Multivalent activation in temporary phosphate tethers: A new tether for small molecule synthesis

Article abstract of DOI:10.1021/ol0512886

(Chemical Equation Presented) A new tether for small molecule synthesis is reported. This functionally active tether mediates the desymmetrization of a pseudo-C₂-symmetric tris-allylic phosphate triester to generate a P-chiral bicyclo[4.3.1]pho

Full text of DOI:10.1021/ol0512886

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3375-3378
Multivalent Activation in Temporary
Phosphate Tethers: A New Tether for
Small Molecule Synthesis
Alan Whitehead, Matthew D. McReynolds, Joel D. Moore, and Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582
phanson@ku.edu
Received June 2, 2005
ABSTRACT
A new tether for small molecule synthesis is reported. This functionally active tether mediates the desymmetrization of a pseudo-C2-symmetric
tris-allylic phosphate triester to generate a P-chiral bicyclo[4.3.1]phosphate containing ample steric and stereoelectronic differentiation for
investigating chemo-, regio-, and stereoselective transformations. Overall, the method reported herein demonstrates a fundamentally new role
of phosphates in synthesis and provides differentiated polyol building blocks for use in natural product synthesis.
The use of temporary tethering of two advanced intermedi-
ates is a powerful approach to streamline synthetic sequences
en route to efficient asymmetric syntheses of complex
biologically active targets. Historically, silicon has been the
most widely used tether,1 in which its orthogonal protecting
group properties and coupling characteristics have served as
the cornerstone of several synthetic strategies.2-4 In contrast,
use of phosphorus-based tethers (P-tethers) has been rela-
tively limited, with use of phosphate tethers being completely
Void in the literature.5 This is a surprising observation when
one considers the potential of phosphorus tethers to mediate
both di- and tripodal coupling and provide multivalent
activation within the phosphate ester appendages for further
transformations.
Despite enormous research on organophosphorus com-
pounds, the general use of phosphate triesters in synthesis
has been relatively limited. The use of phosphate triesters
in complex synthesis has focused primarily on nucleophilic
displacement reactions of allylic phosphates6 and cross-
coupling/reduction reactions with enolphosphates.7 These
reaction processes utilize the leaving group ability of a
phosphate monoanion,8 where a single ester moiety is
(1) For a comprehensive review on disposable tethers, see: (a) Gauthier,
D. R., Jr.; Zandi, K. S.; Shear, K. J. Tetrahedron 1998, 54, 2289-2338.
(b) For a review on temporary silicon-tethered (Si-tethered) reactions, see:
Fensterbank, L.; Malacria, M.; Sieburth, S. M. Synthesis 1997, 8, 813-
854.
(2) For a recent review on temporary silicon-tethered (TST) strategies,
see: (a) White, J. D.; Carter, R. G. In Science of Synthesis: Houben-Wehl
Methods of Molecular Transformations; Fleming, I., Ed.; Georg Thieme
Verlag: New York, 2001; Vol. 4, pp 371-412 and references therein.
(3) For use of Si tethers in metathesis reactions, see: (a) Fu, G. C.;
Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426-5427. (b) Evans, P. A.;
Cui, J.; Gharpure, S. J.; Polossoukhine, A.; Zhang, H.-R. J. Am. Chem.
Soc. 2003, 125, 14702-14703 and references therein. (c) Maifeld, S. V.;
Miller, R. L.; Lee, D. J. Am. Chem. Soc. 2004, 126, 12228-12229 and
references therein.
(4) (a) Leighton, J. L.; Chapman, E. J. Am. Chem. Soc. 1997, 119,
12416-12417. (b) Wang, X.; Meng, Q.; Nation, A. J.; Leighton. J. L. J.
Am. Chem. Soc. 2002, 124, 10672-10673. (c) Hackman, B. M.; Lombardi,
P. J.; Leighton J. L. Org. Lett. 2004, 6, 4375-4377 and references therein.
(5) For examples of other P(III)/P(V)-based tethers, see: (a) Rubinstenn,
G.; Esnault, J.; Mallet, J.-M.; Sinay, P. Tetrahedron: Asymmetry 1997, 8,
1327-1336. (b) Sprott, K. T.; McReynolds, M. D.; Hanson, P. R. Org.
Lett. 2001, 3, 3939-3942.
(6) (a) Yanagisawa, A.; Noritake, Y.; Nomura, N.; Yamamota H. Synlett
1991, 251-253. (b) Kacprzynski, M. A.; Hoveyda, A. H. J. Am. Chem.
Soc. 2004, 126, 10676-10681 and references therein.
(7) (a) Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21,
2531-2534. (b) Sato, M.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron
Lett. 1981, 22, 1609-1612. (c) Nicolaou, K. C.; Shi, G.-Q.; Gaertner, P.;
Gunzner, J. L.; Agrios, C.; Huber, R.; Chadha, R.; Huang, D. H. J. Am.
Chem. Soc. 1997, 119, 8105-8106.
(8) Phosphate monoanions possess a pKa of roughly 1.5.
10.1021/ol0512886 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/28/2005

activated (monovalent activation) and the remaining ester
positions serve as ancillary substituents. Our interest in the
development of new methods in phosphorus chemistry9 has
led us to investigate the possibility of exploiting both
multipodal coupling and multivalent activation in phosphate
triesters, which by their nature present opportunities to
investigate selective processes. We now report a new method
that embodies several underdeveloped areas of phosphate
chemistry, namely their use as removable, functionally active
tethers capable of multipodal coupling and multivalent
activation and their subsequent role as latent leaving groups
in a number of unprecedented selective cleavage reactions.
In addition, stereoelectronic effects within the bicyclic
framework lend orthogonal protecting group stability. Over-
all, the method demonstrates a fundamentally new role of
phosphates in synthesis and provides a facile approach to
differentiated polyol building blocks for use in natural
product synthesis.
Scheme 1
duced 1 (81%) as confirmed by X-ray crystallographic
analysis. Use of Grubbs’ first-generation catalyst (PCy3)2(Cl)2-
RudCHPh (cat-A)13 gave poorer yields.
With 1 in hand, we initially examined hydrolytic protocols
for tether removal. Although hydrolysis of phosphate esters,
using both acid and base, has been extensively studied,14
selective phosphate hydrolysis15 is quite limited.16 Exposure
of 1 to a variety of acidic hydrolysis conditions [MeOH/
HCl, 10% HCl (aq)/dioxane, and TMSCl], revealed a
remarkable stability profile in 1. This enhanced acid stability
can be rationalized by the lack of lone pairs on the adjacent
oxygen atoms antiperiplanar (app) to the PdO as shown in
Figure 1, and as evident in previously studied bicyclic
phosphate systems.17
We chose to utilize the tether desymmetrization method
developed by Burke and co-workers10 in order to construct
the P-chiral bicyclo[4.3.1]phosphate 1 (Figure 1) containing
Alternatively, basic hydrolysis conditions are known to
stop at the stage of the monoanion salt due to decreased
electrophilicity at the PdO moiety.18 Hydrolysis of 1 was
thus anticipated to stop at one or more of the regioisomeric
phosphate mono-acid salts 7a-c (Figure 2).
Experimentally, treatment of 1 with LiOH (aq) in dioxane
led to quantitative and selective cleavage as evidenced by
the appearance of a major singlet appearing at -0.06 ppm
in the 31P NMR spectrum (rs ) 44:1). A 13C NMR
Figure 1.
ample steric and stereoelectronic differentiation for inves-
tigating chemo-, regio-, and stereoselective transformations.
Overall, 1 possesses electrophilic character at seven of its
nine non-oxygen atoms allowing for nucleophilic attack at
phosphorus or any of six carbinol and allylic phosphate
carbons [C(3), C(6), and C(8)] and [C(4), C(5), and C(12)],
respectively.
In an optimized procedure, diol 4 is produced directly from
the reaction of dichloro-1,3-anti-diol 211 with a 9-fold excess
of sulfonium ylide, generating 4 (80%) and circumventing
the isolation of volatile epoxide 3. Coupling of diol 4 with
POCl3 afforded phosphoryl monochloride 5 in excellent yield
(Scheme 1). Subsequent reaction with lithium allyloxide
afforded phosphate triester 6. Final ring-closing metathesis
(RCM) using [(IMesH2)(PCy3)(Cl)2RudCHPh; cat-B]12 pro-
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(13) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110. (b) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2039-2041.
(14) (a) Cox, J. R., Jr.; Ramsay, J. O. B. Chem. ReV. 1964, 64, 317. (b)
Bunton, C. A. Acc. Chem. Res. 1970, 3, 257-265. (b) Westheimer, F. Acc.
Chem. Res. 1968, 1, 70-78. (c) Gorenstein, D. G.; Rowell, R.; Taira, K.
Stereoelectronic Effects in Phosphate Esters. ACS Symp. Ser. 1981, 171,
69-75. (d) Fanni, T.; Taira, K.; Gorenstein, D. G.; Vaidyanathaswamy,
R.; Verkade, J. G. J. Am. Chem. Soc. 1986, 108, 6311-6314 and references
therein.
(15) Thatcher, G. R. J.; Kluger, R. Mechansim and Catalysis of
Nucleophilic Substitution in Phosphate Esters. AdV. Phys. Org. Chem. 1989,
25.
(16) The most prominent synthetic case is a recent report by Imanishi
and co-workers; see: Miyashita, K.; Ikejiri, M.; Kawasaki, H.; Maemura,
S.; Imanishi, T. J. Am. Chem. Soc. 2003, 125, 8238-8243.
(17) It is known that when oxygen lone pairs occupy a trans-app position
to an adjacent polar bond (P-OR), they donate electron density from their
lone pair orbital, n, to the antibonding O-P σ*, thus weakening the PdO
bond and increasing the basicity at O. Conversely, lack of app lone pairs
imparts orthogonal stability to hydrolysis with acid. (a) Deslongchamps, P.
Stereoelectronic Effects In Organic Chemistry; Pergamon Press: Oxford,
1983. (b) Vande Griend, L. J.; Verkade, J. G.; Pennings, J. F. M.; Buck, H.
M. J. Am. Chem. Soc. 1977, 99, 2459-2463.
(9) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem. ReV.
2004, 104, 2239-2258.
(10) (a) Burke, S. D.; Muller, N.; Beaudry C. M. Org. Lett. 1999, 1,
1827-1829. (b) Burke, S. D.; Voight, E. A. Org. Lett. 2001, 3, 237-240.
(c) Lambert, W. T.; Burke, S. D. Org. Lett. 2003, 5, 515-518.
(11) Following the protocol of Rychnovsky and co-workers, we have
synthesized 2 on a 100-g scale starting from 2,4-pentanedione; see:
Rychnovsky, S. D.; Griesgraber, G.; Powers, J. P. Org. Synth. 2000, 77,
1-11.
(18) The half-life of trimethyl phosphate (MeO)3PO in a 1 M solution
of NaOH in water at 35 °C is 30 min; the corresponding half-life of the
resulting hydrolyzed phosphate salt (MeO)2PO2Na is 11 years. Westheimer,
F. H. Science 1987, 235, 1173-1178.
3376
Org. Lett., Vol. 7, No. 15, 2005

Scheme 3
Figure 2.
comparative analysis of both the product and 1 showed a
diagnostic upfield shift of the resonance corresponding to
the C(8) carbinol, indicating regioisomer 7a as the major
cleavage product (Scheme 2). Further evidence for 7a is seen
all P-O ester bonds. Phosphate 1 was completely stable to
Super Hydride (Et3BHLi), LiBH4, and BH3‚THF in THF at
rt, demonstrating no product decomposition.
Interest in revealing additional selective processes led us
to examine regioselective and potentially diastereoselective
SN2′ cuprate displacement reactions. Initial use of ethyl
cuprate21 resulted in SN2′ attack at the more accessible
external terminal olefin of 1 to yield phosphonic acid 10 in
excellent yield (rs ∼ 8:1). Subsequent reduction with Red-
Al removed the phosphonic acid tether to yield diol diene
11.
Scheme 2
With this latter example in hand, we next turned to
investigating stereofacial bias and stereoelectronic effects in
cuprate additions to phosphate triester 1 with the goal of
producing 1,3,4-stereotriads 13 and 15 found in the southern
hemisphere of dolabelides A-D.22 This stereotriad is also
found in a number of other biologically active natural
products including salicylihalamides A and B,23 bitungolides
A-F,24 rhizoxin and rhizoxin D,25 and discodermolide.26
Initially, we studied the reactivity of the partially hydroge-
nated analogue 12 which was treated with ethyl cuprate,
followed by Red-Al to provide diol 13 as the sole product
(Scheme 4). This reaction occurs via a highly regio- and
stereoselective anti-SN2′ attack27 at the C(5) olefinic carbon
(rs ) >99:1, ds ) >99:1), where proper orthogonal
alignment of the CdC π* and C-OP(O) σ* orbitals in path
A allows for anti-SN2′ attack to proceed exclusively at C(5)
on the convex face of 12.
in the loss of C-P coupling at the C(8) carbinol position, as
expected for cleavage of the C(8)O-P bond to form 7a.
Studies focusing on mechanistic details of this selective
hydrolysis event are underway. In contrast, treatment of 1
with PhSLi showed remarkable quantitative and complete
selectivity (rs ) >99:1) for phosphate displacement at C(3),
leading to 8 containing the differentiated 1,3-anti diol subunit
(Scheme 3). This transformation is in agreement with
precedent showing soft nucleophilic preference for attack at
C vs P.14a
Having established the high selectivity for the cuprate
addition into 1, we turned our attention to generating more
elaborate systems via preferential functionalization of the
external olefin. Therefore, hydroboration of 1 with 9-BBN
(20) (a) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc. 2001,
123, 4161-4167. (b) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2001, 40, 3667-3670.
(21) Calaza, M. I.; Hupe, E.; Knochel, P. Org. Lett. 2003, 5, 1059-
1061.
We next examined reductive removal using conditions
previously developed by Bartlett.19 Reaction with LiAlH4
(Et2O at 0 °C, 15 min) led to exhaustive removal of the
phosphate tether to produce triol 9, a building block for the
central subunit in the potent phosphatase inhibitor fostrie-
cin.16,20 This result is consistent with the addition of hard
hydride anions at phosphorus and subsequent cleavage of
(22) Ojika, M.; Nagoya, T.; Yamada, K. Tetrahedron Lett. 1995, 36,
7491-7494.
(23) (a) Wu, Y.; Seguil, O. R.; De Brabander, J. K. Org. Lett. 2000, 2,
4241-4244. (b) Holloway, G. A.; Hugel, H. M.; Rizzacasa, M. A. J. Org.
Chem. 2003, 68, 2200-2204. (c) Snider B.; Song, F. Org. Lett. 2001, 3,
1817-1820.
(24) Sirirath, S.; Tanaka, J.; Ohtani, I. I.; Ichiba, T.; Rachmat, R.; Ueda,
K.; Usui, T.; Osada, H.; Higa, T. J. Nat. Prod. 2002, 65, 1820-1823.
(25) Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W.
Tetrahedron Lett. 1999, 40, 4145-4148.
(26) Smith, A. B., III; Kaufman, M. D.; Beauchamp, T. J.; LaMarche,
M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823-1826 and references therein.
(27) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063-3066.
(19) Bartlett, P. A.; Jernstedt, K. K. Tetrahedron Lett. 1980, 21, 1607-
1610.
Org. Lett., Vol. 7, No. 15, 2005
3377

ity of diol 16 onto chloride 5. Tandem RCM/exhaustive
hydrogenation31 using the second-generation Grubbs catalyst,
afforded saturated bicyclic phosphate 18. Reduction of 18
with LiAlH4 produced triol 19 in excellent yield (94%).
Alternatively, selective hydrolysis using the aforementioned
LiOH conditions generated 20 with quantitative conversion
and complete regioselectivity (rs ) >99:1), further demon-
strating the ability to generate complex differentiated polyol
subunits (Scheme 6).
Scheme 4
Scheme 6
followed by mild oxidation of the borane with sodium
perborate and subsequent TBDPS-protection afforded silyl
protected primary alcohol 14 in moderate yield (Scheme 5).
Scheme 5
In conclusion, we have demonstrated the utility of mul-
tivalent activation via a phosphate tether where latent leaving
group ability has been harnessed in selective cleavage
reactions within the bicyclic framework of 1. Taken col-
lectively, these features uncover new dimensions in phos-
phate chemistry. Additional studies probing mechanistic
features, as well as applications in total synthesis, are
underway and will be reported in due course.
As anticipated, treatment with a Me2Zn-derived cuprate
produced the corresponding phosphate acid as a single
product as witnessed by 31P NMR. Subsequent methylation
to the phosphate ester, followed by reductive cleavage of
the phosphate ester with Red-Al, led to fully deprotected
triol 15 in excellent yields.28
Further potential of this method was showcased in the
rapid assembly of tetrol 19, which represents an advanced
intermediate in the synthesis of feigrisolide B,29 with direct
application to tetranactin30 (Scheme 4). In this example, the
phosphate tether serves to mediate both the RCM desym-
metrization event and to parlay the stereochemical complex-
Acknowledgment. This investigation was generously
supported by funds provided the National Institutes of Health
(NIGMS, RO1-GM58103) and the NIH Training Grant in
Dynamical Aspects of Chemical Biology (A.W.). We thank
Dr. David Vander Velde for assistance with NMR measure-
ments and Dr. Todd Williams for HRMS analysis. The X-ray
structure of compound 1 was determined by Dr. Douglas R.
Powell.
Supporting Information Available: Experimental details
and spectroscopic data of new compounds, including X-ray
crystallographic analysis of 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
(28) The TBDPS protecting group unexpectedly was removed.
(29) Tang, Y.-Q.; Sattler, I.; Thiericke, R.; Grabley, S.; Feng, X.-Z. J.
Antibiot. 2000, 53, 934-943.
(30) Ando, K.; Oishi, H.; Hirano, S.; Okutomi, T.; Suzuki, K.; Okazaki,
H.; Sawada, M.; Sagawa, T. J. Antibiot. 1971, 24, 347-352.
OL0512886
(31) Louie, J.; Bielawski, C. H.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312.
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