Highly convergent synthesis of chiral bicyclophosphinates by domino hydrophosphinylation/michael/michael reaction

Article abstract of DOI:10.1021/ol2019345

Diastereoselective domino reactions of iminoalcohols and allenyl H-phosphinates produce chiral phosphorus bicycles in a regio- and stereoselective fashion. A predictive model for diastereoselection is used for these new chiral phosphinic esters.

Full text of DOI:10.1021/ol2019345

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5076–5079
Highly Convergent Synthesis of Chiral
Bicyclophosphinates by Domino
Hydrophosphinylation/Michael/Michael
Reaction
†
†
‡
ꢀ ꢀ
ꢀ †
€
Pierre Fourgeaud, Benedicte Dayde, Jean-Noel Volle, Jean-Pierre Vors,
Arie Van der Lee,§ Jean-Luc Pirat,† and David Virieux*,†
AM2N, Institut Charles Gerhardt, UMR 5253, ENSCM, 8, rue de l’Ecole Normale,
F-34296 Montpellier, France, Bayer CropScience SAS, 14/20 rue Pierre Baizet,
ꢀ
BP 9163, 69263 Lyon Cedex 09, France, and IEM, Universite Montpellier 2,
Case courrier 047, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
ꢁ
david.virieux@enscm.fr
Received July 18, 2011
ABSTRACT
Diastereoselective domino reactions of iminoalcohols and allenyl H-phosphinates produce chiral phosphorus bicycles in a regio- and
stereoselective fashion. A predictive model for diastereoselection is used for these new chiral phosphinic esters.
Modern organic synthesis has benefited from the devel-
opment of highly selective methods for the efficient con-
struction of potentially useful target molecules. Domino or
cascade reactions which are the combination of multiple
transformationsina singlepotare now routinelyemployed
inthe synthesisof complexandevenchiraltargetmolecules
constituting a powerful tool for organic chemists.1 Often
mild and environmentally friendly, domino reactions
also provide a shortened and atom-economical synthesis,
substantially decreasing the wastes associated with the
production of organic compounds. Toward the goal of
improving chemical efficiency, the ability to execute se-
quential reactions in one pot is conceptually challenging.
Hence, in modern organic chemistry, the conception of
new domino reactions has emerged as an exciting brain
bender puzzle to solve synthetic problems.
Alleneshavebeen demonstratedtobeanimportantclass
of chemicals, but they remain underused because these
functions are often thought to be highly reactive.2 Despite
this putative drawback, they were recently involved as
useful intermediates in several addition3 or cyclization
reactions.4
(2) (a) The Chemistry of Ketenes, Allenes, and Related Compounds,
Part 1; Patai, S., Ed.; John Wiley & Sons: New York, 1980. (b) Allenes in
Organic Synthesis; Schuster, H. F., Coppola, G. M., Eds.; John Wiley &
Sons: New York, 1984. (c) Ma, S. Handbook of Organopalladium Chem-
istry for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York,
2002. (d) Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, 2004. (e) Ma, S. In Topics in Organometallic
Chemistry; Tsuji, J., Ed.; Springer-Verlag: Heidelberg, 2005. (f) Ma, S.
Acc. Chem. Res. 2009, 42, 1679.
† AM2N, Institut Charles Gerhardt.
‡ Bayer CropScience SAS.
§
ꢀ
IEM, Universite Montpellier 2.
(1) For recent reviews, see: (a) Tietze, L. F.; Beifuss, U. Angew.
Chem., Int. Ed. Engl. 1993, 32, 131. (b) Waldmann, H. In Organic
Synthesis Highlights II; Waldmann, H., Ed.; Wiley-VCH: Weinheim, 1995;
pp 193ꢀ202. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115. (d) Malacria, M.
Chem. Rev. 1996, 96, 289. (e) Padwa, A. Chem. Commun 1998, 1417.
(f) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304. (g) Nicolaou, K. C.;
Montagnon, T.; Snyder, S. A. Chem. Commun 2003, 551. (h) Nicolaou,
K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
(3) For electrophilic additions to allenes, see: (a) He, G.; Fu, C.; Ma, S.;
Guo, H.; Qian, R.; Guo, Y. Tetrahedron 2009, 65, 4877. (b) Guo, H.; Qian,
R.; Guo, Y.; Ma, S. J. Org. Chem. 2008, 73, 7934. For nucleophilic
additions: (c) Bhuvan Kumar, N. N.; Kumara Swamy, K. C. Tetrahedron
Lett. 2008, 49, 7135. (d) Khusainova, N. G.; Berdnikov, E. A.; Mostovaya,
O. A.; Rybakov, S. M.; Cherkasov, R. A. Russ. J. Org. Chem. 2007, 43,
1703. (e) de los Santos, J. M.; Lopez, Y.; Aparicio, D.; Palacios, F. J. Org.
Chem. 2008, 73, 550. (f) Chakravarty, M.; Kumara Swamy, K. C. Synthesis
2007, 3171. For catalyzed additions (dihydrocarbonylation): (g) Guo, H.;
Ma, S. Adv. Synth. Catal. 2008, 350, 1213.
€
7134. (i) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int.
Ed. 2007, 46, 1570.
r
10.1021/ol2019345
Published on Web 09/02/2011
2011 American Chemical Society

In this context, we focused on H-phosphinylallene re-
agents, a surprisingly quite stable class of bothnucleophilic
and electrophilic allenes where the electronic properties of
the two unsaturated carbonꢀcarbon bonds determine the
chemo- or regioselectivity of their reactions.5 Seeking to
develop streamlined phosphorus heterocyclic syntheses,
we begun to explore the combination of a useful bicyclic
ring formation involving PꢀC, CꢀO, and CꢀN bond-
forming processes in a single step using H-phosphinyl
allenes.6
Table 1. Synthesis of 1,3-Azaphospholenes 4bꢀg
Allenyl H-phosphinic esters 1a,b were obtained in two
steps from the combination of anhydrous hypophos-
phorous acid with, respectively, 2-methyl-3-butyn-2-ol
and 1-ethynyl-1-cyclohexanol in 90% and 85% yields.7
Afterward, allenyl H-phosphinic acids were quantita-
tively esterified under neutral conditions by the reaction
of triethylorthoformate in refluxing chloroform leading
to the corresponding allenyl H-phosphinates 1a,b. These
reagents were then allowed to react with imines 2aꢀd
(Table 1). The rate and the yield of the reaction were
strongly dependent on the starting imines 2; using benzal-
dehyde N-phenylimine (entry 1, Table 1), only hydropho-
sphinylation reaction took place resulting in the formation
of a diastereomeric mixture of the R-aminophosphinyl
allene 3a in 75% yield. Whatever the activating agents
diaste-
reomer
ratio
isolated
R3 time yielda
entry
R1
3a Me
R2
1
2
3
4
5
6
7
Ph
Ph
Ph
75b
84
75
49
80
76
45
49/51
56/44
40/60
49/51
52/48
51/49
49/51
4b Me
4c Me
4d Me
Bn 12 h
pCF3-C6H4 Bn
4 d
2 d
5 d
5 d
5 d
iPr
Bn
Bn
4e (CH2)5 Ph
4f (CH2)5 pCF3-C6H4 Bn
4g (CH2)5 iPr Bn
a Most of the reactions were conducted on a scale of 3.12 mmol of
allene. b Only phosphinyl allene 3a was obtained during the reaction, and
no cyclization product 4a was observed.
(PTSA, BF3 OEt2, Agþ, Pd2þ, NaH, t-BuOK), no cycli-
3
zation product was observed from allene 3a, whereas
for a stronger nucleophile (R3 = benzyl, entries 2ꢀ7,
Table 1), we obtained the 1,3-azaphospholenes 4bꢀg in
40ꢀ84% yields in acetonitrile at 70 °C with modest
diastereoselectivity.8
(S)-2-amino-butanol or ethanolamine resulted in the
formation of the corresponding 1-oxa-3-aza-6-phos-
phabicyclo[3.3.0]octanes 6aꢀe in 45ꢀ80% yields after
chromatography on silica gel (Table 2).
On the basis of those results, we decided to examine the
behavior of iminoalcohols 5 in such a cyclization process.
Some of these imines would embed a chiral center
associated with a hydroxy function featuring another
nucleophilic reacting center. The reaction of allenes 1a,b
with imines 5 derived from (R)- or (S)-phenylglycinol,
Table 2. Synthesis of 1-Oxa-3-aza-6-phosphabicyclo-
[3.3.0]octanes 6aꢀe
(4) (a) Jiang, X.; Chen, J.; Ma, S.; Kong, W. Org. Biomol. Chem. 2008,
6, 3606. (b) Enchev, D. D. Phosphorus, Sulfur Silicon Relat. Elements
2008, 183, 2649. (c) Chakravarty, M.; Bhuvan Kumar, N. N.; Sajna,
K. V.; Kumara, K. C. Eur. J. Org. Chem. 2008, 4500. (d) Panossian, A.;
Fleury-Bregeot, N.; Marinetti, A. Eur. J. Org. Chem. 2008, 3826. (e) Fei,
Y.; Xiongdong, L.; Jinbo, Z.; Yihua, Y.; Ma., S. J. Org. Chem. 2009, 74,
1130. (f) Brel, V. K.; Belsky, V. K.; Stash, A. I.; Zavodnik, V. E.; Stang,
P. J. Eur. J. Org. Chem. 2005, 512.
(5) Phosphorus allene formation, see: (a) Macomber, R. S.; Kennedy,
E. R. J. Org. Chem. 1976, 41, 3191. (b) Enchev, D. D.; Preslavski, T.
Phosphorus Sulfur 2005, 180, 2127. (c) Xu, C.; Yu-Xiu, L.; Wang, W.;
Cao, R. Z.; Liu, L. Heteroatom. Chem. 2002, 13, 633. (d) Rudinskas,
A. J.; Hullar, T. L.; Salvador, R. L. J. Org. Chem. 1977, 42, 2771.
(e) Milton, M. D.; Onodera, G.; Nishibayashi, Y.; Uemura, S. Org. Lett.
2004, 6, 3993. (f) Komeyama, K.; Kobayashi, D.; Yamamoto, Y.;
Takehira, K.; Takaki, K. Tetrahedron 2006, 62, 2511.
(6) For double-addition-cyclization, see: (a) Ma, S.; Jiao, N. Angew.
Chem. Int. Ed 2002, 41, 4737. For hydroamination/Claisen reactions,
see: (b) Ma, D.; Zhu, W. Org. Lett. 2001, 3, 3927. For imino-ene
reactions, see: (c) Borzilleri, R. M.; Weinreb, S. M.; Parvez, M. J. Am.
Chem. Soc. 1995, 117, 10905.
R1
6a Me
R2
time (d) isolated yielda diastereomer ratio
(R)-Ph-
(S)-Ph-
(S)-Et-
H-
7
7
65
70
45
80
56
50/50
50/50
41/11/33/15b
32/15/30/23b
50/50
6b Me
6c Me
6d Me
4
2
6e -(CH2)5- (S)-Ph-
11
a Most of the reactions were conducted on a scale of 3.12 mmol of
allene. b Major diastereomers are epimers at the phosphorus centers.
(7) (a) Yudelevich, V. I.; Belakhov, V. V.; Komarov, E. V.; Ionin,
B. I.; Petrov, A. A. Dokl. Chem. 1983, 269, 146. (b) Belakhov, V. V.;
Yudelevich, V. I.; Kamarov, V. Y.; Ionin, B. I.; Myasnikova, G. L.;
Roschin, V. J. Gen. Chem. USSR 1985, 55, 39.
(8) Previously reported oxaphospholene syntheses: (a) Trishin, Yu.
G.; Mingazova, B. F.; Konovalova, I. V. Russ. J. Gen. Chem. 1995, 65,
142. (b) Trishin, Yu. G.; Namestnikov, V. I.; Bel’skii, V. K. Russ. J. Gen.
Chem. 1999, 69, 1588.
To confirm the structure, one diastereomer of 6a was
crystallized for X-ray crystallographic analysis. Two
different crystals were obtained and both adopted chiral
space group P212121. X-ray structures of polymorphs
6a-I and 6a-II of phosphabicyclo[3.3.0]octane 6a are
Org. Lett., Vol. 13, No. 19, 2011
5077

given in Figure 1. The two polymorphs exhibited similar
conformations: oxazaphosphabicyclooctane adopted as
expected a cis ring junction where the pyramidal nitro-
gen and all of the substituents on chiral carbons were on
the convex face of the molecule. The two polymorphs
differed mainly by the orientation of the methyl group
of ethyl phosphinic ester function as illustrated in
Figure 1.9
five-membered intramolecular H-bonded ring.12 Then, the
preferential formation of the major diastereomer pair of 6a
could be explained by the control exerted by the alcohol
present in imine 5 and the steric hindrance induced by the
phenyl group on the si face (Scheme 1). Hence, formation
of intermediates 7 occurred by the delivery of the racemic
allenylphosphinate 1a to the less hindered re face of the
imine. With these precedents in mind, we also thought
about the possibility of a kinetic resolution of the racemic
allenylphosphinate 1a under these double asymmetric
induction conditions. Unfortunately, no or very low level
of double diastereodifferentiation were seen in such
conditions.
The next step was the formation of azaphospholene 8.
Afterward, the stereoselective oxa-Michael reaction re-
quired the presence of an adequate electron-deficient
insaturation. The stereochemical outcome of such cycliza-
tion was influenced by the previously created stereocenters
of the azaphospholene ring. We suspected that diastereo-
mers 6a were formed under thermodynamically controlled
conditions. To demonstrate this hypothesis, a proton
exchange reaction was carried out. It was conducted after
ring closure from a pure sample of 6a and was validated by
the 1H and 13C NMR experiments in deuterated methanol
(Figure 2).
The proton exchange between the deuterium atom of
methanol and hydrogen atoms of methylene group PCH2
was fast and complete deuteration took place in the NMR
tube at room temperature in less than five minutes. The
ABX proton signal at 2.30 ppm completely disappeared in
1H NMR according to the deuteration of the carbon atom.
Similarly in 13C NMR, the doublet signal at 28.83 ppm
which should become a doublet of quintuplet also disap-
peared due probably to the combination of a high multi-
plicity and the loss of NOE enhancement. Moreover, FAB
mass spectrometry data in an aprotic matrix (NPOE) gave
a m/z ratio equal to 388 consistent with C22H27D2O3NP
formula.
The full configuration of both diastereomers of 6a was
confirmed and elucidated by NOESY correlations and 1H
NMR (Figure 3). H-1 and H-2 proton were easily attrib-
uted through their difference of chemical shifts due to a
strong shielding for hydrogen H-2 contacting phenyl ring
(Δδ = 0.72 and 0.78 ppm). The NOESY correlation of
H-2 to H-3 on both diastereomers led to the assignment of
cis phenyl-isopropyl group stereochemistry. Relative con-
figuration at phosphorus was determined by comparison
of the chemical shifts of the protons of ethyl ester methy-
lene. According to the X-ray data, the trans Ph-OEt ste-
reoisomer showed weakly diastereotopic protons (Δδ =
0.03 ppm) respectively at 3.98 ppm (Ha) and 4.01 ppm
(Hb) whereas the cis one exhibited a greater difference
(Δδ = 0.48 ppm, δHa = 3.23 ppm and δHb = 3.71 ppm).
Diastereomers of 6a were only epimer at the phosphorus
atom.
Figure 1. X-ray of polymorphs of phosphabicyclo[3.3.0]octane
6a-I and 6a-II.
In agreement with the formation of the aminophosphi-
nyl allene 7, we assumed that the first step of the reac-
tion was the diastereoselective imine hydrophosphination.
31P NMR monitoring confirmed the formation of four
diastereomers 7. Their chemical shifts around 40 ppm,
1
together with the disappearance of the JPH coupling,
were consistent with the R-aminophosphinate linkage
(Scheme 1). When R2 = Ph, a 41/40/9/10 diastereomeric
ratio was observed, confirming that R2 acted as a
stereocontroller.10 Then a 5-endo-dig amino-Michael
reaction on the C2 allenyl group followed by an isomer-
ization of the resulting double bond and a 5-exo-trig
reaction of oxygen afforded compounds 6a. Interest-
ingly, no azaphospholene intermediate 8 was observed
and final bicycles 6a at 62 ppm were formed. We were
pleased to obtain only two diastereomers of 6a arising
from the major pair of diastereomers
We assumed that a hydrophosphinylation reaction of
imine took place under kinetic control (Scheme 1).11 In
aprotic solvent, the stereochemical outcome of the reaction
was mainly controlled by the possibility of formation of a
(9) The X-ray crystallographic coordinates have been deposited at
the Cambridge Crystallographic Data Centre, under deposition num-
bers CCDC 785343 and 785344. These data can be obtained free of
charge from Cambridge Crystallographic Data Centre: http://www.
ccdc.cam.ac.uk/data_ request/cif. See also the Supporting Information
for more crystallographic details.
(10) Taking into account that phosphinyl allene was racemic, the
diastereoselectivity was 81/19.
(11) (a) Pirat, J.-L.; Monbrun, J.; Virieux, D.; Volle, J.-N.; Tillard,
M.; Cristau, H.-J. J. Org. Chem. 2005, 70, 7035. (b) Cristau, H.-J.;
Monbrun, J.; Tillard, M.; Pirat, J.-L. Tetrahedron Lett. 2003, 44, 3183.
For reviews on stereoselective hydrophosphonylation of imines, see:
(c) Nakamura, S.; Nakashima, H.; Yamamura, A.; Shibata, N.; Torua, T.
Specific rotations were determined for both diaster-
eomers of 6a and 6b. As expected, the trans-6a and
trans-6b have respectively a þ73.1° and ꢀ72.5° specific
rotation, whereas the cis-6a and cis-6b presented
ꢀ
Adv. Synth. Catal. 2008, 350, 1209. (d) Merino, P.; Marques-Lopez, E.;
Herrera, R. P. Adv. Synth. Catal. 2008, 350, 1195.
(12) (a) Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetra-
hedron 1995, 51, 9179. (b) Heydary, A.; Karimian, A.; Ipaktschi, J.
Tetrahedron Lett. 1998, 39, 6729.
5078
Org. Lett., Vol. 13, No. 19, 2011

Scheme 1. Proposed Mechanism for the Formation of 1-Oxa-3-aza-6-phosphabicyclo[3.3.0]octane 6a
Figure 3. Absolute configuration of 1-oxa-3-aza-6-phosphabicyclo-
[3.3.0]octane diastereomers of 6a.
þ14.1° and ꢀ13.5°, confirming the influence of the stereo-
genic center on the chiral iminoalcohol starting materials.
In summary, we have developed a new, practical, and
diastereoselective domino reaction for the synthesis of
highly functionalized and chiral phosphorus bicycles from
simple iminoalcohols and allenyl H-phosphinates. A pre-
dictive model for diastereoselection was used along with
the attribution of all chiral centers of the molecules.
Further work on these chiral bicyclic structures will be
related to the free chiral phosphinic acids which could be
used as chiral Brønsted acid in metal-free enantioselective
catalysis.
Acknowledgment. This research was supported in part
by a Grant from Bayer CropScience and from the Langue-
doc-Roussillon country.
Figure 2. 1H and 13C NMR spectra of hydrogen/deuterium
exchange of 6a.
Supporting Information Available. Synthetic proce-
dures and spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5079