Preparation and double Michael addition reactions of a synthetic equivalent of the Nazarov reagent

Article abstract of DOI:10.1021/ol400934c

A synthetic equivalent of the Nazarov reagent, the silyl derivative 2, able to undergo base-catalyzed double Michael addition reactions with α,β-unsaturated carbonyl compounds has been developed. The new reagent satisfactorily reacts with unsaturated indo

Full text of DOI:10.1021/ol400934c

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Preparation and Double Michael Addition
Reactions of a Synthetic Equivalent of the
Nazarov Reagent
,†
Mercedes Amat,* Federica Arioli, Maria Perez, Elies Molins, and Joan Bosch
†
†
‡
†
ꢀ
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine
ꢁ
(IBUB), University of Barcelona, 08028-Barcelona, Spain, and Institut de Ciencia de
Materials (CSIC), Campus UAB, 08193-Cerdanyola, Spain
amat@ub.edu
Received April 4, 2013
ABSTRACT
A synthetic equivalent of the Nazarov reagent, the silyl derivative 2, able to undergo base-catalyzed double Michael addition reactions with R,β-
unsaturated carbonyl compounds has been developed. The new reagent satisfactorily reacts with unsaturated indolo[2,3-a]quinolizidine lactams
to give pentacyclic yohimbinone-type derivatives.
The Nazarov reagent (methyl or ethyl 3-oxo-4-pentenoate)1
is a well-known annelating agent that has been extensively
used in terpene and alkaloid syntheses.2 Its usefulness and
Scheme 1. A Synthetic Equivalent of the Nazarov Reagent
synthetic versatility stem from its dense functionalization,
with a nucleophilic acidic carbon in the β-keto ester
moiety and an electrophilic carbon included in an
R,β-unsaturated ketone fragment (Scheme 1). The
Nazarov reagent (1) has successfully been used in a
ketones,3 β-dicarbonyl compounds,4 enamino esters,5
variety of Robinson-type annulations with enolizable
imines,6 enamines,7 dienamines,8 and (thio)imidates,9 in
which the reagent undergoes an initial Michael addition and
† University of Barcelona.
‡
ꢁ
Institut de Ciencia de Materials.
the resulting β-keto ester enolate acts as a nucleophile.
(1) (a) First reported by: Nazarov, I. N.; Zavyalov, S. I. Zh. Obshch.
Khim. 1953, 23, 1703. Engl. Transl. 1953, 23, 1793. Chem. Abstr. 1954,
48, 13667h. For improved preparations, see: (b) Zibuck, R.; Streiber,
J. M. J. Org. Chem. 1989, 54, 4717–4719. (c) Zibuck, R.; Streiber, J. M.
Org. Synth. 1993, 71, 236–241 and references cited therein.
ꢀ
(5) Gassama, A.; d’Angelo, J.; Cave, C.; Mahuteau, J.; Riche, C. Eur.
J. Org. Chem. 2000, 3165–3169.
(6) (a) Dodd, D. S.; Oehlschlager, A. C.; Georgopapadakou, N. H.;
Polak, A.-M.; Hartman, P. G. J. Org. Chem. 1992, 57, 7226–7234. (b)
Nagata, K.; Sekishiro, Y.; Itoh, T. Heterocycles 2007, 72, 175–179.
(7) (a) Stork, G.; Guthikonda, R. N. J. Am. Chem. Soc. 1972, 94,
5109–5110. (b) Kametani, T.; Hirai, Y.; Kajiwara, M.; Takahashi, T.;
Fukumoto, T. Chem. Pharm. Bull. 1975, 23, 2634–2642. (c) Shono, T.;
Hamaguchi, H.; Sasaki, M.; Fujita, S.; Nagami, K. J. Org. Chem. 1983,
(2) Zibuck, R. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, 1995; Vol. 5, pp 3558À3559.
(3) (a) Wenkert, E.; Afonso, A.; Bredenberg, J. B-S.; Kaneko, C.;
Tahara, A. J. Am. Chem. Soc. 1964, 86, 2038–2043. (b) Schkeryantz,
J. M.; Luly, J. R.; Coghlan, M. J. Synlett 1998, 723–724. (c) Beauhaire,
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(4) (a) Pelletier, S. W.; Chappel, R. L.; Prabhakar, S. J. Am. Chem.
Soc. 1968, 90, 2889–2895. (b) Brutcher, F. V.; Vanderwerff, W. D.;
Dreikorn, B. J. Org. Chem. 1972, 37, 297–302. (c) Caselli, A. S.; Collins,
D. J.; Stone, G. M. Aust. J. Chem. 1982, 35, 799–808. (d) Watson, A. T.;
Park, W. Y.; Wiemer, D. F.; Scott, W. J. J. Org. Chem. 1995, 60, 5102–
5106. (e) Ling, T.; Chowdhury, C.; Kramer, B. A.; Vong, B. G.;
Palladino, M. A.; Theodorakis, E. A. J. Org. Chem. 2001, 66, 8843–
8853. (f) Ghosh, S.; Rivas, F.; Fischer, D.; Gonzalez, M. A.; Theodorakis,
E. A. Org. Lett. 2004, 6, 941–944.
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(9) (a) Trost, B. M.; Kunz, R. A. J. Am. Chem. Soc. 1975, 97, 7152–
7157. (b) Celerier, J. P.; Eskenazi, C.; Lhommet, G.; Maitte, P.
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(d) Ortuno, J. C.; Langlois, Y. Tetrahedron Lett. 1991, 32, 4491–4494.
r
10.1021/ol400934c
XXXX American Chemical Society

However, the instability of 1 under basic conditions10
has restricted its use in annulations with R,β-unsaturated
carbonyl derivatives, in which the reagent successively acts
as a Michael donor and a Michael acceptor.11,12 To over-
come this limitation, as well as the difficulties associated
with the preparation and purification of the Nazarov
reagent, more stable modified reagents substituted at the
olefinic carbons13 and suitable precursors allowing its in
situ generation14 have been developed. In contrast with the
original Nazarov reagent, the substituted reagents, exten-
sively used by Deslongchamps, react in their enolate form,
smoothly undergoing base-catalyzed double Michael
addition reactions to give cis-decalin derivatives.13
Scheme 2. Attempted Double Michael Addition with the
Nazarov Reagent, 1
In this letter we present a stable and practical synthetic
equivalent of the Nazarov reagent, the silyl derivative 2,
that we have developed in the context of our studies on the
use of tryptophanol-derived lactams in the enantioselective
synthesis of indole alkaloids.15 We envisaged a straightfor-
ward approach to pentacyclic yohimbine-type derivatives,
in which the carbocyclic E ring would be assembled by a
double Michael addition of the Nazarov reagent (1) to
unsaturated indoloquinolizidine lactams 4. These lactams,
which incorporate an additional activating electron-
withdrawing substituent, were prepared in good overall
yields by conventional methods from the known lactam
3,16 as outlined in Scheme 2.
Initial attempts to perform the annulation of the Nazarov
reagent 1 with unsaturated lactam 4a (Cs2CO3/ CH2Cl2
or KF/MeOH) were unsuccessful, resulting in complete
degradation of 1. When using lactam 4b, which bears a
benzenesulfonyl activating substituent, annulation occurred
to some extent, pentacycle 5b being isolated in very low
yield from the resulting complex mixture.
methyl substituted Nazarov reagent 617 with the above
lactams 4a and 4b to give the respective pentacyclic
derivatives 8a and 8b as single stereoisomers in excellent
yields18 (Scheme 3). Although it was possible to stereo-
selectively remove the benzenesulfonyl group of 8b with
retention of the configuration,19 the presence of the methyl
substituent in the carbocyclic E ring makes pentacyclic
derivative 9 unsuitable for the synthesis of yohimbine-type
natural products.
At this point, we decided to design a synthetic equivalent
of the Nazarov reagent that would overcome the incon-
veniences and limitations of the original reagent 1. Bearing
inmindthatR-silylatedvinylketoneshavebeenextensively
used as surrogate vinyl ketones in annulation reactions,20
we planned to prepare a Nazarov-type reagent, such as 2,
silylated at the R-position of the enone (Scheme 4). The
R-trimethylsilyl group would increase the electrophilicity
of the β-carbon, stabilize the R-anion formed upon
Michael addition, and slow down the polymerization due
to its steric bulk. Additionally, being R-ketonic in the final
compound, the silyl substituent could readily be removed
by nucleophiles.
Despite these unsatisfactory results, the viability of our
double Michael addition strategy was confirmed by the
successful Cs2CO3-mediated reaction of the more stable
(10) Benetti, S.; Carlo, S.; De Risi, C.; Pollini, G. P.; Veronese, A. C.;
Zanirato, V. Synlett 2008, 2609–2612.
(11) (a) For the double Michael addition of the Nazarov reagent to a
nitroalkene, see: Albertini, E.; Barco, A.; Benetti, S.; Risi, C. D.; Pollini,
G. P.; Romagnoli, R.; Zanirato, V. Tetrahedron Lett. 1994, 35, 9297–
9300. (b) However, see: Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe, H.;
Takemoto, Y. Tetrahedron 2006, 62, 365–374.
(12) For the use of the Nazarov reagent in organocatalytic asym-
metric tandem Michael/MoritaÀBaylisÀHillman reactions, see: Cabrera,
ꢀ
S.; Aleman, J.; Bolze, P.; Bertelsen, S.; Jorgensen, K. A. Angew. Chem., Int.
Ed. 2008, 47, 121–125.
ꢀ
(13) (a) Lavallee, J.-F.; Deslongchamps, P. Tetrahedron Lett. 1988,
ꢀ
29, 5117–5118. (b) Lavallee, J.-F.; Spino, C.; Ruel, R.; Hogan, K. T.;
Deslongchamps, P. Can. J. Chem. 1992, 70, 1406–1426.
(14) (a) Ellis, J. E.; Dutcher, J. S.; Heathcock, C. H. Synth. Commun.
1974, 4, 71–77. (b) Wakselman, C.; Molines, H. Synthesis 1979, 622–623.
(c) Michael, J. P.; Zwane, M. I. Tetrahedron Lett. 1992, 33, 4755–4758.
See also ref 10.
The silyl derivative 2 waspreparedfrom(1-bromovinyl)-
trimethylsilane (10) via the known21 allylic alcohol 11, by a
route inspired in the preparation of the Nazarov reagent
1.1b,c Dess-Martin oxidation of 11, followed by acylation
of the unstable acrolein derivative 12 with the enolate
(15) (a) Amat, M.; Santos, M. M. M.; Bassas, O.; Llor, N.; Escolano,
ꢀ
ꢀ
C.; Gomez-Esque, A.; Molins, E.; Allin, S. M.; McKee, V.; Bosch, J.
ꢀ
ꢀ
J. Org. Chem. 2007, 72, 5193–5201. (b) Amat, M.; Gomez-Esque, A.;
Escolano, C.; Santos, M. M. M.; Molins, E.; Bosch, J. J. Org. Chem.
ꢀ
2009, 74, 1205–1211. (c) Perez, M.; Arioli, F.; Rigacci, G.; Santos,
M. M. M.; Gomez-Esque, A.; Escolano, C.; Florindo, P.; Ramos, C.;
(18) When the reaction from 4b was conducted for shorter times,
mixtures of 8b and the intermediate Michael adduct 7b were formed.
(19) The cis D/E ring junction in 9 and 16 was evident from the
positive NOE effect between 15-H and 20-H.
(20) Stork, G.; Ganem, B. J. Am. Chem. Soc. 1973, 95, 6152–6153.
(21) Lipshutz, B. H.; Mollard, P.; Lindsley, C.; Chang, V. Tetra-
hedron Lett. 1997, 38, 1873–1876.
ꢀ
ꢀ
Bosch, J.; Amat, M. Eur. J. Org. Chem. 2011, 3858–3863. (d) Amat, M.;
ꢀ
Ramos, C.; Perez, M.; Molins, E.; Florindo, P.; Santos, M. M. M.;
Bosch, J. Chem. Commun. 2013, 49, 1954–1956.
(16) Allin, S. M.; Thomas, C. I.; Doyle, K.; Elsegood, M. R. J. J. Org.
Chem. 2005, 70, 357–359.
(17) Pollet, P.; Gelin, S. Synthesis 1978, 142–143.
B
Org. Lett., Vol. XX, No. XX, XXXX

epi-allo-yohimbinone derivative 16 by reductive removal
of the activating benzenesulfonyl group.19
Scheme 3. Double Michael Addition of Methyl
3-Oxo-4-hexenoate (6)
The absolute configuration of 5b was unambiguously
established by X-ray crystallography. In turn, the 3-H/15-H
cis relationship in the isomers 14a and 14b (as well as in 19;
see Scheme 6) was deduced from the positive NOE effect
between these protons. With these assignments taken into
account, the NMR chemical shifts of the protons and
carbons at the 3- and 14-positions were of diagnostic value
to assign the C-3, C-15, and C-20 relative stereochemistry
of the pentacyclic derivatives reported in this work
(see tables in the Supporting Information).
Scheme 5. Double Michael Addition of the Nazarov Reagent
Equivalent 2 to Unsaturated Lactams 4
of methyl acetate, and IBX oxidation of the resulting
β-hydroxy ester 13 gave 2 in 53% overall yield in four
steps. This silylated Nazarov reagent was stable in storage
at À20 °C under nitrogen for several months.22
Scheme 4. Preparation of the New Nazarov Reagent 2
Similar satisfactory results were obtained in the reaction
of the silylated Nazarov reagent 2 with unsaturated lac-
tams 18 (Scheme 6), which lacks the O-Boc hydroxymethyl
substituent, and 20 (Scheme 7), unprotectedat the hydroxy
function and indole nitrogen. The former was prepared
from the known saturated lactam 1725 as outlined in
Scheme 6, whereas the latter by was prepared by TFA
treatment of the above lactam 4a.
Somewhat surprisingly, whereas lactam 18 behaved like
lactams 4, stereoselectively leading to an all-cis pentacycle,
19, the annulation from 20 took place with opposite facial
selectivity, giving pentacycle 21 as the major product.26
The stereochemical outcome of the double Michael
additions deserves comment. The configuration of the
C-15 stereocenter is generated in the initial attack of the
Nazarov enolate, and it is known that conjugate addition
to unsaturated indolo[2,3-a]quinolizidine lactams usually
To our delight, reagent 2 satisfactorily reacted with
unsaturated lactams 4a and 4b to give double Michael
addition products, in which the trimethylsilyl group had
undergone in situ protodesilylation.23 Thus, treatment of
4a with 2 under the reaction conditions outlined in Scheme
5 stereoselectively led to a single pentacycle 14a in excellent
yield. A subsequent removal of the Boc protecting group
provided 15. A similar reaction from 4b afforded a diaste-
reoisomeric mixture of pentacycles 14b and 5b (2:1 ratio;
64%),24 the latter being stereoselectively converted to the
(22) Reagent 2 was stable enough to be purified by flash chromato-
graphy. Although TLC showed that no significant decomposition
occurred on stirring a CH2Cl2 solution of 2 at 0 °C for 2 h in the presence
of Cs2CO3, extensive polymerization was observed when the experiment
was performed at rt.
(23) In some runs from 4b, a trimethylsilyl derivative was detected
(NMR) during chromatografic purification of the crude reaction
mixture.
(24) When the reaction was carried out at a higher concentration
(0.1 M), an inversion of the stereochemistry was observed (5b/14b ratio
2:1; 62% yield). There are few cases in which concentration has a
dramatic effect on the stereoselectivity of a reaction: Yang, F.; Zhu,
Y.; Yu, B. Chem. Commun. 2012, 48, 7097–7099 and ref cited therein.
(25) Allin, S. M.; Khera, J. S.; Thomas, C. I.; Witherington, J.; Doyle,
K.; Elsegood, M. R. J.; Edgar, M. Tetrahedron Lett. 2006, 47, 1961–
1964.
(26) Trace amounts of the 15,20-epimer were also formed.
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of 22a with 1 had only resulted in a very poor yield of 23a.
In contrast, the silylated derivative 2 satisfactorily gave the
respective highly functionalized cis-decalins 23a30 and 23b
in acceptable yields.
Scheme 6. Double Michael Addition of the Nazarov Reagent
Equivalent 2 to Unsaturated Lactam 18
Scheme 8. Double Michael Addition of the Nazarov Reagent
Equivalent 2 to Enones 22
Scheme 7. Double Michael Addition of the Nazarov Reagent
Equivalent 2 to Unsaturated Lactam 20
In summary, we have developed a synthetic equivalent
of the Nazarov reagent, the silyl derivative 2, which is able
to participate in Cs2CO3-promoted double Michael annu-
lations with R,β-unsaturated carbonyl compounds, avoid-
ing the polymerization problem associated with the original
Nazarov reagent. Starting from unsaturated indolo[2,3-a]-
quinolizidine lactams, this silylated Nazarov reagent
allows the straightforward construction of pentacyclic
yohimbinone-type systems.
leads to trans 3-H/15-H derivatives, although, for steric
reasons, a reversal of the facial selectivity is observed when
the indole nitrogen is Boc-protected.27 On the other hand,
the cis D/E ring junction28 results from stereoelectronic
control during the second Michael addition.29
To further illustrate the synthetic usefulness of the
silylated Nazarov reagent 2 as a synthetic equivalent of
the original reagent 1, we also studied Cs2CO3-promoted
double Michael annulations from cyclohexenones 22a and
22b (Scheme 8). Earlier attemptstoperform the annulation
Acknowledgment. Financial support from the MICIN,
Spain (Project CTQ2012-35250) and the AGAUR,
Generalitat de Catalunya (Grant 2009-SGR-1111) is grate-
fully acknowledged. Thanks are also due to the MECD
(Spain) for a fellowship to F.A.
Supporting Information Available. Detailed experimen-
tal procedures for all new compounds, tables with 1H and
13C NMR chemical shifts of the pentacyclic derivatives,
(27) (a) Naito, T.; Miyata, O.; Ninomiya, I. Heterocycles 1987, 26,
1739–1742. (b) Overman, L. E.; Robichaud, A. J. J. Am. Chem. Soc.
1
copies of H and 13C NMR spectra for selected com-
€
1989, 111, 300–308. (c) Gomez-Pardo, D.; Desmaele, D.; d’Angelo, J.
pounds, and X-ray crystallographic information file
(CIF) for 5b. This material is available free of charge
via the Internet at http://pubs.acs.org.
Tetrahedron Lett. 1992, 33, 6633–6636. (d) Deiters, A.; Petterson, M.;
Martin, S. F. J. Org. Chem. 2006, 71, 6547–6561. See also ref 25. The
trans 3-H/15-H stereochemistry in 8 can be rationalized by considering
that the substituent at the terminal carbon of the Nazarov reagent 6
slows down cyclization, thus allowing equilibration at C-15.
(28) All pentacyclic derivatives prepared in this work were predomi-
nantly (or completely) enolic in solution, as expected for a cis-D/E ring
junction in yohimbinone-type systems: (a) Albright, J. D.; Goldman, L.
J. Org. Chem. 1965, 30, 1107–1110. (b) Brutcher, F. V., Jr.; Vanderwerff,
W. D.; Dreikorn, B. J. Org. Chem. 1972, 37, 297–302.
(30) TLC of the crude reaction mixture showed the presence of a
major compound and only minor amounts of the final product 23a.
After flash chromatography, cis-decalin 23a was the only isolated
compound, thus suggesting that protodesilylation mainly occurs during
evaporation and purification.
ꢀ
(29) Berthiaume, G.; Lavallee, J.-F.; Deslongchamps, P. Tetrahedron
Lett. 1986, 45, 5451–5454.
The authors declare no competing financial interest.
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