Efficient construction of polycyclic derivatives via a highly selective cui-catalyzed domino reductive-aldol cyclization

Article abstract of DOI:10.1021/ol802879f

A versatile methodology for the diastereo-and enantioselective domino reductive-aldol cyclizations is reported. By using a copper (l)/diphosphane ligand, various five-and six-membered rings were generated with good to excellent diastereo-and enantioselect

Full text of DOI:10.1021/ol802879f

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1217-1220
Efficient Construction of Polycyclic
Derivatives via a Highly Selective
CuI-Catalyzed Domino Reductive-Aldol
Cyclization
Julia Deschamp and Olivier Riant*
Unite´ de Chimie Organique et Me´dicinale, UniVersite´ Catholique de LouVain,
Place Louis Pasteur, 1 1348 LouVain-la-NeuVe, Belgium
oliVier.riant@uclouVain.be
Received December 15, 2008
ABSTRACT
A versatile methodology for the diastereo- and enantioselective domino reductive-aldol cyclizations is reported. By using a copper (I)/diphosphane
ligand, various five- and six-membered rings were generated with good to excellent diastereo- and enantioselectivities (cis:trans up to 100:0
and ee up to 95%).
The asymmetric construction of polycyclic compounds
represents an important challenge in organic synthesis. These
skeletons are often basic building blocks for the synthesis
of biologically active natural products. Therefore, the use
of tandem, domino, or cascade processes is a powerful tool
to enhance the synthetic efficiency.1,2
Recently, excellent progress has been achieved in the area
of reductive-aldol reactions for the construction of several
contiguous stereocenters in one-pot.3 However, only few
methodologies described the synthesis of bi- and tricyclic
compounds by using the reductive-aldol cyclization.
Our team has recently described an efficient method for
the diastereo- and enantioselective domino reductive-aldol
reaction between methyl acrylate and a ketone4a or an
aldehyde,5 catalyzed by a copper (I) precursor combined with
an appropriate chiral diphosphane, in the presence of an
organosilane as reducing agent. These promising results
prompted us to investigate the scope of this methodology
for the synthesis of polycyclic compounds.
These reactions are proposed to proceed by the in situ
formation of a metal enolate through the conjugated addition
of a metal hydride specie onto the Michael acceptor. Then,
the intramolecular nucleophilic attack on the electrophile
formed the aldol-type adduct after a final reaction with
the hydride source. The domino reductive-aldol reactions take
the advantage of avoiding the preactivation of the nucleophile
(metal-enolate) in an independent step in contrast to the
Mukaiyama-type reactions.6
Our initial experiment was conducted with a catalytic
amount of the air stable precatalyst CuF(PPh3)3•2MeOH7 1
and (S)-MeO-BIPHEP L1 (1 mol %) on the diketo-ester 2a
(R ) Et),8 in the presence of phenylsilane as the hydride
source at room temperature.
(1) Reviews on domino reaction: (a) Tietze, L. F. Chem. ReV. 1996, 96,
115–136. (b) Fogg, D. E.; dos Santos, E. N. Coord. Chem. ReV. 2004, 248,
2365–2379
.
(2) For reviews on domino, cascade reactions in total synthesis see: (a)
Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Comm. 2003,
551-564. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134–7186. (c) Chapman, C. J.; Frost, C. G. Synthesis
2007, 1–21. (d) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
We were pleased to observe a complete conversion onto
the single product 3a after 2 h of reaction. Moreover, only
1993, 32, 131–163
.
10.1021/ol802879f CCC: $40.75
Published on Web 02/16/2009
2009 American Chemical Society

two diasteroisomers9 cis-3a and trans-3a were formed over
the four possible isomers and were isolated with a good 80%
yield.10 A trans selectivity was observed (trans-3a:cis-3a 68:
32), albeit with a low enantioselectivity (ee(trans-3a):23%)
for the major trans-3a isomer. We then studied the influence
of different parameters. The most representative results are
summarized in Table 1.
Table 1. Asymmetric Copper-Catalyzed Reductive-Aldol
Cyclization of Substrate 2a-c Catalyzed by CuF(PPh3)3•2MeOH
1/L*a
When the (S)-MeO-BIPHEP ligand L1 was used at -50
°C, we observed a significant improvement of the enanti-
oselection of the trans isomer with a slight increase of the
cis:trans ratio (Table 1, entries 2 versus 1). We then screened
entry
2
L* temp (°C) cis-3:trans-3b ee(cis-3)/ee(trans-3) (%)b
1
2
3
4
5
6
7
8
9
2a L1
2a L1
2a L2
2a L2
2a L3
2a L4
2b L3
2c L2
2c L3
25
-50
25
32:68
24:76
57:43
68:32
82:18
73:27
72:28
100:0
100:0
100:0
100:0
14/23
35/70
82/47
89/63
92/33
-91/-72
84/60
86
(3) For reviews on reductive-aldol reactions see: (a) Chiu, P. Synthesis
2004, 2210-2215. (b) Nishiyama, H.; Shiomi, T. Top. Curr. Chem. 2007,
279, 105–137. Selected references: for intermolecular reductive-aldol
reaction [Rh]: (c) Taylor, S. J.; Morken, J. P. J. Am. Chem. Soc. 1999, 121,
12202–12203. (d) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem.
Soc. 2000, 122, 4528–4529. (e) Nishiyama, H.; Shiomi, T.; Tsuchiya, Y.;
Matsuda, I. J. Am. Chem. Soc. 2005, 127, 6972–6973. (f) Jang, H.-Y.;
Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 15156–
15157. (g) Jung, C. K.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 17051–
17056. (h) Bee, C.; Han, S. B.; Hassan, A.; Lida, H.; Krische, M. J. J. Am.
Chem. Soc. 2008, 130, 2746–2747[Ir]: (i) Zhao, C. X.; Duffey, M. O.;
Taylor, S. J.; Morken, J. P. Org. Lett. 2001, 3, 1829–1831[Co]: (j) Lumby,
R. J. R.; Joensuu, P. M.; Lam, H. W. Org. Lett. 2007, 9, 4367–4370. For
intramolecular reductive-aldol reaction [Rh]: (k) Krische, M. J. Eur. J. Org.
Chem. 2004, 3953–3958. (l) Jang, H. Y.; rische, M. J. Acc. Chem. Res.
2004, 37, 653–661. (m) Bocknack, B. M.; Wang, L.-C.; Krische, M. J.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5421–5424[Co]: (n) Baik, T.-G.;
Luis, A. L.; Wang, L.-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123,
5112–5113. (o) Wang, L.-C.; Jang, H.-Y.; Roh, Y.; Lynch, V.; Schultz,
A. J.; Wang, X.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448–9453.
(p) Lam, H. W.; Joensuu, P. M.; Murray, G. J.; Fordyce, E. A. F.; Prieto,
O.; Luebbers, T. Org. Lett. 2006, 8, 3729–3732[Cu]: (q) Chiu, P.; Chen,
B.; Cheng, K. F. Tetrahedron Lett. 1998, 39, 9229–9232. (r) Chiu, P.; Szeto,
C. P.; Geng, Z.; Cheng, K. F. Org. Lett. 2001, 3, 1901–1903. (s) Chiu, P.;
Szeto, C. P.; Geng, Z.; Cheng, K. F. Tetrahedron Lett. 2001, 42, 4091–
4093. (t) Chiu, P.; Leung, S. K. Chem. Comm. 2004, 2308–2309. (u) Chung,
W. K.; Chiu, P. Synlett 2005, 55–58. (v) Agapiou, K.; Cauble, D. F.; Krische,
M. J. J. Am. Chem. Soc. 2004, 126, 4528–4529. (w) Lam, H. W.; Joensuu,
P. M. Org. Lett. 2005, 7, 4225–4228. (x) Lam, H. W.; Murray, G. J.; Firth,
J. D. Org. Lett. 2005, 7, 5743–5746. When the preparation of this manuscript
Lipshutz reported an enantioselective reductive-aldol reaction for the
construction of cyclic compound: (y) Lipshutz, B. H.; Amorelli, B.; Unger,
J. B. J. Am. Chem. Soc. 2008, 130, 14378–14379, All references about
reductive aldol reaction are summarized in the Supporting Information.
(4) (a) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew.
Chem., Int. Ed. 2006, 45, 1292–1297. In the same time, Shibasaki reported
a similar catalytic system with low to moderate selectivities: (b) Zhao, D. B.;
Oisaki, K.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 1403–
1407. For studies on the influence of the TaniaPhos structure see: (c) Zhao,
D.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128,
14440–14441. For catalytic asymmetric reductive-aldol of allenic esters to
ketones see: (d) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2006, 128, 7164–7165.
-50
-50
-50
-50
-50
-50
-50
-50
95
-86
-95
10 2c L4
11 2c L5
a Reactions were carried out in a 0.1 M solution in toluene at the
indicated temperature under an oxygen free argon-atmosphere in presence
of 2a-c (1 mmol), CuF(PPh3)3•2MeOH 1 (1 mol %), chiral ligand L* (1
mol %) and phenylsilane (1.4 equiv) for 2 h. b cis:trans ratio and
enantiomeric excesses were determined by chiral GC analysis; see Sup-
porting Information for details.
a wide range of chiral diphosphane ligands and found that
the TaniaPhos ligands L2-L5 gave the best selectivities,
without any loss of the excellent reactivity of the catalytic
system (Figure 1).11 Although a low cis:trans selectivity was
Figure 1. MeO-BIPHEP Ligand and TaniaPhos-type Ligands.
(5) Chuzel, O.; Deschamp, J.; Chausteur, C.; Riant, O. Org. Lett. 2006,
8, 5943–5946.
(6) (a) Muka¨ıyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503–7509. (b) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 5644–5645.
observed at room temperature, a promising ee of 82% was
reached for the cis isomer with the TaniaPhos ligand L2
(Table 1, entry 3). A slight enhancement of the cis:trans ratio
and the enantioselectivity was again observed when the
reaction was carried out at -50 °C (Table 1, entry 4), and
this temperature was then kept for further optimizations.
Increasing the steric bulkiness around the phosphorus atom
with the ligand L3 gave further improvement of both cis:
trans ratio to 82:18 and an excellent enantioselectivity of
92% for the major cis-3a isomer (Table 1, entry 5). We also
noticed a similar enantioselectivity with the hydroxy ana-
logue TaniaPhos L4 (Table 1, entry 6 versus 5).
(7) CuF(PPh3)3•2MeOH was prepared according to a literature procedure:
Gulliver, D. J.; Levason, W.; Webster, M. Inorg. Chim. Acta 1981, 52,
153–159.
(8) The diketo-ester 2a is easily prepared in two-steps, starting from
the commercially available 2-methyl-1,3-cyclohexanedione. (a) Huddleston,
R. R.; Krische, M. J. Org. Lett. 2003, 5, 1143–1146. (b) Thiemann, T.;
Umeno, K.; Wang, J.; Tabuchi, Y.; Arima, K.; Watanabe, M.; Tanaka, Y.;
Gorohmaru, H.; Mataka, S. J. Chem. Soc., Perkin Trans. 1 2002, 2090–
2110.
(9) Cis and trans nomenclature referred to the relation of the different
substituents on the bicyclic junction.
(10) The relative configuration were determined by NOE experiments
on each pure isolated isomers, see Supporting Information for details. The
absolute configuration are determined on the dehydrated compound 6b by
comparison of the optical rotation value of the latter with the reported value
[R]20 -85.6 (c ) 3.4 in CHCl3) and -140 (c ) 2.1 in CHCl3) the
configuration is S. Yamazaki, J.; Bedekar, A. V.; Watanabe, T.; Tanaka,
K.; Watanabe, J.; Fuji, K. Tetrahedron Asymmetry 2002, 13, 729–734.
(11) Ferrocenyl ligands like JosiPhos, WalPhos and MandyPhos were
also tested but gave low selectivities.
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Org. Lett., Vol. 11, No. 6, 2009

Table 2. Asymmetric Copper-Catalyzed Reductive-Aldol Cyclization of Substrate 2c or 4a-e Catalyzed by 1/L3*a
a Reactions were carried out in a 0.1 M solution in toluene at indicated temperature under an oxygen free argon-atmosphere in presence of 4a-e (1
mmol), CuF(PPh3)3•2MeOH 1 (1 mol %), chiral ligand L* (1 mol %) and phenylsilane (1.4 equiv) for 1 h. b cis:trans ratio and enantiomeric excesses were
determined by chiral GC analysis. For details see Supporting Information. c Isolated yields of cis-5a-e.
We then studied the influence of the steric hindrance on
the ester moiety of our precursors 2a-c; if the bulkiness
around the chiral copper enolate intermediate was increased,
it might influence the course of the stereoselection of our
model reaction. The domino process was first carried out on
the substrate 2b (R ) Me) with the TaniaPhos ligand L3
(table 1, entry 7); we noted that the selectivities were
decreased as expected. The Substrate 2c (R ) t-Bu) was then
tested with TaniaPhos ligands L2-L4 (Table 1, entries
8-10), and in our delight, we found that the only cis-3c
diastereoisomer was formed in all cases. When the bulkier
ligands L2 and L5 were used, a 95% enantiomeric excess
was finally obtained in both cases for the cis isomer cis-3c.
This reaction proved to be highly reproducible and larger
scale reactions could also be performed with an equal
efficiency at lower catalyst loading. A 10mmol scale reaction
was carried out with a 0.5 mol % loading of the copper/L3
catalyst. A complete conversion was observed after 15 min
at -50 °C and the bicyclic adduct cis-3c was isolated in a
80% yield and a 95% enantioselectivity.
procedures (see Supporting Information). As mentioned
earlier, only one cis diastereoisomer 3c was formed from
the C2-symmetrical precursor 2c with a 95% enantioselec-
tivity. We observed the formation of 5-membered rings from
precursors 5a and 5c (Table 2, entries 1 and 3), with excellent
diastereoselectivity, albeit with moderate enantioselectivities.
Indeed, a decrease in the enantioselection to 66% was
measured for the 5,5-bicyclic adduct cis-5c while the 6,5-
bicyclic adduct cis-5a was obtained with a reasonable 80%
ee. However, the formation of 6-membered ring was carried
out with excellent cis-selectivities as well as high enanti-
oselectivities (Table 2, entries 2 and 4). However, under the
optimized conditions, the substrates bearing longer lateral
tether that could generate 7- an 8-membered rings, only result
in simple reduction. Furthermore, by replacing the ester by
a nitrile group, we observed the formation of only one cis-
isomer but alas, with no enantiomeric excess.
We also checked the possibility to introduce different
substituants on the quaternary carbon of the precursors 4e
(Table 2, entry 5); the reductive-aldol cyclization was
achieved on the allyl precursor 4e and the resulting allyl-
substituted bicyclic adduct cis-5e was isolated in a 70% yield
as a single cis-isomer and a 94% enantiomeric excess. This
substrate cis-5e behaved with equal efficiency compared to
the methyl analogue cis-3c.
We then investigated the scope of this methodology on
the synthesis of enantiomerically enriched bicyclic adducts
bearing various ring sizes and substitutions under the
previous optimized conditions (Table 2). All the cyclization
precursors 2c and 4a-e were easily prepared by literature
Org. Lett., Vol. 11, No. 6, 2009
1219

We found that an optimum procedure was built up with a
preformed catalyst prepared in situ by a ligand exchange
between the air stable precatalyst CuF(PPh3)3•2MeOH and
the appropriate chiral ligand. As we have already noticed,4a,5
this class of copper hydride species have shown a high
reactivity toward the reductive-aldol cyclization. These
results show that the combination of a straightforward access
to the precursors, the low catalyst loading, a scalable
procedure, and the high selectivities reached in most cases,
should allow to an easy access to new chiral building blocks
for asymmetric synthesis.
the construction of new angular tricyclic compounds such
as 9 by using the allyl-substituted bicyclic adduct cis-5e
(Scheme 2).
Scheme 2. Formation of the Tricyclic Adduct 9
We next investigated access of synthetically useful scaf-
folds by studying the behavior of the 6,6-bicyclic adducts
3a-c toward dehydratation (scheme 1). Indeed, the products
The cross metathesis of the allyl group and tertbutyl
acrylate of adduct cis-5e was first carried out with a catalytic
amount of the second generation Hoveyda’s catalyst, and
afforded the cyclization precursor 8 in a good 85% yield.14
Then, the reductive-aldol cyclization of 8 was performed in
our standard conditions, and we were finally pleased to
observe the formation of the new expected angular tricyclic
adduct 9 as a single diastereoisomer in a good 70% yield
after purification.15
Scheme 1. Dehydratations of Bicyclic Adducts 3a-c
In summary, we have developed an efficient methodology
for the construction of bicyclic scaffolds. The domino
reductive-aldol cyclization, catalyzed by a copper (I) precur-
sor combined with the appropriate chiral diphosphane ligand
in the presence of phenylsilane, is highly diastereo- and
enantioselective for a range of different substrates and
enabled us to prepare various bicylic compounds in an
enantiomerically enriched form. Moreover, this strategy has
also been successfully extended to the synthesis of a new
angular tricyclic compound. This versatile method may be
used to synthesize more highly substituted molecules. Current
efforts are focused on using these building blocks for the
synthesis of biologically active compounds. Further studies
in this area will be reported in due course.
6a-b are often used in total synthesis and are prepared in
several steps starting from the well-known Wieland-Miescher
ketone.12 By our method, only 4 steps are required to afford
the enantio-enriched compound 6a-b.
After several trials on the reagents and reaction conditions,
it was found that mesyl chloride and triethylamine reacted
smoothly with the bicyclic adducts trans-3a and trans-3b to
give the conjugated unsaturated esters 6a,b in good isolated
yields. When those conditions were applied to the bicyclic
adducts cis-3a and cis-3c, the dehydration occurred too, but
the non conjugated alkenes 7a, 7b, and 7c were the sole
products in those reaction, and were isolated with 65% yields
after purification.13
Acknowledgment. This work was supported by the
Universite´ catholique de Louvain. Dr. B. Pugin (Solvias) and
Dr. R. Schmid (Hoffman-La Roche) are gratefully acknowl-
edged for the generous gift of chiral ligands. SHIMADZU
Benelux is gratefully acknowledged for financial support for
the acquisition of a FTIR-8400S spectrometer. Ms Sonia
Gharbi (UCL) is grateful ackowlegded for the synthesis of
the precursor 4d.
The possibility to use substitutions on the quaternary
carbon of the cyclization precursors enabled us to consider
(12) For the preparation of the Wieland-Miescher ketone, see: (a)
Wieland, P.; Miescher, K. HelV. Chim. Acta 1950, 33, 2215–28. (b)
Buschschacher, P.; Fu¨rst, A.; Gutzwiller, J. Org. Synth. 1969, 368–373. (c)
Welch, S. C.; Hagan, C. P.; White, D. H.; Fleming, W. P.; Trotter, J. W.
J. Am. Chem. Soc. 1977, 99, 549–556. (d) Hagiwara, H.; Uda, H. J. Org.
Chem. 1988, 53, 2308–2311. (e) Bui, T.; Barbas, C. F., III Tetrahedron
Lett. 2000, 41, 6951–6954. For some examples for the use of the Wieland-
Miescher ketone in total synthesis, see: (f) Cheung, W. S.; Wong, H. N. C.
Tetrahedron 1999, 55, 11001–11016. (g) Yajima, A.; Mori, K. Eur. J. Org.
Chem. 2000, 4079–4091. (h) Ling, T.; Chowdhury, C.; Kramer, B. A.; Vong,
B. G.; Palladino, M. A.; Theodorakis, E. A. J. Org. Chem. 2001, 66, 8843–
8853. (i) Ghosh, S.; Rivas, F.; Fischer, D.; Gonzalez, A.; Theodorakis, E. A.
Org. Lett. 2004, 6, 941–944.
Supporting Information Available: Experimental details,
spectroscopic data for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL802879F
(14) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791–799. (b) Garber, S. B.; Kingsbury,
J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168–
8179. (c) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet. Chem.
2001, 634, 215–221.
(13) Similar results were obtained in presence of the burgess’ reagent.
Moreover, the dehydration was also achieved in presence of SOCl2 but the
olefin was isolated with 30-40% yields. Katoh, T.; Mizumoto, S.; Fudesaka,
M.; Takeo, M.; Kajimoto, T.; Node, M. Tetrahedron Asymmetry 2006, 17,
1655–1662.
(15) We observed a total conversion of 8 in presence of a large excess
of phenylsilane.
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Org. Lett., Vol. 11, No. 6, 2009