiral carbon.
Resulting compounds 3a, 3c and 3d can be used as bicyclic precursors of different anthracyclinones. © 1999
Elsevier Science Ltd. All rights reserved.
Considerable attention has been paid to the Pummerer reaction as a synthetically useful process.1
Besides acetic anhydride, or the more electrophilic trifluoroacetic anhydride, other useful promoters of
these reactions are trimethylsilyl trifluoromethanesulfonate (TMSOTf) and O-silylated ketene acetals,
which allow the reactions to be carried out at lower temperatures. The intramolecular capture of the
thionium ion by aromatic rings, a Friedel–Crafts-like process, has been used to prepare polycyclic ring
systems.2 The asymmetric Pummerer reaction of optically active sulfoxides has also been investigated,3
with the O-silylated ketene acetals being the best promoters.
In the course of our studies directed towards the preparation of optically pure anthracyclinones,4 the
bicyclic compounds 4, precursors of the desired tetracyclic system, were obtained from 3a. This thioether
was obtained in a highly stereoselective manner, by intramolecular capture of the thionium ion generated
Scheme 1.
∗
†
Corresponding author.
In memory of Professor J. de Pascual Teresa.
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02025-0
tetl 15953

262
when optically pure β-hydroxy-β-cyano sulfoxide 2a was treated under Pummerer conditions (Scheme
1). As a promoter of this reaction we used TMSOTf and DIPEA5 (di-isopropylethylamine) instead of
Ac2O or (CF3CO)2O to avoid the competition between the nucleophilic counterion (TfO−) and the
aromatic ring for the Pummerer intermediate.
The cyano group of 3a was transformed into COCH3, methyl, ethyl and other groups, which are usually
present in the natural anthracyclinones, but some of these transformations required the use of sequences
longer than expected.4 This prompted us to investigate the cyclization of other enantiomerically pure
sulfinyl derivatives, which could be more easily transformed into the typical substituents at C-9 of
anthracyclinones. Additionally, the high stereoselectivity observed in the synthesis of 3a (80% de),
suggested that an efficient intramolecular asymmetric Pummerer rearrangement was taking place which
deserved a more detailed study. In this paper we describe the results obtained in the intramolecular
asymmetric Pummerer reaction of enantiomerically pure β–hydroxysulfoxides 2a–2e and 20b (Table 1)
when they are treated with TMSOTf and DIPEA to give their corresponding benzylthioethers 3a–3e and
30b.
Table 1
Reaction conditions for the synthesis of compounds 2 and 20
The synthesis of 2a (entry 1, Table 1) has been previously reported.4 Compounds 2b and 20b were
prepared by highly stereoselective reduction of 14 with DIBAL-H and DIBAL-H/ZnBr2, respectively
(Table 1, entries 2 and 3). DIBAL-H reduction6 yielded a 4:96 mixture of 2b and 20b that are epimers
at the hydroxylic carbon (89% yield). Compound 2b was obtained as the sole diastereoisomer by
treatment of 1 with DIBAL-H/ZnBr2.7 Reactions of 1 with ethynyl and vinyl Grignard reagents (entries
4 and 5, Table 1) were carried out following the previously described conditions.8 Ethynyl magnesium
bromide yielded a 90:10 mixture of the two possible carbinols, 2c and 20c, whereas reaction with
the vinyl derivative resulted in a 84:16 mixture of epimers 2d and 20d. These mixtures were easily
separated by chromatography. The isolated yields of the major diastereoisomers, 2c and 2d, were
60 and 55%, respectively. Finally, compound 2e (entry 6, Table 1) was the major component of the
85:15 readily separated mixture obtained from the reaction of 1 with Me3Al/ZnBr2, under previously
reported conditions.9 The absolute configurations of the carbinols indicated in Table 1, were assigned
on the basis of the well-established stereochemical course of the corresponding reactions of reduction,6
hydrocyanation,10 and alkylation,8,9 taking into account that the configuration at sulfur in the starting
sulfoxides is not affected by the conditions used.

263
The Pummerer reactions of 2a–2e and 20b were studied using TMSOTf (4.5 equiv.) and DIPEA (4.5
equiv.). The reaction of 2b at room temperature yielded a 8:1 mixture of the two cyclized products, 3b
and 5b,11 epimers at the benzylic carbon (Scheme 2), which were easily separated by chromatography.
The major product was isolated in 81% yield. When the reaction was carried out at 0°C, compound 3b
was formed exclusively. Under similar conditions, the 96:4 mixture of 20b and 2b yielded a 7:3 mixture
of 30b and 50b at room temperature but only 30b (92% ee) at 0°C. Compounds 3b and 30b, which
exhibited identical physical and spectroscopic features, showed the opposite sign of optical rotation
which proves that they are enantiomers (Scheme 2). The same behaviour was observed for 5b and 50b.
1
The stereochemistry of these compounds was established (Scheme 2) from their H NMR parameters.
As the STol group must adopt a pseudoaxial arrangement in order to avoid allylic strain with the OMe
group, the main difference between compounds 30b and 50b (or 3b and 5b) is the axial or equatorial
arrangement of H-2, easily deduced from its vicinal coupling constant with H-3a. Compounds 3b and
30b, the major components of their respective reaction mixtures, have a cis-relationship between the OH
and STol groups, whereas it is trans for the minor isomers, 5b and 50b. These results demonstrate that
the configuration induced at the benzylic carbon is related to that of the hydroxylic carbon of the starting
sulfoxide (R from 2b and S from 20b) and is independent of the configuration of the sulphur.
Scheme 2.
The reaction of 2a with TMSOTf and DIPEA at 0°C yielded a 9:1 mixture of 3a and 5a.4 Optically
pure 3c was only formed from 2c (Table 2), but partially racemized 3c (80% ee) was obtained from a
9:1 mixture of 2c and 20c. This last reaction required 1 hour to complete, a longer reaction time than for
the above-mentioned reactions of 2a, 2b and 20b (30 min). After 90 min, the reaction of 2d yielded
a 1:1 mixture of 3d and 6d, which remained unaltered with time. Compound 6d was characterized
Table 2
Cyclization reaction of β-ketosulfoxides 2a–e with TMSOTf/DIPEA

264
as the trimethylsilyl derivative of the starting carbinol 2d.12 After 2 hours at rt, reaction of 2e with
TMSOTf–DIPEA did not afford the expected bicyclic compound (an acyclic thioether was exclusively
formed13). These results suggest that increasing the size of the R group in the starting hydroxysulfoxide
makes the intramolecular capture of the Pummerer intermediate by the aromatic ring more difficult.
The absolute configuration of compounds 3a, 3c–e13 was established from the cis-relationship between
their STol and OH groups which was deduced from their 13C NMR spectra14,15 assuming that the known
configuration at the hydroxylic carbons is not affected by the reaction conditions.
The configuration induced at the benzylic carbon is S for all compounds of Table 2, allowing the
OH and STol group to become cis. The sulfinyl configuration has no significant influence on the
stereochemical course of the reactions, which suggests that the formation of intimate ion pairs between
the sulfenium ion and the Me3SiO− counterion (which would block one of the faces of the sulfenium
intermediate to the attack of the nucleophile16) must be excluded.
Scheme 3.
As the deprotonation step proceeds through an E2-type elimination, the formation of the anti-
sulfenium intermediate would be favoured from steric grounds (see Scheme 3). We postulate formation
of the free sulfenium ion,17 which evolves into the bicyclic compounds by an intramolecular attack of the
nucleophilic ring. This attack takes place according to the Felkin–Anh model of Cram’s rule (Scheme 3).
The OTMS (perhaps associated with the TMSO− counterion17) adopts the orthogonal arrangement with
respect to the C_S+ bond. The favoured TS for diastereoisomers 2 and 20, which makes the trajectory of
the attacking nucleophile coincident with that of Dunitz’s rule,18 will be A and B, respectively (Scheme
3), both yielding compounds with the STol and OTMS in a cis arrangement. This model would also
explain why the reactivity decreases on increasing the size of the R group.
Acknowledgements
Financial support from DGICYT, Spain (Project PB98-0078), is gratefully acknowledged.
References
1. (a) DeLucchi, O.; Miotti, U.; Modena, G. Organic Reactions; Paquette, L. A., Ed.; John Wiley: New York, 1991; Chapter 3,
pp. 157–184. (b) Grierson, D. S.; Husson, H. P. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford,
1991; Vol. 6, pp. 909–947.
2. For a recent review, see: Padwa, A.; Gunn Jr., D. E.; Osterhout, M. H. Synthesis 1997, 1353–1377, and references cited
therein.
3. Kita, Y.; Shibata, N. Synlett 1996, 289, and references cited therein.
4. García Ruano, J. L.; García Paredes, C.; Hamdouchi, C. Tetrahedron: Asymmetry 1999, 10, 2935.
5. Craig, D.; Daniele, K.; MacKenzie, A. R. Tetrahedron 1992, 48, 7803.

265
6. Carreño, M. C.; García Ruano, J. L.; Martín, A. M.; Pedregal, C.; Rodriguez, J. H.; Rubio, A.; Sánchez, J.; Solladié, G. J.
Org. Chem. 1990, 55, 2120.
7. Barros, D.; Carreño, M. C.; García Ruano, J. L.; Maestro, M. C. Tetrahedron Lett. 1992, 33, 2733.
8. Bueno, A. B.; Carreño, M. C.; García Ruano, J. L. An. Quim. 1994, 90, 442.
9. Carreño, M. C.; García Ruano, J. L.; Maestro, M. C.; Pérez González, M.; Bueno, A. B.; Fisher, J. Tetrahedron 1993, 49,
11009.
10. (a) García Ruano, J. L.; Martín, A. M.; Rodriguez, J. H. Tetrahedron Lett. 1991, 32, 3195. (b) García Ruano, J. L.; Martín,
A. M.; Rodriguez, J. H. J. Org. Chem. 1992, 57, 7235. (c) García Ruano, J. L.; Martín, A. M.; Rodriguez, J. H. J. Org. Chem.
1994, 59, 533. (d) Escribano, A.; García Ruano, J. L.; Martín, A. M.; Rodriguez, J. H. Tetrahedron 1994, 50, 7567.
11. The products can be isolated as alcohols or their OTMS derivatives, depending on the conditions used for their isolation
(Ref. 4).
12. Trimethylsilyl derivatives were isolated in all cases instead of the starting alcohols when the reactions were stopped before
completion, thus suggesting they are formed before the Pummerer reactions.
13. The reaction of the TMSO derivative of 2e with TFAA afforded a complex reaction mixture containing 3e (10% isolated
yield).
14. Compound 3b [1S,2R]: [α]D20=+293.2 (c 0.76 CHCl3). 1H NMR (500 MHz) δ: 7.50, 7.10 (AA0BB0, J=8.06 Hz, 4H), 6.70
(s, 2H), 4.74 (dd, J=4.4, 1.8 Hz, 1H), 4.04 (m, 1H), 3.79 (s, 3H), 3.70 (s, 3H), 2.96 (ddd, J=18.25, 6.35, 1.35 Hz, 1H), 2.61
(d, J=11.1 Hz, 1H, OH) 2.57 (ddd, J=18.6, 12.25, 6.9, 1H), 2.36 (s, 3H), 2.0 (m, 1H), 1.93 (cd, J=12.35, 6.4 Hz, 1H). 13
C
NMR (75 MHz) δ: 151.15, 150.95, 136.75, 133.88, 131.66, 129.46, 126.63, 125.56, 108.47, 107.68, 69.14, 55.26, 55.45,
53.25, 27.71, 23.15, 21.02. Compound 30b [1R,2R]: 1H NMR (500 MHz) δ: 7.49, 7.15 (AA0BB0, J=8.08 Hz, 4H), 6.74 (s,
2H), 4.50 (t, J=2.35 Hz, 1H) 4.26 (m, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 2.86 (ddd, J=18.3, 7.1, 1.75, 1H), 2.69 (ddd, J=18.3,
12.05, 6.8, 1H), 2.54 (J=12.1, 7.05, 2.0 Hz, 1H), 2.37 (s, 3H), 1.95 (m, 1H), 1.57 (sbs, 1H, OH). 13C NMR (75 MHz) δ:
152.24, 150.93, 137.27, 132.57, 132.43, 129.62, 126.22, 122.56, 108.71, 107.98, 68.04, 55.93, 55.55, 47.90, 22.86, 21.07,
1
17.42. Compound 3a [α]D20=+288.6 (c 0.5 CHCl3). H NMR δ: 7.46, 7.07 (AA0BB0, J=8.04 Hz, 4H), 6.69 (s, 2H), 4.96
(d, J=2.3 Hz, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 2.74 (m, 2H), 2.33 (s, 3H), 2.16 (m, 2H). 13C NMR (75 MHz) δ: 150.79,
150.62, 136.79, 133.69, 132.05, 129.15, 123.88, 123.43, 120.70, 108.98, 108.23, 72.00, 55.72, 55.41, 53.57, 29.75, 22.11,
1
21.29, 1.09. Compound 3c [α]D20=+348.3 (c 0.6 CHCl3). H NMR δ: 7.51, 7.11 (AA0BB0, J=8.1 Hz, 4H), 6.68 (s, 1H),
4.80 (d, J=1.8 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.11 (s, 1H, OH), 3.1–2.8 (m, 2H), 2.33 (s, 3H, CH3), 2.30 (s, 1H), 2.15
(m, 2H). 13C NMR δ: 150.8 (2C), 137.2, 133.1, 131.9, 129.7, 125.7, 125.0, 108.5, 107.7, 84.0, 72.7, 69.0, 56.9, 55.5, 31.8,
1
22.7, 21.0. Compound 3d [α]D20=+138.3 (c 0.6 CHCl3). H NMR δ: 7.40, 7.01 (AA0BB0, J=8.17 Hz, 4H), 6.60 (s, 2H),
5.90 (dd, J=17.30, 10.65 Hz, 1H), 5.24 (dd, J=17.30, 1.56 Hz, 1H), 5.00 (dd, J=10.65, 1.56 Hz, 1H), 4.66 (d, J=2.4 Hz, 1H),
3.75 (s, 3H), 3.69 (s, 3H), 2.59 (m, 2H), 2.30 (s, 3H), 1.98 (m, 2H), 1.55 (s, 1H, OH), 0.7(s, 9H). 13C NMR δ: 150.9, 150.6,
141.0, 135.5, 131.2, 128.7, 127.0, 124.8, 114.4, 107.9, 107.7, 55.8, 55.7, 55.6, 53.79, 29.3, 22.6, 21.0, 2.45. Compound 3e
[α]D20=+174 (c 0.1 CHCl3). 1H NMR δ: 7.48, 7.11 (AA0BB0, J=8.1 Hz, 4H), 6.66 (s, 1H), 4.42 (d, J=2.2 Hz, 1H), 3.77 (s,
3H), 3.68 (s, 3H), 2.93 (ddd, J=18.53, 6.68, 1.3 Hz, 1H), 2.51 (m, 1H), 2.33 (s, 3H, CH3), 1.98 (m, 1H), 1.80 (m, 1H), 1.57
(sbs, 1H, OH), 1.23 (s, 3H). 13C NMR δ: 151.18, 151.04, 136.79, 134.03, 131.55, 129.48, 127.34, 124.52, 108.15, 107.62,
70.50, 58.06, 55.52, 55.47, 32.54, 23.56, 22.78, 21.05.
15. According to the influence of the substituents at C-2 on the chemical shifts of C-4 (see: Eliel, E.; Wilen, S.H. Stereochemistry
of Organic Compounds; John Wiley & Sons, 1994, pp. 717) the δC-4 values observed for 3a and 3c–e (22–22.6 ppm) suggest
they must exhibit the same configuration as 3b (δC-4=23.19 ppm) with STol and OH in a cis arrangement, but different from
5b (δC-4=17.40 ppm).
16. In these cases, the configuration of the sulfoxides is the main controller of the stereoselectivity of the Pummerer
rearrangement. See: Kita, Y.; Shibata, N.; Fukui, S.; Bando, M.; Fujita, S. J. Chem. Soc., Perkin Trans. 1 1997, 1763,
and Ref. 3.
17. This could be justified by association of the TMSO− ion to the other OTMS group present in the molecule. This interaction
has been previously invoked (Shibata, N.; Fujita, S.; Gyoten, M.; Matsumoto, K.; Kita, Y. Tetrahedron Lett. 1995, 36, 109).
18. Bürgi, H. B.; Dunitz, J. D.; Schefter, E. J. Am. Chem. Soc. 1973, 95, 5065.