[2,3]-Sigmatropic rearrangements of 2-phosphineborane 2-propen-1-ols: Rapid access to enantioenriched diphosphine monoxide derivatives

Article abstract of DOI:10.1021/ol400310h

Hydrophosphination of secondary propargylic alcohols generates phosphine-containing allylic alcohols that undergo facile [2,3]-sigmatropic rearrangements with chlorophosphines, furnishing highly enantioenriched, crystalline diphosphine monoxides. The conf

Full text of DOI:10.1021/ol400310h

ORGANIC
LETTERS
2013
Vol. 15, No. 5
1136–1139
[2,3]-Sigmatropic Rearrangements of
2‑Phosphineborane 2‑Propen-1-ols:
Rapid Access to Enantioenriched
Diphosphine Monoxide Derivatives
†
ꢀ
Carl A. Busacca,* Bo Qu, Elisa Farber, Nizar Haddad, Nicole Gret, Anjan K. Saha,
Magnus C. Eriksson, Jiang-Ping Wu, Keith R. Fandrick, Steve Han, Nelu Grinberg,
Shengli Ma, Heewon Lee, Zhibin Li, Michael Spinelli, Austin Gold, Zhuzhu Wang,†
Guijun Wang,‡ Peter Wipf,† and Chris H. Senanayake
Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury
Road, Ridgefield, Connecticut 06877, United States, Department of Chemistry,
Center for Chemical Methodologies and Library Development, University of Pittsburgh,
219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States, and Department
of Chemistry and Biochemistry, Old Dominion University, 4541 Hampton Boulevard,
Norfolk, Virginia 23529, United States
carl.busacca@boehringer-ingelheim.com
Received February 4, 2013
ABSTRACT
Hydrophosphination of secondary propargylic alcohols generates phosphine-containing allylic alcohols that undergo facile [2,3]-sigmatropic
rearrangements with chlorophosphines, furnishing highly enantioenriched, crystalline diphosphine monoxides. The configuration at the newly
formed stereocenter is opposite to that expected based on prior studies, and an ab initio computational evaluation of the possible transition states
was performed to help explain the stereochemical course of the reaction.
Allylic alcoholsand their derivatives demonstratea large
number of useful transformations with both nucleophiles
and electrophiles.11 We have recently developed the first
uncatalyzed hydrophosphination of propargylic alcohols
and amines with phosphine boranes.2,3 These facile reac-
tions proceed at or below ambient temperature and utilize
bench-stable phosphine boranes rather than pyrophoric-
free phosphines.4 The phosphine-containing products de-
rived from propargylic alcohols possess an allylic alcohol
moiety that can be utilized to introduce additional car-
bonꢀheteroatom bonds onto the carbon chain. Previous
studies by Knochel5 on [2,3]-sigmatropic rearrangements
of allylic alcohols (lacking any phosphine substitution)
with chlorophosphines inspired us to examine the reactivity
† University of Pittsburgh.
‡ Old Dominion University.
(1) For reviews, see: (a) Emer, E.; Sinisi, S.; Capdevila, M. G.;
Petruzziello, D.; De Vincentiis, F.; Cozzi, P. G. Eur. J. Org. Chem.
2011, 647–666. (b) Lu, Z.; Ma, S. Angew. Chem. 2008, 120, 264–303.
Angew. Chem., Int. Ed. 2008, 47, 258–297. (c) Pfaltz, A.; Lautens, M.
Allylic Substitution Reactions. In Comprehensive Asymmetric Catalysis
IꢀIII; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag:
Berlin, 1999; pp 833ꢀ884. (d) Trost, B. M.; Zhang, T.; Sieber, J. D. Chem.
Sci. 2010, 1, 427–440.
ꢀ
(2) Busacca, C. A.; Qu, B.; Farber, E.; Haddad, N.; Gret, N.; Saha,
A. K.; Eriksson, M. C.; Wu, J.-P.; Fandrick, K. R.; Han, S.; Grinberg,
N.; Ma, S.; Lee, H.; Li, Z.; Spinelli, M.; Gold, A.; Wang, G.; Wipf, P.;
Senanayake, C. H. Org. Lett. 201310.1021/ol400309y.
(3) See also: Mimeau, D.; Gaumont, A.-C. J. Org. Chem. 2003, 68,
7016–7022.
(4) Staubitz, A.; Robertson, A. P. M.; Sloan, M. E.; Manners, I.
Chem. Rev. 2010, 110, 4023–4078.
(5) (a) Liron, F.; Knochel, P. Chem. Commun. 2004, 304–305.
(b) Dermay, S.; Harms, K.; Knochel, P. Tetrahedron Lett. 1999, 40,
4981–4984.
r
10.1021/ol400310h
Published on Web 02/21/2013
2013 American Chemical Society

of the new hydrophosphination adducts toward phos-
phorus electrophiles. As shown in Scheme 1, treatment of
(R)-(þ)-1 with three different chlorophosphines R2P-Cl
generated the rearrangement products (E)-2, -3, and -4 in
good overall yields as single enantiomers. The configura-
tionatthe new stereocenterwas anticipated tobe(S) onthe
basis of the suprafacial nature of the rearrangement6 and
earlier precedent,5 yet a VCD analysis of 4 (Figure 1)
showed that the new stereogenic carbon had in fact the
(R)-configuration.
Scheme 1. Rearrangements of Allylic Alcohol (þ)-1
Figure 1. Calculated and experimental VCD spectra of phos-
phine oxide 4.
Next, 12 different aryl- and alkylchlorophosphines5
were examined in the rearrangement of P-chiral alcohol
(S,RP)-(ꢀ)-5, as shown in Table 1. Alcohol (ꢀ)-5 was
obtained from the base-mediated, uncatalyzed hydropho-
sphination of enantioenriched (ꢀ)-phenylbutynol, as pre-
viously reported (Scheme 1).2 The rearrangement products
of(ꢀ)-5 weregenerallyformedassinglediastereomerswith
E-geometries, and each of the bis-phosphineborane deri-
vatives 6aꢀl was isolated in good yield as a crystalline
solid. X-ray structures of two products, 6d and 6l, derived
from aryl and alkyl chlorophosphines, respectively, show
that the isolated products also possess the unexpected (S)-
configuration at the newly formed stereogenic carbon
(Figure 2), in agreement with the stereochemical course
of the reaction observed for (þ)-1.
Figure 2. Crystal structures of 6d (left) and 6l (right).
straight alkyl chains, such as in 6k and 6j, as well as
branched chains, such as the cyclohexyl substituents in
6l, did not interfere with the process.
In all cases, a uniform stereochemical course was ob-
served, and the P-chirality had no apparent effect on the
rearrangement.7
The unexpected stereochemical outcome of the reaction
was further explored through an ab initio analysis of the
transition state of the [2,3]-rearrangement leading to 6l
(Figure 3). Models for the conversion of 5 to the (R,Z)-
isomer 6l* and the (S,E)-isomer 6l were minimized using
molecular mechanics calculations in Spartan’10,8 and the
resulting geometries were subjected to a transition-state
calculation at the HF-6311þG** level of theory. TSA
leading to 6l* was found to be 5.0 kcal/mol higher in
energy than the transition state TSB leading to the (S,E)-
isomer 6l. This difference in energy is mainly due to a
significant A1,2-interaction between the methyl substituent
and the phosphineꢀborane group in TSA, which provides
a more severe steric clash than the A1,3-strain between the
methyl group and the allylic substituents in TSB. Accordingly,
the presence of the bulky phosphineꢀborane substituent at
the 2-position of the alkene redirects the stereochemical
The [2,3]-sigmatropic rearrangement allowed access to a
broad variety of allylic phosphine oxides. Ortho-substituents
on the phenyl rings of 6a were well tolerated, as were
electron-donating groups such as the methoxide functions
in 6c and 6d. The conversion was also high with naphthyl
(6e) and furan (6i) groups on the phosphine oxide. Finally,
(6) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885–902.
(7) (a) Legrand, O.; Brunel, J. M.; Buono, G. Tetrahedron 2000, 56,
595–603. (b) Velder, J.; Robert, T.; Weidner, I.; Neudoerfl, J.-M.; Lex,
J.; Schmalz, H.-G. Adv. Synth. Catal. 2008, 350, 1309–1315. (c) Tayama,
E.; Otoyama, S.; Tanaka, H. Tetrahedron: Asymmetry 2009, 20, 2600–
2608. (d) Miyata, O.; Hashimoto, J.; Iba, R.; Naito, T. Tetrahedron Lett.
2005, 46, 4015–4018. (e) Denmark, S. E.; Marlin, J. E.; Rajendra, G.
J. Org. Chem. 2013, 78, 66–82.
(8) Wavefunction, Inc., Irvine, CA.
Org. Lett., Vol. 15, No. 5, 2013
1137

Table 1. Rearrangement Products
course of the sigmatropic rearrangement opposite to the
results previously obtained by Knochel et al.5
was confirmed by X-ray analysis (Figure 4). The confor-
mation of 7 is very similar to that of 6l in the solid state; the
Amine-mediated deprotection of BH3-protected dipho-
sphine monoxides provides the corresponding dipho-
sphines in high yield. Treatment of 6l, for example, with
DABCO in toluene at 70 °C led to the deboronated 7 in
87% yield (Scheme 2).9 The structure of this diphosphine
^ ꢁ
(10) For reviews, see: (a) Charette, A. B.; Cote, A.; Desrosiers, J.-N.;
Bonnaventure, I.; Lindsay, V. N. G.; Lauzon, C.; Tannous, J.; Boezio,
A. A. Pure Appl. Chem. 2008, 80, 881–890. (b) Grushin, V. V. Chem. Rev.
2004, 104, 1629–1662. (c) Grushin, V. V. Organometallics 2001, 20,
3950–3961. (d) Faller, J. W.; Grimmond, B. J.; D’Alliessi, D. G. J. Am.
Chem. Soc. 2001, 123, 2525–2529. (e) Fukuzaki, Y.; Tomita, Y.;
Terashima, T.; Ouchi, M.; Sawamoto, M. Macromolecules 2010, 43,
5989–5995. (f) Sgarbossa, P.; Pizzo, E.; Scarso, A.; Sbovata, S. M.;
Michelin, R. A.; Mozzon, M.; Strukul, G.; Benetollo, F. J. Organomet.
Am. Chem. Soc. 2001, 123, 2525–2529.
(9) (a) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato,
K. J. Am. Chem. Soc. 1990, 112, 5244–5252. (b) Imamoto, T.; Watanabe,
J.; Wada, Y.; Masuda, H.; Yamada, H.; Tsuruta, H.; Matsukawa, S.;
Yamaguchi, K. J. Am. Chem. Soc. 1998, 120, 1635–1636.
1138
Org. Lett., Vol. 15, No. 5, 2013

Scheme 2. Deprotection of Diphosphine 6l
Figure 4. Crystal structure of 7.
can be subjected to a stereospecific [2,3]-sigmatropic re-
arrangement with chlorophosphines to give diversely sub-
stituted diphosphine monoxides in high overall yields.
After removal of the borane protective group, these novel
PꢀP species with stereogenic phosphorus and carbon atoms
can serve as chiral ligands in catalytic asymmetric trans-
formations,9,10 and we are currently investigating pertinent
applications.
Figure 3. Ab initio transition-state analysis of the [2,3]-rearran-
gement of (S,RP)-(ꢀ)-5.
only major difference is the rotation of P2 to minimize the
allylic strain.
In conclusion, we have developed a new, straighforward
synthesis of BH3-protected diphosphine monoxides. Mild
hydrophosphination of enantioenriched propargylic alco-
hols provides 2-phosphineborane 2-propen-1-ols, which
Supporting Information Available. Experimental pro-
cedures, compound characterization, and chiral HPLC
analyses. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 5, 2013
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