Tandem retro-aldol/Wittig/Michael and related cascade processes

Article abstract of DOI:10.1016/j.tetlet.2009.02.115

A number of novel tandem sequences initiated by a retro-aldol process are described along with preliminary scope and limitation studies. These include (i) retro-aldol/Wittig trapping/intramolecular Michael addition, (ii) retro-aldol/aza-Wittig/intramolecu

Full text of DOI:10.1016/j.tetlet.2009.02.115

Tetrahedron Letters 50 (2009) 3378–3380
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Tetrahedron Letters
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Tandem retro-aldol/Wittig/Michael and related cascade processes
Sandra Beltrán-Rodil a, James R. Donald a, Michael G. Edwards a, Steven A. Raw b, Richard J. K. Taylor a,
*
a Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
b AstraZeneca, Process Research and Development, Silk Road Business Park, Charter Way, Macclesfield, Cheshire SK10 2NA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of novel tandem sequences initiated by a retro-aldol process are described along with preli-
minary scope and limitation studies. These include (i) retro-aldol/Wittig trapping/intramolecular Michael
addition, (ii) retro-aldol/aza-Wittig/intramolecular imine addition, (iii) retro-aldol/Henry/intramolecular
Michael addition and (iv) retro-aldol/Knoevenagel/intramolecular Michael addition sequences. A range of
novel functionalised cyclopentanes, and related systems, are described which should prove to be useful
synthetic building blocks.
Received 22 December 2008
Revised 9 February 2009
Accepted 16 February 2009
Available online 21 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
There is great current interest in the development of new tan-
dem and telescoped processes.1 We have been active in this area2,3
and herein report a series of novel cascade sequences initiated by a
retro-aldol process. The retro-aldol reaction is well known4–8 but, to
our knowledge, has been little exploited in preparative chemistry.5,6
The process can be effected enzymatically8 but a base-mediated
process4–7 seemed to be better suited to our intended purposes.
The research by Rodriguez and Zweifel7 describing the use of com-
mercially available trimethylamine N-oxide (TMAO) to effect the
retro-aldol reaction seemed to provide a useful initial protocol.
In order to assess the viability of a retro-aldol-initiated tandem
sequence we investigated the process outlined in Scheme 1. The
readily available 2,2-di(carboethoxy)cyclopentanol 19 was chosen
as the first substrate to investigate; it was felt that the double acti-
vation of the resulting retro-aldol enolate would facilitate the pro-
cess. On treatment of cyclopentanol 1 with TMAO in acetonitrile at
reflux,7 in the presence of t-butoxycarbonylmethylene(triphenyl-
phosphorane), we were delighted to isolate the novel trisubsti-
tuted cyclopentane 4 in 76% yield.10 In this one-pot process we
had effected a retro-aldol reaction followed by Wittig trapping
and then intramolecular Michael addition. It should be noted that
the overall transformation corresponds to the formal displacement
of an unactivated secondary alcohol of the neopentyl structural
type by an ester enolate.
Having demonstrated the potential of such a retro-aldol-initi-
ated sequence, we went on to optimise the reaction conditions
(Table 1). As can be seen, reducing the recommended6 large excess
of TMAO from ten equivalents to two resulted in incomplete con-
version (NMR analysis) with a small amount of the intermediate
alkene 3 being identified (entry ii).
The use of other bases was also investigated. We were pleased to
discover that a range of amine bases could be employed successfully
in acetonitrile as solvent. These included tetramethylpiperidine
(TMP), tetramethylguanidine (TMG), 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) as well as triethylamine and 7-methyl-1,5,7-
triazabicyclo[4.4.0]dec-5-ene (MTBD). With stoichiometric triethyl-
amine in acetonitrile, the only product observed was alkene 3 (entry
iii) whereas, under the same conditions, the more basic MTBD gave
only cyclopentane 4 (entry iv).
However, further optimisation produced two sets of conditions,
each utilising only 5 mol % MTBD, which efficiently produced E-al-
kene 3 or cyclopentane 4 depending on the choice of reaction
solvent. Thus, cyclopentane 4 is best prepared using catalytic MTBD
in MeCN at reflux (80%, entry v).11 On changing to dichloromethane
CO Bu-t
2
CO Bu-t
2
10 equiv.
OH
O
Me NO
3
MeCN
CO Et
2
CO Et
2
CO Et
2
CO Et
2
Ph P=CHCO Bu-t
3
2
Michael
76%
Δ, 18 h
CO Et
2
CO Et
2
CO Et
2
CO Et
2
retro-
aldol
2
1
3
4
Scheme 1.
* Corresponding author. Tel.: +44 (0)1904 432606; fax: +44 (0)1904 434523.
E-mail address: rjkt1@york.ac.uk (R.J.K. Taylor).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.115

S. Beltrán-Rodil et al. / Tetrahedron Letters 50 (2009) 3378–3380
3379
at reflux, the use of catalytic MTBD gave only E-alkene 3 (80%, entry
vi).
propanone and cyanomethylene(triphenylphosphorane) generated
the corresponding substituted cyclopentanes 5–8 in 71–83% yield.
This success encouraged us to investigate other sequences ini-
tiated by a retro-aldol reaction that would give products display-
ing diverse substitution patterns (Scheme 3). We first explored
the use of the commercially available Staudinger imino phos-
phorane, N-(triphenylphosphoranylidene)aniline 9. Treatment of
2,2-di(carboethoxy)cyclopentanol 1 with 5 mol % MTBD and imi-
We next examined the scope of the retro-aldol/Wittig/intramo-
lecular Michael addition sequence in terms of the phosphorane
component (Scheme 2). Thus, 2,2-di(carboethoxy)cyclopentanol
1, on treatment with 5 mol % MTBD and ethoxycarbonylmethyl-
ene(triphenylphosphorane), N-methoxy-N-methylamino(triphenyl-
phosphoranylidene)acetamide, 1-triphenylphosphoranylidene-2-
Table 1
Preliminary studies on the retro-aldol sequence involving alcohol 1a
CO Bu-t
2
CO Bu-t
2
OH
CO Et
2
CO Et
2
CO Et
2
Ph P=CHCO Bu-t
3
2
+
CO Et
2
CO Et
2
CO Et
2
base, solvent, Δ
(see Table)
1
3
4
Entry
Base (equiv)
Solvent /conditions
Yield 3(%)
Yield 4 (%)
i
ii
iii
iv
v11
vi
TMAO (10 equiv)
TMAO (2 equiv)
Et3Nc (1.2 equiv)
MTBD (1.2 equiv)
MeCN
MeCN
MeCN
MeCN
MeCN
D
D
D
D
D
, 18 h
, 16 h
, 19 h
, 15 h
, 16 h
—
76
83b
—
56
80
—
17b
78(E:Z = 97:3)
—
—
MTBDd (0.05 equiv)
MTBD (0.05 equiv)
CH2Cl2 D, 18 h
80%(E only)
a
Reaction conditions: 1 (0.26 mmol), ylide (0.31 mmol), solvent (5 mL).
Ratio obtained by NMR analysis of unpurified reaction mixture.
Similar results obtained with TMP, TMG and DBU.
b
c
d
With 0.01 equiv of MTBD, 4 (55%) and 3 (10%) were obtained.
O
CO Et
2
Me
CO Et
CO Et
2
2
Ph P=CHCO Et
3
2
Ph P=CHCOMe
3
CO Et
2
CO Et
2
83%
71%
5
OH
7
CO Et
2
CO Et
2
Ph P=CHCON(Me)OMe
3
80%
CON(Me)OMe
1
CN
Ph P=CHCN
3
CO Et
2
CO Et
2
5 mol% MTBD
MeCN (PrCN for 7)
Δ, 16 - 18 h
81%
CO Et
2
CO Et
2
6
8
Scheme 2.
NO
2
NHPh
Ph P=NPh 9
3
MeNO
2
13%
CO Et
CO Et
2
2
OH
80%
CO Et
CO Et
2
2
CO Et
2
10
13
14
CO Et
2
Ph P=NTMS 11
3
CO Et
EtO C
2
2
NHBoc
1
CH (CO Et)
2
2
2
then (Boc) O
2
CO Et
2
CO Et
2
42%
1.2 equiv. MTBD
(5 mol% for 11)
MeCN
68%
CO Et
CO Et
2
2
12
Δ, 18 - 22 h
Scheme 3.

3380
S. Beltrán-Rodil et al. / Tetrahedron Letters 50 (2009) 3378–3380
CO Bu-t
2
CO Bu-t
2
OH
OH
1.2 equiv. MTBD
1.2 equiv. MTBD
SO Ph
2
SO Ph
2
MeCN, Δ, 16 h
SO Ph
SO Ph
2
MeCN, Δ, 16 h
2
SO Ph
2
SO Ph
2
SO Ph
2
SO Ph
2
Ph P=CHCO Bu-t
3
2
Ph P=CHCO Bu-t
3
2
94%
89%
18
15
17
16
CO Bu-t
2
CO Bu-t
2
OH
1.2 equiv. MTBD
PrCN, Δ, 16 h
OH
Ph
5 mol% MTBD
Ph
MeCN, Δ, 16 h
NBoc
O
NBoc
NO
2
NO
2
Ph P=CHCO Bu-t
3
2
Ph P=CHCO Bu-t
93%(anti:syn = 1.4:1)
3
2
71%
O
22
19 (ca. 1:1)
20
21
Scheme 4.
nophosphorane 9 gave cyclopentylamine derivative 10 in excel-
Acknowledgements
lent yield via a retro-aldol/aza-Wittig/intramolecular imine addi-
tion
sequence.
The
use
of
N-
We thank the University of York for studentship support (SBR
and JRD) and Elsevier Science for postdoctoral funding (MGE).
trimethylsilyl(triphenylphosphoranylidene)amine 11 produced
the rather unstable parent cyclopentylamine after work-up; for
characterisation purposes the amine was trapped with (Boc)2O
giving carbamate 12. Again, these tandem transformations corre-
spond to Mitsunobu-type displacements of an unactivated sec-
ondary alcohol, in this case by the formal use of benzylamine
or t-butylcarbamate; of course, such amine nucleophiles are
insufficiently acidic to participate in Mitsunobu processes, thus
emphasising the value of these tandem sequences.
Nitromethane could also be used, with the resulting retro-aldol/
Henry/intramolecular Michael addition sequence giving (nitrom-
ethyl)cyclopentane 13, albeit in low yield. Finally, a retro-aldol/
Knoevenagel/intramolecular Michael addition sequence produced
adduct 14 in 42% yield.
At this point, we moved on to look at other substrates (Scheme
4). The readily available12 bis-sulfones 15 and 17 were investigated
first. The cyclopentanol example 15 underwent the expected retro-
aldol reaction/Wittig trapping/intramolecular Michael addition
giving cyclopentane 16 in 94% yield. In contrast, and under the
same conditions, the corresponding bis-sulfonyl cyclohexanol 17
gave alkene 18 (containing a small amount of the isomeric decon-
jugated alkene) and cyclisation was not observed, even under forc-
ing conditions.
Next, nitro-substituted cyclohexanols were investigated. No reac-
tion was observed on treatment of 2-nitrocyclohexanol with t-but-
oxycarbonylmethylene(triphenylphosphorane) and base but the
corresponding benzylated nitrocyclohexanol analogue 19 reacted
to produce cyclohexane 20 in excellent yield (the reaction was
incomplete using acetonitrile as solvent and butyronitrile was re-
quired for efficient conversion). This is the first example of a retro-al-
dol sequence using a monoactivated substrate13 and the first cascade
sequence resulting in a cyclohexane system. Finally, a heterocyclic
example was studied. Pyrrolidone derivative 2114 underwent a ret-
ro-aldol-like ring-opening/Wittig trapping/intramolecular Michael
addition sequence producing adduct 22 in 71% yield.15
References and notes
1. Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006.
2. For a review see: Taylor, R. J. K.; Reid, M.; Foot, J. S.; Raw, S. A. Acc. Chem. Res.
2005, 38, 851, and references cited therein.
3. For recent examples see: Robinson, R. S.; Taylor, R. J. K. Synlett 2005, 1003;
Cayley, A. N.; Cox, R. J.; Ménard-Moyon, C.; Schmidt, J. P.; Taylor, R. J. K.
Tetrahedron Lett. 2007, 48, 6556; Donald, J. R.; Edwards, M. G.; Taylor, R. J. K.
Tetrahedron Lett. 2007, 48, 5201; McAllister, G. D.; Oswald, M. F.; Paxton, R. J.;
Raw, S. A.; Taylor, R. J. K. Tetrahedron 2006, 62, 6681; Bromley, W. J.; Gibson, M.;
Lang, S.; Raw, S. A.; Whitwood, A. C.; Taylor, R. J. K. Tetrahedron 2007, 63, 6004;
Donald, J. R.; Taylor, R. J. K. Synlett 2009, 59.
4. For a review see: Dzhafarov, M. K. Russ. Chem. Rev. (Engl. Trans.) 1992, 61, 363.
5. For a notable exception see: Ullmann, A.; Gruner, M.; Reissig, H.-U. Chem. Eur. J.
1999, 5, 187.
6. There are several cases where the retro-aldol reaction has been exploited to
adjust stereochemistry—for elegant examples see: White, J. D.; Cutshall, N. S.;
Kim, T. S.; Shin, H. J. Am. Chem. Soc. 1995, 117, 9780; Moloney, M. G.; Yaqoob, M.
Tetrahedron Lett. 2008, 49, 6202.
7. Rodriguez, M. J.; Zweifel, M. J. Tetrahedron Lett. 1995, 37, 4301; Rodriguez, M. J.
International Patent WO 96/15142 (23.05.1996); Chem. Abstr. 1996, 125,
115162.
8. Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 2000, 611, and references cited
therein.
9. Conti, P.; Roda, G.; Stabile, H.; Vanoni, M. A.; Curti, B.; De Amici, M. Il Farmaco
2003, 58, 683; Grigg, R.; Reimer, G. J.; Wade, A. R. J. Chem. Soc., Perkin Trans. 1
1983, 1929.
10. All novel compounds were fully characterised spectroscopically and by HRMS.
11. Preparation of 2-tert-butoxycarbonylmethyl-cyclopentane-1,1-dicarboxylic
acid diethyl ester 4:
A round-bottomed flask equipped with a reflux
condenser and stir bar was charged with 2-hydroxycyclopentane-1,1-
a
dicarboxylic acid diethyl ester 1 (61.5 mg, 0.267 mmol), tert-butoxycarbonyl-
methylene(triphenylphosphorane) (122 mg, 0.320 mmol) and dry CH3CN
(5 mL) and the reaction maintained under an Ar atmosphere. MTBD in
CH3CN was added via microsyringe (0.14 M
, 96.5 lL, 0.0135 mmol,
0.05 equiv). The reaction mixture was then allowed to stir at reflux for 16 h.
After cooling to rt, CH2Cl2 (25 mL) and water (25 mL) were added to partition
the reaction mixture. The organic layer was then washed with HCl (1 M, 25 mL)
and brine (25 mL) and dried over Na2SO4. The solvent was removed in vacuo
and the product purified by flash column chromatography (silica gel, eluting
with Et2O/pet. ether, 1:9) to afford tert-butoxy ester 4 (70.5 mg, 80%) as a
colourless oil, Rf 0.6 (Et2O/pet. ether, 1:1); IR (neat) 3451 (w), 2978 (m), 2875
(s), 1725 (s), 1452 (m), 1388 (m), 1367 (m), 1259 (s), 1149 (s), 1099 (m), 1030
(m), 945 (w), 918 (w), 855 (m), 762 (w), 731 (m) cmÀ1; dH (400 MHz, CDCl3)
4.25–4.08 (4H, m), 2.73 (1H, dddd, J 11.0, 11.0, 7.5, 3.5 Hz), 2.65 (1H, dd, J 15.5,
3.5 Hz), 2.36 (1H, ddd, J 13.5, 9.0, 7.0 Hz), 2.11–2.00 (3H, m), 1.88–1.78 (1H, m),
1.68–1.56 (1H, m), 1.49–1.46 (1H, m), 1.43 (9H, s), 1.25 (3H, t, J 7.0 Hz), 1.24
(3H, t, J 7.0 Hz); dC (100 MHz, CDCl3) 171.9, 171.8, 171.1, 80.1, 62.5, 60.9 (Â2),
42.4, 37.3 , 33.9, 30.6, 27.8, 22.4, 13.9, 13.8; m/z (ESI) 351 [MNa]+; [HRMS (ESI):
calcd for C17H28O6Na: 351.1778, found: [MNa]+, 351.1783 (–1.3 ppm error)].
12. Craig, D.; Lawrence, R. M.; Tapolczay, D. J. Synlett 1997, 1001.
In summary, we have established the synthetic viability of a
number of cascade sequences initiated by a retro-aldol reaction.
These comprise (i) retro-aldol/Wittig trapping/intramolecular
Michael addition, (ii) retro-aldol/aza-Wittig/intramolecular imine
addition, (iii) retro-aldol/Henry/intramolecular Michael addition
and (iv) retro-aldol/Knoevenagel/intramolecular Michael addition
sequences. These tandem processes have been used to prepare a
range of novel functionalised cyclopentanes, and related systems,
which should prove to be useful synthetic building blocks. We
are currently optimising and extending these processes and inves-
tigating applications in target synthesis.
13. Retro-aldol sequences were not observed with 2-carboethoxycyclopentanol or
2-carboethoxy-2-benzylcyclopentanol as starting materials.
14. Guzman, A.; Romero, M.; Muchowski, J. M. Can. J. Chem. 1990, 68, 791.
15. For an enantioselective approach to related compounds, see: Gheorghe, A.;
Schulte, M.; Reiser, O. J. Org. Chem. 2006, 71, 2173.