Synthesis of P-stereogenic phospholene boranes via asymmetric deprotonation and ring-closing metathesis

Article abstract of DOI:10.1021/ol303253h

The first examples of the asymmetric synthesis of P-stereogenic vinylic phospholene boranes are described. The synthetic approach is concise and flexible. The route involves (i) asymmetric deprotonation-allylation of a dimethyl phosphine borane; (ii) telescoped regioselective deprotonation, paraformaldehyde trapping, and hydroxyl group elimination to give a diene; and (iii) ring-closing metathesis.

Full text of DOI:10.1021/ol303253h

ORGANIC
LETTERS
2013
Vol. 15, No. 1
192–195
Synthesis of P‑Stereogenic Phospholene
Boranes via Asymmetric Deprotonation
and Ring-Closing Metathesis
Xiao Wu,† Peter O’Brien,*,† Simon Ellwood,‡ Francesco Secci,† and Brian Kelly§
Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.,
Givaudan Schweiz AG, 138 Uberlandstrasse, 8600 Du€bendorf, Switzerland, and
Celtic Catalysts Ltd., Nova Centre, Belfield Innovation Park, Dublin 4, Ireland
peter.obrien@york.ac.uk
Received November 27, 2012
ABSTRACT
The first examples of the asymmetric synthesis of P-stereogenic vinylic phospholene boranes are described. The synthetic approach is concise
and flexible. The route involves (i) asymmetric deprotonationꢀallylation of a dimethyl phosphine borane; (ii) telescoped regioselective
deprotonation, paraformaldehyde trapping, and hydroxyl group elimination to give a diene; and (iii) ring-closing metathesis.
3-Methyl-1-phenyl-2-phospholene-1-oxide rac-1 (Scheme 1)
is a commercially available phosphine oxide that has been
exploited in two rather different catalytic processes. For
example, Marsden et al. reported the use of rac-1 in the
catalytic synthesis of phenanthridines and benzoxazoles.1
This process involves a catalytic aza-Wittig reaction and is
related to the same group’s work on a chiral phosphine-
mediated aza-Wittig reaction.2 In addition, O’Brien and co-
workers described the use of phospholane oxide rac-2 (2:1
mixture of diastereomers, obtained from rac-1 by hydro-
genation, Scheme 1) as a precatalyst in a catalytic Wittig
process.3 Although both applications of phospholene oxide
rac-1 were used to prepare achiral products, we reasoned
that enantiopure (R)- or (S)-1 could be a versatile catalyst
for future developments of catalytic asymmetric aza-Wittig,
(E)- and/or (Z)-selective Wittig, and other chiral phosphine-
mediated reactions. Herein, we report the asymmetric
synthesis of P-stereogenic phospholene boranes (R)-3 (R1 =
Ph or t-Bu) via a concise and synthetically flexible route.
Scheme 1. Useful Phospholene and Phospholane Oxides
There are no previous reports on the asymmetric syn-
thesis of P-stereogenic phospholenes such as 1, 2, or 3.4
Indeed, to the best of our knowledge, there are only two
examples of the preparation of enantioenrichedcyclicvinyl
phosphines similar to 1, both of which were reported by
Pietrusiewicz and co-workers: a bicyclic phospholene
oxide (98% ee) was prepared via a resolution route,5 and
a hydroxy phospholene borane (55% ee) was prepared by
† University of York.
‡ Givaudan.
§ Celtic Catalysts.
(1) Marsden, S. P.; McGonagle, A. E.; McKeever-Abbas, B. Org.
Lett. 2008, 10, 2589.
€
(4) For a review, see: Holz, J.; Gensow, M.-N.; Zayas, O.; Borner, A.
Curr. Org. Chem. 2007, 11, 61.
(5) Pakulski, Z.; Demchuk, O. M.; Frelek, J.; Luboradzki, R.;
Pietrusiewicz, K. M. Eur. J. Org. Chem. 2004, 3913.
(6) Pakulski, Z.; Koprowski, M.; Pietrusiewicz, K. M. Tetrahedron
2003, 59, 8219.
(2) (a) Headley, C. E.; Marsden, S. P J. Org. Chem. 2007, 72, 7185.
(b) Lertpibulpanya, D.; Marsden, S. P.; Rodriguez-Garcia, I.; Kilner,
C. A. Angew. Chem., Int. Ed. 2006, 45, 5000.
(3) O’Brien, C. J.; Tellez, J. L.; Nixon, Z. S.; Kang, L. J.; Carter,
A. L.; Kunkel, S. R.; Przeworski, K. C.; Chass, G. A. Angew. Chem., Int.
Ed. 2009, 48, 6836.
r
10.1021/ol303253h
Published on Web 12/21/2012
2012 American Chemical Society

s-BuLi/(ꢀ)-sparteine-mediated deprotonationꢀelimination
of an epoxy phospholane borane.6 Thus, we recognized the
need to develop a simple and general approach for the
asymmetric synthesis of phospholene boranes (R)-3. Our
strategy is presented in Scheme 2.
1 h and then reacted with methallyl bromide. This gave
rac-9 in 90% yield (Scheme 3). Next, regioselective lithia-
tion of rac-9 was achieved using s-BuLi in THF (ꢀ78 °C,
1 h); subsequent trapping with a solution of solid para-
formaldehyde in THF gave hydroxy phosphine borane
rac-10 in 48% yield. There was no evidence of the other
regioisomeric trapped product from this reaction. Tosylation
of rac-10 (TsCl, pyridine, CH2Cl2) gave tosylate rac-11 in
only 34% yield, but elimination to give diene rac-12 pro-
ceeded efficiently (98% yield) using potassium tert-butoxide
in Et2O at rt. The low yields in the preparation of hydroxy
phosphine borane rac-10 and tosylate rac-11 were due to
problems during chromatography: for rac-10, polarity was
the issue, whereas, for rac-11, degradation to unknown
Scheme 2. Strategy for the Synthesis of Phospholene Boranes
1
byproducts occurred. Since the H NMR spectra of the
crude products rac-10 and rac-11 obtained after workup
indicated they were cleanly formed, we explored a telescoped
process for the conversion of rac-9 into rac-12 where the
crude product from each step was taken forward into the
next step. In this way, diene rac-12 was generated in 86%
yield from rac-9 over three steps, with only chromatographic
purification in the last step (Scheme 3).
The asymmetry in the synthesis of phospholene boranes
(R)-3 would be introduced in the first step by chiral base-
mediated deprotonation of phosphine boranes 4 using
s-BuLi and (ꢀ)-sparteine (via the Evans protocol7);8 sub-
sequent allylation would then afford allylated phosphine
boranes (S)-5. Next, regioselective lithiation9 of the less
sterically hindered methyl group followed by trapping with
paraformaldehyde should generate hydroxy phosphine
boranes (R)-6. Then, elimination of the hydroxy group (via
the tosylate) would give dienes (R)-7. Finally, ring-closing
metathesis should deliver the desired phospholene boranes
(R)-3. This route is flexible to allow different R1 and R2
substituents to be incorporated, and the enantiomeric prod-
ucts (S)-3 could be accessed using our group’s (þ)-sparteine
surrogate10 in place of (ꢀ)-sparteine in the first step.11
Scheme 3. Synthesis of Diene Phosphine Borane rac-12
To start with, the proposed route was validated and
optimized with the preparation of racemic phospholene
oxide rac-13 (Scheme 3 and Table 1). Thus, phosphine
borane 8 was lithiated using s-BuLi in THF at ꢀ78 °C for
(7) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc.
1995, 117, 9075.
(8) For our previous work on Evans-style asymmetric synthesis of
phosphine boranes and sulfides, including catalytic asymmetric depro-
tonation, see: (a) McGrath, M. J.; O’Brien, P. J. Am. Chem. Soc. 2005,
127, 16378. (b) Genet, C.; Canipa, S. J.; O’Brien, P.; Taylor, S. J. Am.
Chem. Soc. 2006, 128, 9336. (c) Gammon, J. J.; Canipa, S. J.; O’Brien, P.;
Kelly, B.; Taylor, S. Chem. Commun. 2008, 3750. (d) Canipa, S. J.;
O’Brien, P.; Taylor, S. Tetrahedron: Asymmetry 2009, 20, 2407.
(e) Granander, J.;Secci,F.;O’Brien, P.;Kelly,B.Tetrahedron:Asymmetry
2009, 20, 2432. (f) Gammon, J. J.; Gessner, V. H.; Barker, G. R.;
Granander, J.; Whitwood, A. C.; Strohmann, C.; O’Brien, P.; Kelly,
B. J. Am. Chem. Soc. 2010, 132, 13992. (g) Carbone, G.; O’Brien, P.;
Hilmersson, G. J. Am. Chem. Soc. 2010, 132, 15445. (h) Granander, J.;
Secci, F.; Canipa, S. J.; O’Brien, P.; Kelly, B. J. Org. Chem. 2011, 76,
4794.
Next, the ring-closing metathesis step was investigated.
This approach to cyclic phosphine boranes/oxides and
phosphonates is well-known,12 including a few examples
of 5- and 6-ring vinyl phospholenes.13 However, there are
(12) (a) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1998, 39,
3939. (b) Bujard, M.; Gouverneur, V.; Mioskowsi, C. J. Org. Chem.
1999, 64, 2119. (c) Trevitt, M.; Gouverneur, V. Tetrahedron Lett. 1999,
40, 7333. (d) Schuman, M.; Trevitt, M.; Redd, A.; Gouverneur, V.
Angew. Chem., Int. Ed. 2000, 39, 2491.
(9) For the regioselective lithiation trapping of a phosphine sulfide,
see: Gammon, J. J.; O’Brien, P.; Kelly, B. Org. Lett. 2009, 11, 5022.
(10) (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P.
J. Am. Chem. Soc. 2002, 124, 11870. (b) O’Brien, P. Chem. Commun.
2008, 655.
(11) Kann was the first to report the use of the (þ)-sparteine
surrogate in the asymmetric deprotonation of phosphine boranes:
(a) Johansson, M. J.; Schwartz, L. O.; Amedjkouh, M.; Kann, N. C.
Eur. J. Org. Chem. 2004, 1894. (b) Johansson, M. J.; Schwartz, L. O.;
Amedjkouh, M.; Kann, N. Tetrahedron: Asymmetry 2004, 15, 3531.
(13) (a) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1999, 40,
3297. (b) Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel,
G. A.; van Boom, J. H. Tetrahedron Lett. 2001, 42, 8231. (c) Dunne,
K. S.; Bisaro, F.; Odell, B.; Paris, J.-M.; Gouverneur, V. J. Org. Chem.
2005, 70, 10803. (d) Harvey, J. S.; Malcolmson, S. J.; Dunne, K. S.; Mek,
S. J.; Thompson, A. L.; Schrock, R. R.; Hoveyda, A. H.; Gouverneur, V.
Angew. Chem., Int. Ed. 2009, 48, 762. (e) Fourgeaud, P.; Midrier, C.;
Vors, J.-P.; Volle, J.-N.; Pirat, J.-L.; Virieux, D. Tetrahedron Lett. 2010,
66, 758. (f) Harvey, J. S.; Giuffredi, G. T.; Gouverneur, V. Org. Lett.
2010, 12, 1236.
Org. Lett., Vol. 15, No. 1, 2013
193

no reported examples of the preparation of carbocyclic
vinyl phospholenes such as rac-13. Initial attempts using
2 mol % of Grubbs’ first and second generation catalysts14
at rt were disappointing (Table 1, entries 1ꢀ3). Use of
Grubbs’ second generation catalyst in CH2Cl2 at rt led to
formation of the phospholene borane rac-13 in ∼20%
conversion (entry 2) which was not improved upon heating
at reflux for 16 h in a subsequent experiment (entry 3).
bromide was then carried out to give allylated phosphine
boranes (S)-9 and (S)-15-17 in 57ꢀ73% yield (Table 2).
The configuration of the products was assigned as
(S) based on the established sense of induction using
s-BuLi/(ꢀ)-sparteine with phosphine boranes 87 and
14.16 In line with literature precedent,7,16 the enantioselec-
tivity was slightly lower with phenyl-substituted 8 (88:12ꢀ
89:11 er, entries 1 and 2) thanwithtert-butyl-substituted14
(93:7ꢀ96:4 er, entries 3 and 4).
Table 1. Investigation of the Ring-Closing Metathesis of Diene
rac-12 To Give Phospholene Borane rac-13
Table 2. Asymmetric LithiationꢀAllylation of Phosphine
Boranes
entry
catalysta
Grubbs I
solvent
temp
12:13b
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
100:0
Grubbs II
rt
77:23
yield
Grubbs II
reflux
rt
83:17c
87:13d
50:50
entry
R1
Ph
R2
product
(%)a
er
Hoveyda-Grubbs II
Hoveyda-Grubbs II
Hoveyda-Grubbs II
Hoveyda-Grubbs II
1
2
3
4
Me
H
(S)-9
73
57
57
58
89:11b
88:12b
96:4c
rt
rt
40:60e
40:60f,g,h
Ph
(S)-15
(S)-16
(S)-17
reflux
t-Bu
t-Bu
Me
H
93:7c
a 2 mol % of Grubbs I or Grubbs II catalyst and 10 mol % of
Hoveyda-Grubbs II catalyst were used. b Ratio of rac-12/rac-13 deter-
mined from the 1H NMR spectrum of the crude product. c Crude
product from entry 2 was used as starting material. d 2 mol % of
Hoveyda-Grubbs II catalyst was used. e Crude product from entry 5
was used as starting material. f Crude product from entry 6 was used as
starting material. g 16 h at rt then 16 h at reflux. h After purification by
chromatography, 36% of rac-13 and 40% of recovered rac-12 were
obtained.
a Yield after purification by chromatography. b Enantiomer ratio (er)
determined by CSP-HPLC (see Supporting Information). c Enantiomer
ratio (er) determined by CSP-HPLC of the corresponding phosphine
sulfides (see Supporting Information).
With enantioenriched allylated phosphine boranes (S)-9
and (S)-15ꢀ17 in hand, their conversion into cyclic phos-
pholene boranes (R)-13 and (R)-21ꢀ23 was carried out
(Table 3). In each case, the telescoped regioselective lithia-
tion, paraformaldehyde trapping, tosylation, and elimina-
tion process worked well to give dienes (R)-12 and (R)-
18ꢀ20 in 56ꢀ71% yields. Finally, ring-closing metathesis
was accomplished using the Hoveyda-Grubbs second gen-
eration catalyst in CH2Cl2 at rt for 40 h. When R2 = H,
1 mol % of catalyst worked well, but for the more sterically
hindered alkenes with R2 = Me, 10 mol % catalyst loading
was required for satisfactory conversions. Of note, good
yields of (R)-21 (71%) (entry 2) and (R)-23 (85%) (entry 4)
were obtained indicating that ring-closing metathesis is
efficient when R2 = H (even with 1 mol % catalyst). Thus,
steric hindrance in the 1,1-disubstituted alkene (when
R2 = Me) explains the lower yields of (R)-13 and (R)-22
(entries 1 and 3). We have confirmed in two cases that the
diene preparation and ring-closing metathesis steps pro-
ceed (as expected) without loss of enantiomer ratio. Thus,
CSP-HPLC of (R)-21 showed it to be 87:13 er, having
been prepared from allylated phosphine borane (S)-15 of
88:12 er (Table 2, entry 2). In addition, (R)-23 (prepared
from allylated phosphine borane (S)-17 of 93:7 er) was
Better results were obtained with the Hoveyda-Grubbs
second generation catalyst15 (entries 4ꢀ6) in CH2Cl2 at rt
provided a higher catalyst loading of 10 mol % was used.
For example, reaction for 48 h at rt and then 16 h at reflux
gave rac-13 in 36% yield, together with 40% of recovered
rac-12(entry 7). It was alsoshown thatthe heating at reflux
did not change the ratio of rac-12 and rac-13 (entries 6ꢀ7).
Based on the results from other examples reported later
(vide infra), we conclude that steric hindrance around the
disubstituted alkene leads to inefficient ring-closing me-
tathesis of rac-12.
Although the final ring-closing metathesis step was low
yielding, we did establish a viable synthetic approach to
phospholene boranes such as rac-13. Our attention thus
switched to investigating additional examples and to car-
rying out the asymmetric synthesis of phospholene bo-
ranes. Thus, using the Evans protocol, phosphine boranes
8 and 14 were lithiated using s-BuLi and (ꢀ)-sparteine in
Et2O at ꢀ78 °C for 3 h. Trapping with methallyl or allyl
(14) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2039. (b) Scholl, M.; Ding, S.; Lee,
C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(15) Garber, S. B.; Kinsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
(16) Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.; Yamada,
H.; Tsuruta, H.; Matsukawa, S.; Yamaguchi, K. J. Am. Chem. Soc.
1998, 120, 1635.
194
Org. Lett., Vol. 15, No. 1, 2013

deprotectionꢀphosphine sulfide formation thus pro-
ceeds with configurational integrity of the intermediate
phosphine.
Table 3. Synthesis of Enantioenriched Phospholene Boranes
In summary, the first examples of the asymmetric synthe-
sis of vinyl phospholene boranes (R)-3 are reported. Cru-
cially, we have established a convenient three-step asym-
metric synthesis that delivers enantioenriched (R)-13 and
(R)-21ꢀ23. The route is flexible to allow the easy variation
of substituents. Since phosphine boranes can be easily
converted into the free phosphines or phosphine oxides,
our work will enable future investigations into stereoselec-
tive aspects of catalytic aza-Wittig/Wittig reactions1ꢀ3 and
related processes.
yield
(%)a
yield
entry
R1
Ph
R2
product
product
(%)a
1
2
3
4
Me
H
(R)-12
(R)-18
(R)-19
(R)-20
58
71
56
60
(R)-13
(R)-21
(R)-22
(R)-23
46b
71c
41b
85c
Ph
t-Bu
t-Bu
Me
H
Acknowledgment. We thank Givaudan, the Wild Fund,
the University of York, and the EU/Celtic Catalysts
(Marie-Curie Transfer of Knowledge grant) for funding.
a Yield after purificationby chromatography. b 10mol % ofHoveyda-
Grubbs II catalyst. c 1 mol % of Hoveyda-Grubbs II catalyst.
Supporting Information Available. Full experimental
procedures, characterization data, and copies of 1H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
converted, via reaction with DABCO in the presence
of sulfur, into the corresponding phosphine sulfide which
was shown to be 95:5 er (by CSP-HPLC). The borane
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
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