Diastereoselective synthesis of P-Stereogenic heterocycles via enyne ring-closing metathesis

Article abstract of DOI:10.1021/ol100098c

Chemical Equation Presented A range of P-containing ene-diynes suitable for desymmetrization was prepared via a two-step process starting from phosphorus oxychloride. In the presence of the Hoveyda-Grubbs II catalyst, these substrates underwent diastereoselective enyne ring-closing metathesis leading to various synthetically useful P-stereogenic heterocycles featuring an exocyclic alkynyl group. These products are amenable to further functional manipulation.

Full text of DOI:10.1021/ol100098c

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1236-1239
Diastereoselective Synthesis of
P-Stereogenic Heterocycles via Enyne
Ring-Closing Metathesis
James Stephen Harvey, Guy T. Giuffredi,† and Ve´ronique Gouverneur*
Chemistry Research Laboratory, Department of Chemistry, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
Veronique.gouVerneur@chem.ox.ac.uk
Received January 14, 2010
ABSTRACT
A range of P-containing ene-diynes suitable for desymmetrization was prepared via a two-step process starting from phosphorus oxychloride. In the
presence of the Hoveyda-Grubbs II catalyst, these substrates underwent diastereoselective enyne ring-closing metathesis leading to various synthetically
useful P-stereogenic heterocycles featuring an exocyclic alkynyl group. These products are amenable to further functional manipulation.
The rapid growth in the field of asymmetric transition-metal-
catalyzed reactions has relied on the availability of a robust
synthetic route to chiral ligands.1 In this context, P-ste-
reogenic phosphines and derivatives are widely recognized
as an important class of compounds, especially since they
have also found applications in organocatalysis2 and for drug
development.3 To date, their use remains relatively limited
in comparison with chiral phosphines bearing stereogenic
carbon centers or possessing axial or planar chirality.4 This
is likely due to the difficulties associated with the develop-
ment of robust and general methods for the stereocontrol-
led creation of a P-stereocenter. For many years, several
research groups have reported various asymmetric syn-
theses of P-stereogenic phosphorus compounds by resolu-
tion5 or using chiral auxiliaries,6 but more recently, the
focus is also on generic approaches featuring catalytic
asymmetric reactions.7
Imamoto et al. have demonstrated that P-stereogenic
ligands bearing alkynyl groups induced excellent enantiose-
lectivity in various transition-metal-catalyzed reactions, a
result which was accounted for evoking the large steric
differentiation at phosphorus.8 These data indicate that
transition metal catalysis would undoubtedly benefit from
the availability of an increased range of P-stereogenic ligands
bearing an alkynyl group (Figure 1).
In light of literature precedents, which demonstrate that
various phosphorus-containing dienes, trienes, and dienynes
are suitable substrates for metathesis,9 we were particularly
interested in developing a diastereoselective enyne ring-
† Author to whom correspondence regarding the X-ray crystal structures
should be addressed.
(1) (a) Zhang, X. Tetrahedron: Asymmetry 2004, 15, 2099. (b) Crepy,
K. V. L.; Imamoto, T. Top. Curr. Chem. 2003, 111, 1. (c) Kagan, H. B.;
Dang Tuan, P. J. Am. Chem. Soc. 1972, 94, 6429. (d) Kagan, H. B.
Asymmetric Synth. 1985, 5, 1. (e) Whitesell, J. K. Chem. ReV. 1989, 89,
1581.
(4) (a) Shibata, Y.; Tanaka, K. J. Am. Chem. Soc. 2009, 131, 12552.
(b) Chen, I. H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2009, 131, 11664. (c) Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.;
Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856. (d) Taylor, A. M.;
Altman, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900.
(5) (a) Pietrusiewicz, K. M.; Zablocka, M. Chem. ReV. 1994, 94, 1375.
(b) Meisenheimer, J.; Lichtenstadt, L. Ber. Dtsch. Chem. Ges. 1911, 44,
356. (c) Campbell, I. G. M.; Way, J. K. J. Chem. Soc. 1961, 2133.
(6) (a) Juge´, S. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 233.
(b) Juge´, S.; Geneˆt, J. P. Tetrahedron Lett. 1989, 30, 2783. (c) Juge´, S.;
Stephan, M.; Laffitte, J. A.; Geneˆt, J. P. Tetrahedron Lett. 1990, 31, 6357.
(d) Brown, J. M.; Carey, J. V.; Russell, M. J. H. Tetrahedron 1990, 46,
4877. (e) Carey, J. V.; Barker, M. D.; Brown, J. M.; Russell, M. J. H.
J. Chem. Soc., Perkin Trans. 1 1993, 831.
(2) (a) Methot, J. L.; Roush, W. R. AdV. Synth. Catal 2004, 346, 1035.
(b) Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org. Chem. 1996, 61, 430. (c)
Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (d) Connon, S. J.
Angew. Chem., Int. Ed. 2006, 45, 3909.
(3) (a) Pirat, J.-L.; Virieux, D.; Clarion, L.; Volle, J.-N.; Bakalara, N.;
Mersel, M.; Montbrun, J.; Cristau, H.-J. Application WO 2009/004096A1,
2009; p 82. (b) Stoianova, D. S.; Whitehead, A.; Hanson, P. R. J. Org.
Chem. 2005, 70, 5880. (c) Stoianova, D. S.; Hanson, P. R. Org. Lett. 2000,
2, 1769. (d) Whitehead, A.; Waetzig, J. D.; Thomas, C. D.; Hanson, P. R.
Org. Lett. 2008, 10, 1421. (e) Waetzig, J. D.; Hanson, P. R. Org. Lett.
2006, 8, 1673.
10.1021/ol100098c  2010 American Chemical Society
Published on Web 02/25/2010

To initiate our investigations, we synthesized a range of
P-containing ene-diynes 3a-f designed to yield a single
regioisomer upon RCM. On the basis of careful mechanistic
work by Lloyd-Jones and co-workers providing evidence for
an “ene-then-yne” pathway for the Ru-catalyzed ring-closing
metathesis of enynes,11 we anticipated that initiation would
occur on the monosubstituted alkene of 3a-f, followed by
cyclization onto one of the two diastereotopic alkynes to afford
the desired desymmetrized P-stereogenic heterocycles. The ene-
diynes 3a-f were prepared via monoaddition of various chiral
unsaturated alcohols to phosphorus oxychloride followed by
double addition of either propynyl magnesium bromide or
trimethylsilylethynyl lithium. This concise synthetic route
allowed for facile diversification of both the ene and diyne
fragments (Table 1). In all cases, the desired dichlorophosphi-
Figure 1. P-Stereogenic ligand with alkynyl groups.
closing metathesis (DSRCM) as a strategically valuable route
to P-stereogenic3c compounds featuring an exocyclic alkynyl
group (Scheme 1). We opted for a catalytic diastereoselective
Table 1. Synthesis of P-Containing Ene-Diynes 3a-f
Scheme 1. Metathesis Approach to P-Stereogenic Compounds
with Alkynyl Groups: Diastereoselective Ene-Diyne Metathesis
entry R′
n
R
product yield (%)a product yield (%)b
desymmetrization process of ene-diynic P-templates bearing
two diastereotopic alkynyl substituents and a secondary
alkoxy group that will serve as stereoinductor. The substrates
selected for this investigation were designed to undergo 1,3-
stereocontrolled ring closure. The products resulting from
enyne metathesis are structurally novel P-stereogenic het-
erocycles bearing the desired exocyclic alkynyl group and a
dienic fragment amenable to rich functionalization. Herein
we report the first example of catalytic diastereoselective ene-
diyne metathesis leading to the formation of various chiral
P-stereogenic heterocycles. Diastereoselective enyne me-
tathesis reactions are scarce in the literature10 and have not
been investigated as a strategy to induce carbon or hetero-
atom stereogenicity. We also demonstrate with two repre-
sentative transformations that the primary product of me-
tathesis can be further manipulated.
1
2
3
4
5
6
Me
Et
Bn
Me
Me
Me
1
1
1
2
2
1
H
H
H
H
Me
Me
2a
2b
2c
2d
2d
2a
72
66
46
46
46
72
3a
3b
3c
3d
3e
3f
56
47
42
55
65
83
a Crude yield after workup. b Isolated yield after purification by silica
gel column chromatography.
nate intermediates 2a-d were obtained in sufficient purity to
be engaged directly in the next step. Pleasingly, the addition of
the alkynyl groups led successfully to the desired ene-diynes
3a-f with overall chemical yields ranging from 42 to 83%.
We investigated next the feasibility of the suggested
diastereoselective metathesis approach to access alkynyl-
substituted P-stereogenic heterocycles. Our initial studies
began with ene-diyne 3a prepared from 1-methylbut-3-enol
and possessing two terminal ethynyl groups (Table 2). When
the reaction was performed using 2 mol % of the Grubbs
catalyst II in DCM at reflux, the desired product 4a was
formed, albeit in low conversion and very modest diaste-
reoselectivity (entry 1). An attempt to increase conversion
(7) (a) Join, B.; Mimeau, D.; Delacroix, O.; Gaumont, A.-C. Chem.
Commun. 2006, 3249. (b) Glueck, D. S. Chem.sEur. J. 2008, 14, 7108.
(c) Brunker, T. J.; Anderson, B. J.; Blank, N. F.; Glueck, D. S.; Rheingold,
A. L. Org. Lett. 2007, 9, 1109. (d) Scriban, C.; Glueck, D. S. J. Am. Chem.
Soc. 2006, 128, 2788. (e) Moncarz, J. R.; Laritcheva, N. F.; Glueck, D. S.
J. Am. Chem. Soc. 2002, 124, 13356. (f) Blank, N. F.; Moncarz, J. R.;
Brunker, T. J.; Scriban, C.; Anderson, B. J.; Amir, O.; Glueck, D. S.;
Zakharov, L. N.; Golen, J. A.; Incarvito, C. D.; Rheingold, A. L. J. Am.
Chem. Soc. 2007, 129, 6847. (g) Blank, N. F.; McBroom, K. C.; Glueck,
D. S.; Kassel, W. S.; Rheingold, A. L. Organometallics 2006, 25, 1742.
(h) Anderson, B. J.; Glueck, D. S.; DiPasquale, A. G.; Rheingold, A. L.
Organometallics 2008, 27, 4992. (i) Chan, V. S.; Stewart, I. C.; Bergman,
R. G.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 2786. (j) Chan, V. S.;
Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 15122. (k)
Genet, C.; Canipa Steven, J.; O’Brien, P.; Taylor, S. J. Am. Chem. Soc.
2006, 128, 9336. (l) Gammon, J. J.; Canipa, S. J.; O’Brien, P.; Kelly, B.;
Taylor, S. Chem. Commun. 2008, 3750. (m) Nishida, G.; Noguchi, K.;
Hirano, M.; Tanaka, K. Angew. Chem., Int. Ed. 2008, 47, 3410.
(9) (a) Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel,
G. A.; van Boom, J. H. Tetrahedron Lett. 2001, 42, 8231. (b) Schuman,
M.; Trevitt, M.; Redd, A.; Gouverneur, V. Angew. Chem., Int. Ed. 2000,
39, 2491. (c) Slinn, C. A.; Redgrave, A. J.; Hind, S. L.; Edlin, C.; Nolan,
S. P.; Gouverneur, V. Org. Biomol. Chem. 2003, 1, 3820. (d) Bisaro, F.;
Gouverneur, V. Tetrahedron 2005, 61, 2395. (e) Dunne, K. S.; Bisaro, F.;
Odell, B.; Paris, J.-M.; Gouverneur, V. J. Org. Chem. 2005, 70, 10803. (f)
McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem. ReV. 2004,
104, 2239. (g) Harvey, J. S.; Malcolmson, S. J.; Dunne, K. S.; Meek, S. J.;
Thompson, A. L.; Schrock, R. R.; Hoveyda, A. H.; Gouverneur, V. Angew.
Chem., Int. Ed. 2009, 48, 762.
(8) Imamoto, T.; Saitoh, Y.; Koide, A.; Ogura, T.; Yoshida, K. Angew.
Chem., Int. Ed. 2007, 46, 8636.
Org. Lett., Vol. 12, No. 6, 2010
1237

Table 2. Optimization Studies for DSRCM of 3a into 4a
Table 3. Scope of Diastereoselective Enyne Ring-Closing
Metathesis
entry cat (mol %) atmosphere solvent conv (%)a
drb
1
2
3
4
5
6
7
8
II (2)
II (2)
II (5)
II (5)
II (10)
I (10)
II (10)
III (10)
Ar
ethylene
Ar
ethylene
Ar
Ar
DCM
DCM
DCM
DCM
34
40
75
73
90
45
>98
>98
3:1
2:1
3:1
3:1
4:1
3:1
10:1
18:1
DCM
toluene
toluene
toluene
Ar
Ar
a Conversion to desired product measured by 400 MHz 1H NMR.
b Measured from the crude by 400 MHz 1H NMR. Mes ) 2,4,6-i-Pr-C6H3.
by conducting this reaction under an atmosphere of ethylene
(Mori’s conditions)12 led to no improvement of the conver-
sion or diastereomeric ratio. Further optimization work
focused on increasing the catalyst loading from 2 to 10 mol
%. With 10 mol % of II, almost full conversion to the desired
product was observed (entry 5). When using an intermediate
catalyst loading of 5 mol %, the reaction stalled at ∼75%
conversion (entries 3 and 4). In all cases, the level of
diastereocontrol remained unsatisfactory. Notably, using the
same Grubbs catalyst II in toluene at reflux instead of
dichloromethane, we were pleased to observe that the product
was formed with a dr of 10:1 (entry 7).13 The level of
diastereocontrol was further improved (dr ) 18:1) using 10
mol % of Hoveyda catalyst III in toluene (entry 8). The
observation that a change of solvent can impact on the
efficiency of a diastereocontrolled ring closure in the context
of the metathesis reaction has not been discussed. It is,
however, well-documented that the nature of the solvent can
modulate catalyst activity or lead to variations in enantiose-
lectivity for asymmetric metathesis reactions.14
a Conversion measured by 400 MHz 1H NMR. b Combined isolated yield
of both diastereomers. c Diasteroselectivity determined by 400 MHz 1H NMR
of the unpurified product. d Not determined. e Only starting material recovered.
strates, the desired products were obtained with conversion
superior to 98% with no trace of oligomer or homodimer
byproducts observed by 1H or 31P NMR. The isolated chemical
yields were consistently high and independent of the substituent
on the stereogenic carbon or the ring size of the product.
Decreasing the steric bulk on the stereogenic center from Bn
to Et or Me led to an increase in selectivity. The dr dropped
significantly for the ring closure of 3d leading to the seven-
membered ethynyl tetrahydro oxaphosphine oxide 4d. Substitu-
tion at the alkynyl motif had a detrimental effect on both
conversion and selectivity (entries 5 and 6). As expected, the
chemistry was easily transposed to the preparation of enan-
tiopure (R)-4a from the chiral nonracemic phosphinate (R)-3a,
which was directly accessible from (R)-4-penten-1-ol.
Having established optimized reaction conditions for the
ring closure of 3a, we extended the scope of the reaction to
ene-diynes 3b-f (Table 3). A range of six- and seven-
membered P-stereogenic heterocycles was made accessible
upon ring-closing metathesis. For ethynyl-substituted sub-
(10) For elegant examples, see: (a) Layton, M. E.; Morales, C. A.; Shair,
M. D. J. Am. Chem. Soc. 2002, 124, 773. (b) Porta, M.; Blechert, S.
Abstracts of Papers, ISOM 18, Aug. 2-7th, 2009. (c) For enantioselective
enyne ring-closing metathesis, see: Lee, Y.-J.; Schrock, R. R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2009, 131, 10652. (d) Kim, S.-H.; Zuercher, W. J.;
Bowden, N. B.; Grubbs, R. H. J. Org. Chem. 1996, 61, 1073.
The relative cis relationship between the alkynyl substitu-
ent and the R′ group of the products was unambiguously
1238
Org. Lett., Vol. 12, No. 6, 2010

confirmed by single-crystal X-ray analysis of 4a and 5b and
was assigned by analogy for the other ring-closed products
(see Supporting Information for details).
Scheme 3. Two-Directional Functionalization
In order to gain more insight into the DSRCM reaction,
further experiments were performed to determine whether
the products obtained upon ring closure were the result
of a kinetically or thermodynamically controlled process.
After separation of the two diastereomers of product 4a
both the major cis and minor trans were subjected
separately to the reaction conditions. The results of these
experiments showed that no epimerization took place, sug-
gesting that the reactions are under kinetic control. A plausible
mechanistic rationale for the observed selectivity is presented
in Scheme 2. The donation of the endocyclic oxygen lone pair
Scheme 2. Rationale for the Observed Selectivity
of CuSO4·5H2O and sodium ascorbate, the desired triazole 5b
was isolated in 73% yield. A single diastereomeric product was
formed, indicating that no epimerization occurred in this process.
The Diels-Alder cycloaddition of 5b with DMAD was also
successful delivering 5c in 68% yield. Compounds 5b and 5c
resemble conspicuously the ligands of the phospha-scorpionates
family.16
In conclusion, we have reported a novel route to P-
stereogenic heterocycles bearing an exocyclic alkynyl group,
based on a key diastereoselective ene-diyne ring-closing me-
tathesis reaction. This is the first report of diastereoselective
enyne metathesis to create stereogenicity at an atom other than
carbon. We have shown that the ring-closed products are
amenable to postmetathesis functionalization via either Diels-
Alder or click chemistry. This work undoubtedly paves the way
for the development of an enantioselective ene-diyne ring-
closing metathesis process from prochiral templates.
into the σ* orbital of the exocyclic PdO bond15 stabilizes both
C and D with C being favored likely due to minimization of
syn-pentane interaction (Scheme 2).
Acknowledgment. We thank the John Fell (062/214) and
With the DSRCM products in hand, we investigated next
the possibility to engage the diene or the alkyne in postmet-
athesis transformations (Scheme 3). The dienic motif would
be amenable to Diels-Alder chemistry, and the alkyne group
could possibly undergo a click-type 1,3-dipolar cycloaddition.
Both reactions will increase structural complexity, leading to a
new family of P-stereogenic ligands suitable for investigation
in the context of catalysis. For these experiments, the ring-closed
product was engaged as a single diastereomer. Compound 4a
was reacted with dimethylacetylene dicarboxylate (DMAD) as
the reacting dienophile. After 7 h in toluene at reflux, the desired
cycloadduct 5a was obtained in 60% yield as a 3:1 mixture of
diastereomers. Upon treatment with benzyl azide and 1 mol %
the EPSRC for very generous funding.
Supporting Information Available: Additional experi-
mental details. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL100098C
(14) (a) Samojlowicz, C.; Bieniek, M.; Zarecki, A.; Kadyrov, R.; Grela,
K. Chem. Commun. 2008, 6282. (b) Funk, T. W.; Berlin, J. M.; Grubbs,
R. H. J. Am. Chem. Soc. 2006, 128, 1840. (c) Grandbois, A.; Collins, S. K.
Chem.sEur. J. 2008, 14, 9323. (d) Fujimura, O.; Grubbs, R. H. J. Org.
Chem. 1998, 63, 824. (e) Sattely, E. S.; Cortez, G. A.; Moebius, D. C.;
Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 8526. (f)
Fujimura, O.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 2499. (g) Lee,
A.-L.; Malcolmson, S. J.; Puglisi, A.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 2006, 128, 5153. (h) Rost, D.; Porta, M.; Gessler, S.; Blechert,
S. Tetrahedron Lett. 2008, 49, 5968.
(11) Lloyd-Jones, G. C.; Margue, R. G.; de Vries, J. G. Angew. Chem.,
Int. Ed. 2005, 44, 7442.
(15) (a) Ruben, E. A.; Plumley, J. A.; Chapman, M. S.; Evanseck, J. D.
J. Am. Chem. Soc. 2008, 130, 3349. (b) Gorenstein, D. G. Chem. ReV. 1987,
87, 1047.
(12) (a) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998,
63, 6082. (b) Kinoshita, A.; Sakakibara, N.; Mori, M. Tetrahedron 1999,
55, 8155.
(16) (a) van Assema, S. G. A.; Tazelaar, C. G. J.; de Jong, G. B.; van
Maarseveen, J. H.; Schakel, M.; Lutz, M.; Spek, A. L.; Slootweg, J. C.;
Lammertsma, K. Organometallics 2008, 27, 3210. (b) Rheingold, A. L.;
Liable-Sands, L. M.; Trofimenko, S. Angew. Chem., Int. Ed. 2000, 39, 3321.
(13) Evans, P. A.; Cui, J.; Buffone, G. P. Angew. Chem., Int. Ed. 2003,
42, 1734.
Org. Lett., Vol. 12, No. 6, 2010
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