Conformationally constrained α-Boc-aminophosphonates via transition metal-catalyzed/curtius rearrangement strategies

Article abstract of DOI:10.1021/jo0262208

A transition metal-catalyzed/Curtius rearrangement sequence toward the development of conformationally constrained α-Boc-aminophosphonates 2-6 is described. An approach using the versatile tert-butylphosphonoacetate moieties 1a and 1b to derive an array of mono- and bicyclic α-Bocaminophosphonate systems is presented. Conformational constraint is incorporated using either the ring-closing metathesis reaction catalyzed by the first generation Grubbs catalyst or intramolecular cyclopropanation mediated by Rh₂(OAc)₄. Using the tert-butyl ester functionality in 1a or 1b as a potential amino group, the Curtius rearrangement provides an efficient route toward the target α-Boc-aminophosphonates.

Full text of DOI:10.1021/jo0262208

Con for m a tion a lly Con str a in ed r-Boc-Am in op h osp h on a tes via
Tr a n sition Meta l-Ca ta lyzed /Cu r tiu s Rea r r a n gem en t Str a tegies
J oel D. Moore, Kevin T. Sprott, and Paul R. Hanson*
Department of Chemistry, University of Kansas, Lawrence, Kansas 66045-7582
phanson@ku.edu
Received J uly 20, 2002
A transition metal-catalyzed/Curtius rearrangement sequence toward the development of confor-
mationally constrained R-Boc-aminophosphonates 2-6 is described. An approach using the versatile
tert-butylphosphonoacetate moieties 1a and 1b to derive an array of mono- and bicyclic R-Boc-
aminophosphonate systems is presented. Conformational constraint is incorporated using either
the ring-closing metathesis reaction catalyzed by the first generation Grubbs catalyst or intramo-
lecular cyclopropanation mediated by Rh2(OAc)4. Using the tert-butyl ester functionality in 1a or
1b as a potential amino group, the Curtius rearrangement provides an efficient route toward the
target R-Boc-aminophosphonates.
In tr od u ction
potent fungicidal, herbicidal, and insecticidal activity.9
Our interest in the synthesis of novel phosphorus com-
pounds via transition metal-catalyzed approaches has
drawn us to a series of biologically active cyclic R-ami-
nophosphonates (Figure 1), the phosphonoester sur-
rogates of R-aminophosphonic acids. These compounds
have shown promise as peptide-related bioactive agents,10
as starting units in the total synthesis of natural product
analogues,11 as haptens in catalytic antibody synthesis,12
and as powerful herbicides.13
Although the synthesis of aminophosphorus com-
pounds and their cyclic derivatives has been extensively
studied,1,4,14 the literature contains relatively few ex-
amples utilizing transition metal-catalyzed processes to
afford either acyclic or cyclic structures.15 Our interest
Aminophosphonic acids and their derivatives have
received considerable attention due to their involvement
in a variety of biological processes.1 These entities have
been shown to serve as inhibitors of GABA-receptors,2
inhibitors of various proteolytic enzymes,3 antitumor
agents,1,4 antihypertensive agents,5 antibacterial agents,6
and haptens for the development of catalytic antibodies.7
They have also served as inhibitors of excitatory trans-
mission,8 and are of agricultural interest due to their
(1) (a) Mader, M. M.; Bartlett, P. A. Chem. Rev. 1997, 97, 1281-
1301. (b) Franz, J . E.; Mao, M. K.; Sikorski, J . A. Glyphosate: A Unique
Global Herbicide; American Chemical Society: Washington, D.C., 1997.
(c) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur, Silicon 1991, 63, 193-
215. (d) Engel, R. Handbook of Organo-phosphorus Chemistry; Marcel
Dekker: New York, 1992. (e) Quin, L. D. A Guide to Organophosphorus
Chemistry; Wiley-Interscience: New York, 2000. (f) Kafarski, P.;
Lejczak, B. Curr. Med. Chem.: Anti-Cancer Agents 2001, 1, 301-312.
(2) (a) Chebib, M.; J ohnston, G. A. R. Clin. Exp. Pharmacol. Physiol.
1999, 26, 937-940. (b) Groth, U.; Lehmann, L.; Richter, L.; Scho¨llkopf,
U. Leibigs Ann. Chem. 1993, 427-431. (c) Nasser, J .; About-J audet,
E.; Collignon, N. Phosphorus, Sulfur, Silicon 1991, 55, 137-146. (d)
Diel, P. J .; Maier, L. Phosphorus Sulfur 1984, 20, 313-321. (e)
Yamazaki, S.; Takada, I.; Moriguchi, Y.; Yamabe, S. J . Org. Chem.
1998, 63, 5919-5928.
(3) (a) Oleksyszyn, J .; Boduszek, B.; Cam, C.-M.; Powers, J . C. J .
Med. Chem. 1994, 37, 226-231. (b) Sampson, N. S.; Bartlett, P. A.
Biochemistry 1991, 30, 2255-2263. (c) Giannousis, P. P.; Bartlett, P.
A. J . Med. Chem. 1987, 30, 1603. (d) Peyman, A.; Budt, K. H.; Spanig,
J .; Stowasser, B.; Ruppert, D. Tetrahedron Lett. 1992, 33, a-4552. (e)
Bird, J .; De Mello, R. C.; Harper, G. P.; Hunter, D. J .; Markwell, R.
E.; Miles-Williams, A. J .; Rahman, S. S.; Ward, R. W. J . Med. Chem.
1994, 37, 158-169.
(7) (a) Pollack, S. J .; Hsiun, P.; Schultz, P. G. J . Am. Chem. Soc.
1989, 111, 5961-5962. (b) Hirschmann, R.; Smith, A. B., III; Taylor,
C. M.; Benkovic, P. A.; Taylor, S. D.; Yager, K. M.; Sprengeler, P. A.;
Benkovic, S. J . Science 1994, 265, 234-237. (c) Smith, A. B., III; Taylor,
C. M.; Benkovic, S. J .; Hirschmann, R. Tetrahedron Lett. 1994, 35,
6853-6856. (d) See also ref 1a.
(8) Crooks, S. L.; Robinson, M. B.; Koerner, J . F.; J ohnson, R. L. J .
Med. Chem. 1986, 29, 1988-1995.
(9) (a) See Sikorski (ref 1b) and Engel (ref 1d). (b) Cameron, D. G.;
Hudson, H. R.; Ojo, I. A. O.; Pianka, M. Phosphorus Sulfur 1988, 40,
183-197. (c) Cameron, D. G.; Hudson, H. R.; Pianka, M. Phosphorus,
Sulfur, Silicon 1993, 83, 21-37. (d) Cameron, D. G.; Hudson, H. R.;
Pianka, M.; Volckman, J . F. Phosphorus, Sulfur, Silicon 1994, 88, 15-
25. (e) Manderscheid, R.; Wild, A. J . Plant Physiol. 1986, 123, 135. (f)
Armheim, N.; Deus, P.; Gehrke, H. C.; Steinrucken, H. C. Plant Physiol.
1980, 66, 830.
(10) Yamazaki, S.; Takada, T.; Imanishi, T.; Moriguchi, Y.; Yamabe,
S. J . Org. Chem. 1998, 63, 5919-5928.
(11) Fadel, A.; Nicolas, T. Tetrahedron: Asymmetry 2000, 11, 2023-
2031.
(12) Ryglowski, A.; Lazaro, R.; Roumestant, M. L.; Viallefont, Ph.
Synth. Commun. 1996, 26, 1739-1745.
(4) (a) Lavielle, G.; Hautefaye, P.; Schaeffer, C.; Boutin, J . A.;
Cudennec, C. A.; Pierre, A. J . Med. Chem. 1991, 34, 1998-2003. (b)
Powers, J . C.; J ackson, D. S.; Ni, L. U.S. Patent 5,686,419, 1999. (c)
Simon, J .; Garlich, J . R.; Goeckeler, W. F.; et al. U.S. Patent 5,066,-
478, 1994.
(5) (a) Goto, K.; Nakamura, S.; Morioka, Y.; Kondo, M.; Naito, S.;
Tsutsumi, K. Chem. Pharm. Bull. 1996, 44, 547-551. (b) Dellaria, J .
F.; Maki, R. G.; Stein, H. H.; Cohen, J .; Whittern, D.; Marsh, K.;
Hoffman, D. J .; Plattner, J . J .; Perun, T. J . J . Med. Chem. 1990, 33,
534-542.
(6) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J . Med. Chem.
1986, 29, 29-40.
(13) (a) Gancarz, R.; Kafarski, P.; Lejczak, B.; Mastalerz, P.;
Wieczorek, J . S.; Przybylka, E.; Czerwinski Phosphorus Sulfur 1983,
18, 373-376. (b) Kramer, W.; Guenther, E.; Loettge, W.; Bech, R.;
Kochmann, W. Environ. Qual. Saf., Suppl. 1975, 3, 686-689. (c) The
herbicide Trakephon: Gu¨nther, E.; Lo¨ttge, W. Ger. Offen. 2.022.228,
1971; Chem. Abstr. 1971, 74, 100219. (d) See Kafarski reviews (refs
1c and 1f) and references therein.
10.1021/jo0262208 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/23/2002
J . Org. Chem. 2002, 67, 8123-8129
8123

Moore et al.
F IGURE 1. Biologically active R-aminophosphonates.
in both ring-closing metathesis (RCM)16 and intramo-
lecular cyclopropanation (ICP)17 led us to explore the tert-
butylphosphonoacetate building block as a potential
amino group via a Curtius rearrangement and thus a
synthon for the construction of an array of conformation-
ally constrained R-Boc-aminophosphonates (Figure 2).
The initial targets we chose have structural similarities
of known biologically relevant R-aminophosphonates. The
strategy we report utilizes the tert-butylphosphonoac-
etates 1a and 1b, in conjunction with an array of
transition metal-catalyzed processes, including Rh2(OAc)4-
catalyzed ICP, ruthenium-catalyzed RCM, and Rh2-
(OAc)4-catalyzed ylide rearrangements.18 Subsequent
F IGURE 2. Versatile phosphonoacetate precursor.
F IGURE 3. Biologically active amino-Cyclopropanes.
t
Curtius rearrangement in the presence of BuOH19,20
Resu lts a n d Discu ssion
generates a number of novel mono- and bicyclic R-ami-
nophosphonates 2-6 (Figure 2).
Our initial focus was directed toward the synthesis of
phosphorus surrogates of cyclopropane-containing amino
acids. Amino acids incorporating cyclopropane rings have
proven to be potent, biologically active compounds (Figure
3). The strategy we devised utilizes Rh2(OAc)4-catalyzed
intramolecular cyclopropanation as outlined in Scheme
1.17 We believed that this would provide a direct route
toward a number of cyclopropane-containing aminophos-
phonates related to the biologically active systems out-
lined in Figures 1 and 3. This strategy augments our
recent efforts utilizing a double diastereoselective ICP
strategy to access bicyclic P-chiral phosphonates analo-
gous to 8.21
(14) (a) Davis, F. A.; McCoull, W.; Titus, D. D. Org. Lett. 1999, 1,
1053-1055. (b) Ranu, B. C.; Hajra, A.; J ana, U. Org. Lett. 1999, 1,
1141-1143. (c) Davis, F. A.; Lee, S.; Yan, H.; Titus, D. D. Org. Lett.
2001, 3, 1757-1760. (d) Maury, C.; Gharbaoui, T.; Royer, J .; Husson,
H.-P. J . Org. Chem. 1996, 61, 3687-3693. (e) Schmidt, U.; Oehme,
G.; Krause, H. Synth. Commun. 1996, 26, 777-781. (f) Sasai, H.; Arai,
S.; Tahara, Y.; Shibasaki, M. J . Org. Chem. 1995, 60, 6656-6657. (g)
Yager, K. M.; Taylor, C. M.; Smith, A. B. J . Am. Chem. Soc. 1994,
116, 9377-9378. (h) Hanessian, S.; Bennani, Y. L. Synthesis 1994,
1272-1274 (i) Hanessian, S.; Bennani, Y. L.; Herve, Y. Synlett 1993,
35-36. (j) Yokomatsu, T.; Shibuya, S. Tetrahedron: Asymmetry 1992,
3, 377-382. (k) Groth, U.; Richter, L.; Scho¨llkopf, U. Tetrahedron 1992,
48, 117-122. (l) Laschat, S.; Kunz, H. Synthesis 1992, 90-95.
(15) (a) Aller, E.; Buck, R. T.; Drysdale, M. J .; Ferris, L.; Haigh, D.;
Moody, C. J .; Pearson, N. D.; Sanghera, J . B. J . Chem. Soc., Perkins
Trans. 1 1996, 2879-2884. (b) Moody, C. J .; Ferris, L.; Haigh, D.;
Swann, E. Chem. Commun. 1997, 2391-2392. (c) Burk, M. J .;
Stammers, T. A.; Straub, J . A. Org. Lett. 1999, 1, 387-390. (d) Kuwano,
R.; Nishio, R.; Ito, Y. Org. Lett. 1999, 1, 837-839. (e) Osipov, S. N.;
Artyushin, O. I.; Kolomiets, A. F.; Bruneau, C.; Dixneuf, P. H. Synlett
2000, 1031-1033. (f) Osipov, S. N.; Artyushin, O. I.; Kolomiets, A. F.;
Bruneau, C.; Picquet, M.; Dixneuf, P. H. Eur. J . Org. Chem. 2001,
3891-3897.
(16) For additional uses of RCM in the production of new phosphorus-
containing compounds see: (a) Leconte, M.; J ourdan, I.; Pagano, S.;
Lefebvre, F.; Basset, J .-M. J . Chem. Soc., Chem. Commun. 1995, 857-
858. (b) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1998, 39,
3939-3942. (c) Bujard, M.; Gouverneur, V.; Mioskowski, C. J . Org.
Chem. 1999, 64, 2119-2123. (d) Hanson, P. R.; Stoianova, D. S.
Tetrahedron Lett. 1999, 40, 3297-3300. (e) Trevitt, M.; Gouverneur,
V. Tetrahedron Lett. 1999, 40, 7333-7336. (f) Hetherington, L.; Greedy,
B.; Gouverneur, V. Tetrahedron 2000, 56, 2053-2060. (g) Stoianova,
D. S.; Hanson, P. R. Org. Lett. 2000, 2, 1769-1772. (h) Schuman, M.;
Trevitt, M.; Redd, A.; Gouverneur, V. Angew. Chem., Int. Ed. 2000,
39, 2491-2493. (i) Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van
der Marel, G. A.; van Boom, J . H. Tetrahedron Lett. 2000, 41, 8635-
8638. (j) Srensen, A. M.; Nielsen, P. Org. Lett. 2000, 2, 4217-4219.
(k) Sprott, K. T.; Hanson, P. R. J . Org. Chem 2000, 65, 7913-7918. (l)
Osipov, S. N.; Artyushin, O. I.; Kolomiets, A. F.; Bruneau, C.; Dixneuf,
P. H. Synlett 2000, 1031-1033. (m) Sprott, K. T.; McReynolds, M. D.;
Hanson, P. R. Synthesis 2001, 612-620. (n) See also refs 15d and 15e.
(17) For the use of R-diazophosphonates in ICP reactions, see: (a)
Callant, P.; D’Haenens, L.; Vandewalle, M. Synth. Commun. 1984, 14,
155-161. (b) Hanson, P. R.; Sprott, K. T.; Wrobleski, A. D. Tetrahedron
Lett. 1999, 40, 1455-1458. (c) For a review containing examples of
intermolecular cyclopropanation reactions of R-diazophosphonates,
see: (d) Regitz, M. Angew. Chem. 1975, 87, 259-268.
(18) (a) Gulea, M.; Marchand, P.; Masson, S.; Saquet, M.; Collignon,
N. Synthesis 1998, 1635-1639. (b) Moore, J . D.; Sprott, K. T.; Hanson,
P. R. Synlett 2001, 5, 605-608.
(19) (a) Hercovet, A.; Le Corre, M.; Carboni, B. Tetrahedron Lett.
2000, 41, 197-199. (b) Coutrot, P.; Grison, C.; Charbvonnier-Ge´rardin,
C. Tetrahedron 1992, 48, 9841-9868. (c) Erion, M. D.; Walsh, C. T.
Biochemistry, 1987, 26, 3417-3425. (d) Chambers, J . R.; Isbell, A. F.
J . Org. Chem. 1964, 29, 832-836.
(20) For recent references utilizing the Curtius rearrangement in
the synthesis of R-amino acids see: (a) Roers, R.; Verdine, G. L.
Tetrahedron Lett. 2001, 42, 3563-3565. (b) Nemes, C.; J eannin, L.;
Sapi, J .; Laronze, M.; Seghir, H.; Auge, F.; Laronze, J .-Y. Tetrahedron
2000, 56, 5479-5492. (c) Abele, S.; Seebach, D. Eur. J . Org. Chem.
2000, 1-15. (d) De Meijere, A.; Ernst, K.; Zuck, B.; Brandl, M.;
Kozhushkov, S. I.; Tamm, M.; Yufit, D. S.; Howard, J . A. K.; Labahn,
T. Eur. J . Org. Chem. 1999, 3105-3115.
(21) Moore, J . D.; Sprott, K. T.; Wrobleski, A. D.; Hanson, P. R. Org.
Lett. 2002, 4, 2357-2360.
8124 J . Org. Chem., Vol. 67, No. 23, 2002

R-Boc-Aminophosphonate
TABLE 1. 1H NMR Da ta of Ma jor a n d Min or Isom er s
SCHEME 1a
proton
δ major
δ minor
H1
H2
H3
H4
H5
4.34
2.44
1.59
4.03
1.38
4.18
2.37
1.66
4.02
1.38
a
Reagents and conditions: (a) Rh2(OAc)4, CH2Cl2, reflux, 91%;
ds 5.5:1; (b) formic acid, neat; (c) (COCl)2, CH2Cl2, DMF (cat.), 0
°C to rt; (d) NaN3, CH3CN, H2O quantitative yield; (e) toluene,
reflux; (f) BuOH, reflux, 50% (five steps).
t
SCHEME 2a
This series began with diazotization of diallylphospho-
noacetate precursor 1b22 giving R-diazo phosphonate 7.17
Cyclopropanation, facilitated by Rh2(OAc)4 carbene gen-
eration, yielded two diastereomeric, [3.1.0]-bicyclic phos-
phonoacetates 8 in a 5.5:1.0 ratio. The mixture was
separated and the major diastereomer was carried through
the optimized Curtius sequence, which entailed formic
acid-mediated ester hydrolysis of the tert-butyl ester
followed by transformation to the acyl chloride. Subse-
quent azide formation using NaN3 in CH3CN/water gave
the acyl azide.23 This product was dissolved in toluene
and refluxed over 4 Å molecular sieves to induce the
Curtius rearrangement; the reaction progress was moni-
tored by infrared spectroscopy. Once the acyl azide peaks
(1740 and 2150 cm-1) vanished and the isocyanate
a
Reagents and conditions: (a) NaH, THF, allyl bromide, 0 °C,
85%; (b) Grubbs catalyst (5 mol %), CH2Cl2, 94%; (c) formic acid,
neat; (d) (COCl)2, CH2Cl2, DMF (cat.); 0 °C to rt; (e) NaN3, CH3CN,
H2O quantitative (three steps); (f) toluene, reflux; (g) tBuOH,
reflux, 48%.
SCHEME 3a
t
appeared (2240 cm-1), BuOH was added, and the reac-
tion mixture was refluxed over 4 Å molecular sieves to
yield the solid carbamate 2. Subsequent recrystallization
and X-ray crystallographic analysis (see Supporting
Information) enabled us to unambiguously prove the cis
relationship between the PdO group and the amino
carbamate in the major diastereomer (Scheme 1).
It is worth noting that initially unambiguous identi-
fication of the major diastereomer 8-cis was problematic
as NOE studies proved to be completely inconclusive.
However, it has been shown that in other constrained
systems, protons within the “cone” of the PdO of the
phosphonate moiety will be shifted downfield relative to
those outside the “cone”.24 Therefore, we postulated that
the major diastereomer was the cis isomer due to the fact
that protons H(1), H(2), and H(4) (Table 1) were all
shifted downfield in the major diastereomer in compari-
son to the same protons in the minor. Similarly, proton
H(3) has a downfield shift in the minor isomer.
a
Reagents and conditions: (a) KOtBu, allyl bromide, CH2Cl2,
0 °C to rt, 76%; (b) Grubbs catalyst (5 mol %), CH2Cl2, 97%; (c)
formic acid, neat; (d) (COCl)2, CH2Cl2, DMF (cat.), 0 °C to rt. (e)
NaN3, CH3CN, H2O quantitative yield (three steps); (f) toluene,
t
reflux; (g) BuOH, reflux 84%.
mixture of diastereomeric P-heterocycles 9 in excellent
yield (Scheme 2). Using the same five-step procedure as
before, Boc-protected R-aminophosphonate 3 was gener-
ated in 48% overall yield as a 1.5:1 mixture of separable
diastereomers.26 Subsequent allylation of an approximate
1:1 mixture of the aforementioned P-heterocyclic diaster-
eomers 9 produced 10 with good yield and with 3:1
diastereoselectivity (Scheme 3). RCM of the major dias-
tereomer gave the [5.5.0]-bicyclic tert-butylphosphonoac-
etate 11 as the cis-fused diastereomer (see Supporting
With 2 in hand, we next turned to an RCM strategy
toward the synthesis of the seven-membered P-hetero-
cyclic R-aminophosphonates 3 (Scheme 2). Monoallylation
of diallyl tert-butylphosphonoacetate (1b) using NaH and
allyl bromide in THF at 0 °C followed by RCM utilizing
the Grubbs benzylidene catalyst25 generated a 1.2:1.0
(22) The tert-butyldialkylphosphonoacetates are readily prepared
using standard Arbuzov reaction of trimethyl phosphite or triallyl
phosphite and tert-butyl iodoacetate.
(23) We also attempted the Curtius rearrangement directly from
the acid using DPPA; however, the isocyanate peak was never detected
by IR.
(25) (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.
(26) It is interesting to note that conditions incorporated in the
Curtius sequence caused complete epimerization at the R-center when
starting from a 13:1 mixture of diastereomers (Scheme 1).
(24) Turnblom, E. W.; Katz, T. J . J . Am. Chem. Soc. 1973, 95, 4292-
4311.
J . Org. Chem, Vol. 67, No. 23, 2002 8125

Moore et al.
SCHEME 4a
SCHEME 6a
a
Reagents and conditions: (a) KOtBu, allyl bromide, CH2Cl2,
0 °C to rt,, 92%; (b) Grubbs catalyst (5 mol %), CH2Cl2, 94%; (c)
formic acid, neat; (d) (COCl)2, CH2Cl2, DMF (cat.), 0 °C to rt. (e)
NaN3, CH3CN, H2O quantitative yield (three steps); (f) toluene,
a
Reagents and conditions: (a) toluene, microwave 45 min, 50%;
t
(b) mCPBA, CH2Cl2, 82%; (c) toluene, reflux; (d) BuOH, reflux,
53% (two steps).
t
reflux; (g) BuOH, reflux, 85%.
SCHEME 5a
It was found that acyl azide 16 did not undergo a
Curtius rearrangement upon refluxing in toluene. In-
stead, acyl azide elimination was prevalent, most likely
arising from direct participation of the adjacent sulfide
lone pairs to yield diene 17. This problem was overcome
via oxidation to the corresponding sulfone. Subsequent
Curtius protocol produced the R-Boc-aminophosphonate
6, containing three different heteroatoms on a single
carbon atom, in 53% overall yield (Scheme 6).
In conclusion, we have shown that the cyclic R-Boc-
aminophosphonates can be synthesized in good yields
utilizing the Curtius rearrangement on conformationally
constrained phosphorus templates generated from either
RCM or Rh2(OAc)4-catalyzed ICP. This work augments
our efforts in the area of producing novel phosphorus
systems utilizing transition metal-catalyzed processes;
the pursuit of broadening the scope of this project in
terms of stereochemical issues and substrate function-
alization is ongoing and will be reported in due course.
a
Reagents and conditions: (a) Rh2(OAc)4, allyl sulfide, CH2Cl2,
80%; (b) Grubbs catalyst (5 mol %), CH2Cl2, 99%; (c) formic acid,
neat; (d) (COCl)2, CH2Cl2, DMF (cat.), 0 °C to rt; (e) NaN3, CH3CN,
H2O, quantitative yield (three steps).
Information) in excellent yield (85-97%). This experi-
ment also proves the selectivity (cis ) major) in the
allylation process of 9. Subjection of 10 to Curtius
conditions gave the corresponding R-Boc-aminophospho-
nate 4 in 84% yield (Scheme 3).
As expected, X-ray analysis demonstrates that the
Curtuis rearrangement of the bicyclic system proceeds
with complete retention of configuration. The cis-ring
juncture [P(14) and C(7A) in Supporting Information]
generated after the initial methathesis 11 event is
maintained in the R-aminophosphonate system 4. In
addition, the carbamate N-H forms an H-bond to the
phosphonate PdO.
Similarly, the synthesis of R-aminophosphonate 5
using the dimethyl tert-butylphosphonoacetate (1a ) build-
ing block began with bisallylation using KOtBu and allyl
bromide in CH2Cl2 at 0 °C. Subsequent RCM produced
12 in excellent yield (Scheme 4). Again, formic acid-
mediated ester deprotection gave the corresponding acid
quantitatively. Acyl chloride formation followed by azide
addition produced the requisite acyl azide. Refluxing in
toluene induced the Curtius rearrangement and subse-
quent addition of tBuOH afforded the Boc-protected
R-aminophosphonate 5 in 85% yield (Scheme 4).
Amending this method to the more elaborate cyclic,
R-sulfonyl, R-aminophosphonate 6 (Schemes 5 and 6)
allowed us to highlight the full potential of this strategy.
Thus, R-diazophosphonoacetate 13,27 in the presence of
Rh2(OAc)4 and diallyl sulfide, undergoes ylide formation
followed by sigmatropic rearrangement producing the
homoallylic R-thio tert-butylphosphonoacetate 14. Sub-
sequent RCM gave the cyclic compound 15. Ester depro-
tection, acyl chloride formation, and treatment with NaN3
gave the cyclic acyl azide 16 in a quantitative, three-step
process (Scheme 5).
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out in flame-
or oven-dried glassware under an argon atmosphere using
standard gastight syringes, cannulaes, and septa. Stirring was
accomplished with oven-dried magnetic stir bars. Methylene
chloride was purified by distillation over CaH2 or by passing
through a purification system28 employing activated Al2O3.
Deuteriochloroform (CDCl3) was stored over molecular sieves
(4 Å) and K2CO3 at room temperature. NaH was used as a
60% mixture in mineral oil. Mass spectral analysis was
performed by the Mass Spectrometry Laboratory at the
University of Kansas. Flash column chromatography was
performed with silica gel (230-400 mesh). Thin-layer chro-
matography was performed on silica gel. Visualization of TLC
spots was effected using UV and KMnO4 stain.
Rep r esen ta tive P r oced u r e for Rin g-Closin g Meta th -
esis (RCM). A solution of substrate in CH2Cl2 was degassed
with argon for 10 min. Grubbs catalyst was added, and the
solution was brought to reflux and monitored by TLC and GC.
The reaction was concentrated under reduced pressure and
subjected to flash chromatography to afford the purified cyclic
phosphonate products.
Rep r esen ta tive P r oced u r e for th e Cu r tiu s Rea r r a n ge-
m en t Sequ en ce. The tert-butyl ester was dissolved in neat
formic acid. Once hydrolysis was complete, excess formic acid
was removed under reduced pressure. The crude acid was
dissolved in CH2Cl2 in a round-bottom flask equipped with
drying tube; the solution temperature was taken to 0 °C.
Oxalyl chloride was added along with one drop of DMF, which
induced CO2 extrusion. Once CO2 extrusion subsided, the
reaction was concentrated under reduced pressure and dis-
solved in CH3CN. A saturated solution of NaN3 in water was
(27) Prepared from 1a in our previously reported sequential (2,3)-
sigmatropic ylide rearrangement/RCM strategy, see ref 18b.
(28) Grubbs, R. H.; Rosen, R. K.; Timmers, F. J . Organometallics
1996, 15, 1518-1520.
8126 J . Org. Chem., Vol. 67, No. 23, 2002

R-Boc-Aminophosphonate
added and reaction was stirred for 5 h. The crude reaction was
dissolved in EtOAc, washed with H2O (2×) and NaCl (2×),
dried (Na2SO4), and concentrated. The crude acyl azide was
dissolved in toluene in a flame-dried pressure tube, 4 Å
molecular. sieves were added, and the reaction was refluxed
and monitored by infrared spectroscopy. Once the acyl azide
peaks vanished and the isocyanate peak was visible, excess
tBuOH was added and the reaction was refluxed until complete
as observed by IR analysis. The crude carbamate was purified
via flash chromatography (hexanes:EtOAc).
130.54, 129.62, 118.40, 80.20, 66.73 (d, J CP ) 5.8 Hz), 62.48
(d, J CP ) 3.8 Hz), 47.21 (d, J CP ) 144.2 Hz), 28.22, 28.02; 31P
NMR (162 MHz, CDCl3) δ 28.28; HRMS calcd for C13H23O5NP
(M + H)+ required 304.1314, found 304.1309. Anal. Calcd for
C
13H22O5NP (major): C, 51.48; H, 7.31; N, 4.62. Found: C,
51.72; H, 7.22; N, 4.37.
Boc-P r otected r-Am in op h osp h on a te 4. Bicyclic tert-
butylphosphonoacetate 11 (250 mg, 0.83 mmol) was subjected
to the general Curtius rearrangement sequence beginning with
ester deprotection in 8 mL of formic acid. The resulting
carboxylic acid (150 mg, 0.62 mmol) was transformed to the
acyl chloride using oxalyl chloride (195 mg, 1.53 mmol) in CH2-
Cl2 (1.8 mL) followed by the addition of 1 drop of DMF. The
crude acyl chloride (161 mg, 0.62 mmol) was dissolved in CH3-
CN (2 mL) and treated with a saturated aqueous solution of
NaN3 (200 mg, 3.1 mmol). The resulting acyl azide (90 mg,
0.33 mmol) was dissolved in toluene (2 mL) and refluxed until
formation of the isocyanate was complete (IR). tBuOH (0.5 mL)
was added and the system was refluxed producing the crude
Boc-protected, bicyclic R-aminophosphonate 4. Flash chroma-
tography (1.5:1 hexanes:EtOAc) generated pure aminophos-
phonate 4 (88 mg, 84%) as a white solid. Mp 146-148 °C; FTIR
1712, 1392, 1366, 1253, 1165 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.85-5.70 (m, 3H), 5.65-5.57 (m, 2H), 4.91-4.82 (m, 2H),
4.81-4.69 (m, 2H), 3.10-2.90 (m, 2H), 2.86-2.77 (m, 2H), 1.42
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.21 (d, J CP ) 15.9
Hz), 127.53, 126.99, 79.32, 67.78 (d, J CP ) 3.7 Hz), 65.09 (d,
J CP ) 105.1 Hz), 32.06, 28.30; 31P NMR (162 MHz, CDCl3) δ
Boc-P r otected r-Am in op h osp h on a te 2-cis (Ma jor ). The
major, bicyclic tbutylphosphonoacetate 8 (140 mg, 0.51 mmol)
was subjected to the Curtius rearrangement sequence begin-
ning with ester hydrolysis in 3 mL of formic acid. The resulting
carboxylic acid (112 mg, 0.51 mmol) was transformed to the
acyl chloride using oxalyl chloride (128 mg, 1.0 mmol) in CH2-
Cl2 (1 mL) followed by the addition of 1 drop of DMF (0 °C to
rt) in a 5-mL round-bottom flask equipped with a drying tube.
The crude acyl chloride (121 mg, 0.51 mmol) was dissolved in
CH3CN (2 mL) and treated with a saturated aqueous solution
of NaN3 (491 mg, 7.6 mmol). The acyl azide (30 mg, 0.12 mmol)
was dissolved in toluene (2 mL) and refluxed until formation
of the isocyanate was complete (IR), tBuOH (0.5 mL) was
added, and the system was refluxed producing the crude Boc-
protected R-aminophosphonate 2. Flash chromatography (2:1
hexanes:EtOAc), followed by recrystallization from ether/
heptane, provided pure aminophosphonate 2 (20 mg, 57%) as
a clear, crystalline solid. Mp 105-107 °C; FTIR 1714, 1392,
32.26; HRMS calcd for
316.1314, found 316.1300. Anal. Calcd for C14H22O5NP: C,
53.33; H, 7.03; N, 4.44. Found: C, 53.51; H, 7.05; N, 4.42.
C
14H23O5NP (M + H)+ required
1365, 1250, 1168 cm-1 1H NMR (500 MHz, CDCl3) δ 5.98
;
(dddd, J ) 16.3, 10.8, 5.6, 5.6 Hz, 1H), 5.43 (s, 1H), 5.37 (dd,
J ) 17.1, 1.1 Hz, 1H), 5.24 (d, J ) 10.3 Hz, 1H), 4.68-4.65
(m, 2H), 4.54 (ddd, J ) 9.2, 3.1, 3.1 Hz, 1H), 4.00 (dd, J )
16.9, 9.3 Hz, 1H), 2.08-2.03 (m, 1H), 1.55-1.49 (m, 1H), 1.45
(s, 10H); 13C NMR (125.77 MHz, CDCl3) δ 156.01, 132.97 (d,
J CP ) 6.4 Hz), 118.20, 80.61, 67.96 (d, J CP ) 5.2 Hz), 65.14 (d,
J CP ) 7.2 Hz), 30.28 (d, J CP ) 197.9 Hz), 28.21, 25.29 (br),
17.65; 31P NMR (162 MHz, CDCl3) δ 39.52; HRMS calcd for
Boc-P r otected r-Am in op h osp h on a te 5. R-Cyclopentene
dimethyl-tert-butylphosphonoacetate 12 (100 mg, 0.36 mmol)
was subjected to the general Curtius rearrangement sequence
beginning with ester deprotection in 3 mL of formic acid. The
resulting carboxylic acid (75 mg, 0.34 mmol) was transformed
to the acyl chloride using oxalyl chloride (65 mg, 0.51 mmol)
in CH2Cl2 (1 mL) followed by the addition of 1 drop of DMF.
The crude acyl chloride (81 mg, 0.34 mmol) was dissolved in
CH3CN (1 mL) and treated with a saturated aqueous solution
of NaN3 (110 mg, 1.7 mmol). The resulting acyl azide (30 mg,
0.12 mmol) was dissolved in toluene (2 mL) and refluxed until
formation of the isocyanate was complete (IR). tBuOH (0.5 mL)
was added and the system was refluxed producing the crude
Boc-protected, bicyclic R-aminophosphonate 5. Flash chroma-
tography (1:1 hexanes:EtOAc) yielded pure aminophosphonate
5 (30.1 mg, 85%) as a white solid. Mp 101-103 °C; FTIR 1716,
C
12H21O5NP (M + H)+ required 290.1157, found 290.1154.
Boc-P r otected r-Am in op h osp h on a te 3. A 13:1 diaster-
eomeric mixture of 9 (400 mg, 1.4 mmol) was subjected to the
general Curtius rearrangement sequence beginning with ester
deprotection in 5 mL of formic acid. The resulting carboxylic
acids (290 mg, 1.3 mmol) were transformed to the acyl
chlorides using oxalyl chloride (397 mg, 3.1 mmol) in CH2Cl2
(2.5 mL) followed by the addition of 1 drop of DMF. The crude
acyl chlorides (315 mg, 1.3 mmol) were dissolved in CH3CN
(2.5 mL) and treated with a saturated aqueous solution of
NaN3 (406 mg, 6.3 mmol). The resulting acyl azides (308 mg,
1.2 mmol) were dissolved in toluene and refluxed until
formation of the isocyanates was complete (IR). Once complete,
tBuOH (0.5 mL) was added and the system was refluxed
producing the crude Boc-protected R-aminophosphonates 3.
Flash chromatography (1.5:1 hexanes:EtOAc) afforded ami-
nophosphonates 3 (160 mg, 48%) as a 1.5:1 (95 mg Major, 65
mg Minor) mixture of separable diastereomers. MINOR
(viscous oil): FTIR 1707, 1391, 1366, 1246, 1164 cm-1; 1H NMR
(400 MHz, CDCl3) δ 5.98-5.88 (m, 2H), 5.83-5.78 (m, 1H),
5.36 (dd, J ) 17.1, 1.3 Hz, 1H), 5.25 (dd, J ) 10.4, 0.7 Hz,
1H), 5.20 (dd, J HP ) 9.0 Hz, J HH ) 6.0 Hz, 1H), 4.74-4.49 (m,
1390, 1366, 1242, 1170 cm-1 1H NMR (400 MHz, CDCl3) δ
;
5.72-5.67 (m, 2H), 4.85 (d, J HP ) 4.4 Hz, 1H), 3.83 (d, J HP
)
10.4 Hz, 6H), 3.15-2.87 (m, 4H), 1.44 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 154.28 (d, J CP ) 5.3 Hz), 127.67 (d, J CP ) 7.5
Hz), 79.69, 58.92 (d, J CP ) 159.4 Hz), 53.46 (d, J CP ) 6.9 Hz),
41.59, 28.21; 31P NMR (162 MHz, CDCl3) δ 31.48; HRMS calcd
for C12H23O5NP (M + H)+ required 292.1314, found 292.1309.
Boc-P r otected r-Am in oph osph on ate 6. R-Acylazido phos-
phonate 16 (30 mg, 0.11 mmol) was dissolved in CH2Cl2 (0.52
mL) and the solution temperature was lowered to 0 °C.
mCPBA (66 mg, 0.38 mmol) was added, and once oxidation
was complete, the crude reaction mixture was subjected to
flash chromatography (2:1 then 1:1 hexanes:EtOAc) to afford
the corresponding R-sulfonylacylazidophosphonate (27 mg,
0.087 mmol, 82%). The acyl azide (17 mg, 0.055 mmol) was
then dissolved in toluene (2 mL) and subjected to the general
4H), 4.21-4.10 (m, 1H), 2.71-2.58 (m, 1H), 2.49 (dddd, J HH
)
25.6 Hz, J HH ) 15.0 Hz, J HP ) 7.6 Hz, J HH ) 2.9 Hz, 1H), 1.43
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.94 (d, J CP ) 10.2
Hz), 132.32 (d, J CP ) 6.1 Hz), 129.43, 128.36, 118.44, 80.21,
66.83 (d, J CP ) 6.7 Hz), 64.03 (d, J CP ) 5.0 Hz), 48.15 (d, J CP
) 144.8 Hz), 29.34 (d, J CP ) 1.4 Hz), 28.24; 31P NMR (162 MHz,
CDCl3) δ 29.07. MAJ OR (white solid): mp. 99-101 °C; FTIR
1709, 1392, 1367, 1247, 1166 cm-1; 1H NMR (400 MHz, CDCl3)
δ 6.01-5.89 (m, 3H), 5.40 (dd, J ) 17.1, 1.3 Hz, 1H), 5.26 (d,
J ) 10.3 Hz, 1H), 4.83-4.69 (m, 2H), 4.64 (dd, J ) 7.1, 6.0
Hz, 2H), 4.42 (ddd, J HP ) 20.2 Hz, J HH ) 14.2 Hz, J HH ) 5.0
Hz, 1H), 2.75-2.57 (m, 2H), 1.43 (s, 9H); 13C NMR (100 MHz,
CDCl3) (154.71 (d, J CP ) 6.3 Hz), 132.39 (d, J CP ) 6.3 Hz),
t
Curtius conditions in BuOH (0.50 mL). Flash chromatography
(1:1 hexanes:EtOAc) generated R-aminophosphonate 6 (10 mg,
53%) as a clear oil. FTIR 1720, 1246, 1154 cm-1; 1H NMR (400
MHz, CDCl3) δ 5.88-5.86 (m, 1H), 5.61-5.58 (m, 1H), 5.51 (s,
1H), 4.04-3.96 (m, 2H), 3.92 (d, J HP ) 2.7 Hz, 3H), 3.90 (d,
J HP ) 2.6 Hz, 3H), 3.65-3.59 (m, 1H), 3.30-3.26 (m, 1H), 1.44
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 152.86 (d, J CP ) 2.0 Hz),
125.46 (d, J CP ) 10.2 Hz), 117.97, 81.46, 73.01 (d, J CP ) 155.2
Hz), 54.80 (d, J CP ) 2.3 Hz), 54.73 (d, J CP ) 2.5 Hz), 49.69,
J . Org. Chem, Vol. 67, No. 23, 2002 8127

Moore et al.
29.81, 28.11; 31P NMR (162 MHz, CDCl3) δ 16.97; HRMS calcd
for C12H23NO7PS (M + H)+ required 356.0933, found 356.0928.
5.23 mmol) was added, and the solution was stirred 5 min,
followed by the addition of allyl bromide (1.0 g, 8.6 mmol). The
reaction progress was monitored by GC; once complete, the
reaction was diluted with EtOAc and extracted with H2O (2×)
and brine (1×). The organic portion was dried (Na2SO4) then
concentrated under reduced pressure and subjected to flash
chromatography (3:1 hexanes:EtOAc) to afford the allylated
adduct 10 (715 mg, 76%) as a clear oil of a 3:1 mix of
r-Dia zo Dia llyl ter t-Bu tylp h osp h on oa ceta te 7. A solu-
tion of phosphonoacetate 8 (550 mg, 2.0 mmol) and CH2Cl2
was cooled to 0 °C, then charged with tBuOK (336 mg, 3.0
mmol) followed by dropwise addition of TsN3 (591 mg, 3.0
mmol). The reaction was warmed to room temperature and
monitored by TLC. Once complete, the reaction was diluted
with EtOAc and extracted with H2O (2×) and brine (1×). The
organic portion was dried (Na2SO4) then concentrated under
reduced pressure and subjected to flash chromatography (3:1
hexanes/EtOAc) to yield 515 mg (85%) as a clear, yellow oil.
FTIR 2130, 1702, 1459, 1370, 1298 cm-1; 1H NMR (400 MHz,
CDCl3) δ 5.92 (dddd, J ) 17.0, 10.7, 5.6, 5.6 Hz, 2H), 5.38
(dddd, J ) 17.1, 2.8, 1.2, 1.2 Hz, 2H), 5.24 (dd, J ) 10.4, 1.2
Hz, 2H), 4.66-4.58 (m, 4H), 1.47 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 162.27 (d, J ) 12.2 Hz), 132.17 (d, J ) 6.9 Hz), 118.33,
83.04, 67.63 (d, J ) 5.5 Hz), 28.10; 31P NMR (162 MHz, CDCl3)
δ 12.25; HRMS calcd for C12H20N2O5P (M + H)+ required
303.1110, found 303.1092.
diastereomers. FTIR 1729, 1393, 1368, 1281, 1251, 1161 cm-1
;
1H NMR (400 MHz, CDCl3) δ 6.05-5.69 (m, 6H) mix, 5.68-
5.55 (m, 2H) mix, 5.38 (ddd, J ) 17.1, 2.9, 1.4 Hz, 1H) major,
5.36 (ddd, J ) 17.1, 2.9, 1.4 Hz, 1H) minor, 5.24 (dd, J ) 10.4,
1.3 Hz, 1H) major, 5.23 (dd, J ) 10.4, 1.2 Hz, 1H) minor, 5.17-
5.08 (m, 4H) mix, 4.79-4.35 (m, 8H) mix, 3.03-2.66 (m, 4H)
mix, 2.65-2.32 (m, 4H) mix, 1.49 (s, 9H) major, 1.46 (s, 9H)
minor; 13C NMR (100 MHz, CDCl3) major: δ 168.81 (d, J CP
)
4.2 Hz), 132.42 (d, J CP ) 15.7 Hz), 132.11 (d, J CP ) 14.9 Hz),
131.41, 127.92, 119.07, 117.63, 82.19, 66.67 (d, J CP ) 6.4 Hz),
63.04 (d, J CP ) 5.0 Hz), 54.72 (d, J CP ) 125.3 Hz), 36.45, 27.84,
27.68 (d, J CP ) 2.5 Hz). 13C NMR (100 MHz, CDCl3) minor: δ
168.76 (d, J CP ) 4.9 Hz), 132.80 (d, J CP ) 6.6 Hz), 132.53 (d,
J CP ) 5.8 Hz), 128.86, 128.52, 119.12, 118.21, 81.99, 66.61 (d,
J CP ) 5.5 Hz), 65.33 (d, J CP ) 5.8 Hz), 54.96 (d, J CP ) 123.7
Hz), 36.50, 28.41 (d, J CP ) 3.4 Hz), 27.81; 31P NMR (162 MHz,
CDCl3) δ 28.00 minor, 27.59 major; HRMS calcd for C16H26O5P
(M + H)+ required 329.1518, found 329.1512.
Bicyclic ter t-Bu tylp h osp h on oa ceta te 11. A 3:1 mixture
of allylated 10 (679 mg, 2.1 mmol) was subjected to general
RCM conditions using Grubbs catalyst (85 mg, 0.1 mmol) and
CH2Cl2 (41 mL). Flash chromatography (2:1 then 1:1 hexanes:
EtOAc) afforded the bicyclic tert-butylphosphonoacetate 11
(604 mg, 2.0 mmol, 97%) as a white solid. Mp 97-99 °C; FTIR
1723, 1393, 1368, 1279, 1160 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.96-5.84 (m, 2H), 5.65 (ddd, J ) 11.5, 3.3, 3.3 Hz, 2H),
4.90-4.64 (m, 4H), 2.70 (dddd, J HH ) 22.2 Hz, J HH ) 14.0 Hz,
J HP ) 7.5 Hz, J HH ) 0.5 Hz, 2H), 2.47 (dddd, J HH ) 19.9 Hz,
J HH ) 14.0 Hz, J HP ) 7.2 Hz, J HH ) 1.0 Hz, 2H), 1.49 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 169.29 (d, J CP ) 2.8 Hz), 127.88
(d, J CP ) 2.1 Hz), 127.45, 82.41, 67.12 (d, J CP ) 6.5 Hz), 60.92
(d, J CP ) 119.3 Hz), 31.95 (d, J CP ) 3.7 Hz), 27.91; 31P NMR
(162 MHz, CDCl3) δ 24.49; HRMS calcd for C14H21O5P (M +
H)+ required 301.1205, found 301.1192.
Cyclop r op yl ter t-Bu t ylp h osp h on oa cet a t e 8 (Ma jor ).
R-Diazo diallyl tert-butylphosphonoacetate 1 (2.1 g, 6.95 mmol)
was dissolved in CH2Cl2 (14 mL), Rh2(OAc)4 (153 mg, 0.35
mmol) was added, and the reaction was stirred at room
temperature for 36 h until cyclopropanation was complete
(TLC analysis). Flash chromatography (gradient 3:1, 2:1, then
1.8:1 hexanes:EtOAc) afforded 225 mg (12%) of 8 (MAJ OR)
and 1.52 g (80%) of a diastereomeric mix of 8, both as colorless
1
oils. FTIR 1729, 1451, 1370, 1270 cm-1; H NMR (500 MHz,
CDCl3) δ 5.93 (dddd, J ) 16.1, 10.6, 5.5, 5.5 Hz, 1H), 5.33 (dd,
J ) 17.1, 1.4 Hz, 1H), 5.21 (dd, J ) 10.4, 0.8 Hz, 1H), 4.68-
4.65 (m, 2H), 4.34 (dd, J ) 9.3, 3.3 Hz, 1H), 4.00 (dd, J ) 21.3,
9.3 Hz, 1H), 2.44-2.39 (m, 1H), 1.59-1.54 (m, 1H), 1.44 (s,
9H), 1.37-1.33 (m, 1H); 13C NMR (125.77 MHz, CDCl3) δ
166.74 (d, J ) 9.4 Hz), 132.69 (d, J ) 5.9 Hz), 117.87, 82.66,
67.66 (d, J ) 4.9 Hz), 64.41 (d, J ) 6.0 Hz), 27.85, 26.34 (d, J
) 8.3 Hz), 23.14 (J ) 175.6 Hz), 18.01 (d, J ) 2.8 Hz); 31P
NMR (162 MHz, CDCl3) δ 36.47; HRMS calcd for C12H21O5NP
(M + H)+ required 275.1048, found 275.1029.
P -Het er ocyclic, Allyl-ter t-b u t ylp h osp h on oa cet a t e
9
(Ma jor ). In a 50-mL round-bottom flask, diallyl-tert-buylphos-
phonoacetate 1b (1.5 g, 5.4 mmol) was dissolved in THF (15
mL) and the reaction was cooled to 0 °C. NaH (117 mg, 5.9
mmol) was added and the solution was stirred for 5 min,
followed by the addition of allyl bromide (590 mg, 4.9 mmol).
The progress of the reaction was monitored by GC; once com-
plete, the reaction was diluted with EtOAc and extracted with
H2O (2×) and brine (1×). The organic portion was dried (Na2-
SO4) then concentrated under reduced pressure and subjected
to flash chromatography (3:1 hexanes:EtOAc) to afford monoal-
lylated diallyl-tert-buylphosphonoacetate (1.5 g, 4.6 mmol,
85%) as a clear oil. Monoallylated diallyl-tert-buylphospho-
noacetate (530 mg, 1.7 mmol) was subjected to general RCM
procedure using Grubbs catalyst (69 mg, 0.08 mmol) and CH2-
Cl2 (34 mL). Flash chromatography (3:1 hexanes:EtOAc)
afforded two diastereomeric cyclic phosphonates 9 (0.488 mg,
94%) as a clear oil. Cuts containing a 13:1 mix of major to
minor were carried on for further reactions. FTIR 1728, 1393,
r-Cyclop en ten e Dim eth yl-ter t-bu tylp h osp h on oa ceta te
12. In a 50-mL round-bottom flask, dimethyl-tert-butylphospho-
noacetate 1a (2.4 g, 10.7 mmol) was dissolved in CH2Cl2 (20
t
mL) and the reaction was cooled to 0 °C. BuOK (3.6 g, 32.1
mmol) was added, the solution was stirred 5 min, followed by
the addition of allyl bromide (4.53 g, 37.5 mmol), and the
reaction progress was monitored by GC. Column chromatog-
raphy (2:1 hexanes:EtOAc) afforded bisallylated dimethyl-tert-
butylphosphonoacetate (2.0 g, 9.8 mmol, 92%) as clear oil. The
bisallylated precursor (1.6 g, 5.3 mmol) was subjected to
general metathesis conditions using Grubbs catalyst (216 mg,
0.3 mmol) in CH2Cl2 (104 mL). Flash chromatography (1:1
hexanes:EtOAc) afforded cyclic phosphonate 12 (1.4 g, 94%)
as a clear oil. FTIR 1724, 1393, 1369, 1255, 1158 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 5.63 (t, J ) 8.1 Hz, 2H), 3.79 (d,
J HP ) 10.6 Hz, 6H), 3.15-3.04 (m, 2H), 3.03-2.87 (m, 2H),
1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.37 (d, J CP
)
1
1369, 1254, 1148 cm-1; H NMR (400 MHz, CDCl3) δ 5.95-
2.6 Hz), 127.81 (d, J CP ) 8.4 Hz), 81.69, 53.28 (d, J CP ) 6.8
Hz), 53.08 (d, J CP ) 137.7 Hz), 38.99 (d, J ) 2.0 Hz), 27.56;
31P NMR (162 MHz, CDCl3) δ 30.89; HRMS calcd for C12H22O5P
(M + H)+ required 277.1205, found 277.1203.
5.78 (m, 2H), 5.67-5.55 (m, 1H), 5.30 (dd, J ) 17.1, 1.4 Hz,
1H), 5.17 (dd, J ) 10.4, 1.1 Hz, 1H), 4.68-4.63 (m, 4H), 3.09
(ddd, J HP ) 23.1 Hz, J HH ) 9.7 Hz, J HH ) 3.1 Hz, 1H), 2.75-
2.25 (m, 2H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.72
(d, J CP ) 5.1 Hz), 132.49 (d, J CP ) 6.7 Hz), 129.91, 127.02,
117.83, 82.06, 66.31 (d, J CP ) 6.4 Hz), 64.31 (d, J CP ) 5.6 Hz),
46.60 (d, J CP ) 124.3 Hz), 27.73, 23.57 (d, J CP ) 4.3 Hz); 31P
NMR (162 MHz, CDCl3) δ 25.84; HRMS calcd for C13H22O5P
(M + H)+ required 289.1205, found 289.1190.
r-Dia zo Meth yld im eth ylp h osp h on oa ceta te (13). The
starting phosphonoacetate (6.0 g, 33 mmol) was subjected to
general diazo transfer conditions (see compound 7), using tosyl
t
azide (7.8 g, 40 mmol) and BuOK (4.8 g, 45 mmol) in CH2Cl2
(100 mL). Flash chromatography (2:1 hexanes/EtOAc) afforded
Allylated P -Heter ocyclic, Allyl-ter t-bu tylph osph on oac-
eta te 10. In a 15-mL round-bottom flask, a 1:1 mix of
diastereomeric 9 (825 mg, 2.9 mmol) was dissolved in CH2Cl2
(5 mL) and the reaction was cooled to 0 °C. t-BuOK (642 mg,
6.14 g (89%) of 1a as a yellow oil. FTIR 2133, 1712, 1437, 1288
cm-1 1H NMR (400 MHz, CDCl3) δ 3.79 (d, J HP ) 16.7 Hz,
;
6H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.45 (d, J CP
) 50 Hz), 53.76 (d, J CP ) 22.7 Hz), 52.50; 31P NMR (162 MHz,
8128 J . Org. Chem., Vol. 67, No. 23, 2002

R-Boc-Aminophosphonate
CDCl3) δ 14.48; HRMS calcd for C5H10N2O5P (M + H)+
required 209.0327, found 209.0318.
0.91 mmol) was added. Once complete, the reaction mixture
was concentrated under reduced pressure, dissolved in EtOAc
(10 mL), washed with H2O and brine, dried (NaSO4), filtered,
and concentrated under reduced pressure. Flash chromatog-
raphy (1:1 hexanes/EtOAc) afforded acyl azide 15 as pure clear
oil (49 mg, 0.17 mmol, 99%). FTIR 2140, 1697, 1461, 1421,
1259 cm-1; 1H NMR (400 Mz, CDCl3) δ 5.90-5.84 (m, 2H), 3.91
(d, J HP ) 10.9 Hz, 3H), 3.87 (d, J HP ) 11.0 Hz, 3H), 3.40-3.11
(m, 2H), 2.94-2.83 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
171.20, 125.80 (d, J CP ) 10.3 Hz), 122.95, 55.16 (d, J CP ) 7.0
Hz), 54.73 (d, J CP ) 7.2 Hz), 52.27 (d, J CP ) 136.7 Hz), 29.18
(d, J CP ) 3.0 Hz), 25.21 (d, J CP ) 5.6 Hz); 31P NMR (162 MHz,
CDCl3) δ 21.08; HRMS calcd for C8H12N3O4PS (M + H)+
required 278.0364, found 278.0347.
P h osp h on a te Dien e Elim in a tion P r od u ct 17. R-Acy-
lazido phosphonate 16 (33 mg, 0.12 mmol) was dissolved in
1,2-dichlorobenzene (0.45 mL), and the resulting mixture was
exposed to microwave irradiation for 5-, 5-, 7-, 8-, 10-, 15-, and
15-min time periods. The reaction was monitored by GC, then
subjected to flash chromatography (hexanes, followed by 1:1
hexanes/EtOAc) to afford diene 17 as a pure yellow oil (11.1
mg, 50%). FTIR 1534, 1250 cm-1; 1H NMR (400 MHz, CDCl3)
δ 6.99 (J HP ) 18.7 Hz, J HH ) 5.7 Hz, 1H), 6.18-6.14 (m, 1H),
5.84-5.78 (m, 1H), 3.79 (d, J ) 11.3 Hz, 6H), 3.29 (ddd, J )
5.3, 2.7, 1.4 Hz); 13C NMR (100 MHz, CDCl3) δ 134.02 (d, J CP
) 9.3 Hz), 125.91 (d, J CP ) 16.2 Hz), 119.94, 119.90, 53.10 (d,
J CP ) 5.5 Hz), 24.17 (d, J CP ) 4.3 Hz); 31P NMR (162 MHz,
CDCl3) δ 17.94; HRMS calcd for C13H23O5PS2 (M + H)+
required 207.0245, found 207.0245.
r-Th ioh om oa llylic P h osp h on a te 14. In a 16 × 125 mm2
oven-dried pressure tube was placed the R-diazophosphonoac-
etate 13 and allyl sulfide in CH2Cl2. Rh2(OAc)4 (0.14 g, 0.32
mmol) was added (color change from green to dark purple) and
the pressure tube was flushed with argon, capped, and placed
in an oil bath at 85-90 °C. Flash chromatography (5:1 then
1.5:1 hexanes/EtOAc) afforded 0.85 g (80%) of R-thiohomoal-
lylic phosphonate 14 as a clear oil. FTIR 1727, 1637, 1456,
1
1394, 1369, 1256 cm-1; H NMR (400 MHz, CDCl3) δ 5.87-
5.74 (m, 2H), 5.19-5.03 (m, 4H), 3.84 (dd, J HP ) 10.7 Hz, J HH
) 1.6 Hz, 3H), 3.79 (dd, J HP ) 10.7 Hz, J HH ) 1.6 Hz, 3H),
3.55-3.43 (m, 2H), 2.86 (dddd, J ) 14.5, 7.7, 6.4, 1.2 Hz, 1H),
2.63 (dddd, J ) 15.0, 15.0, 7.37, 1.2 Hz, 1H), 1.43 (d, J ) 1.5
Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 166.51, 132.55, 132.03
(d, J CP ) 9.7 Hz), 118.61, 118.45, 83.20, 55.79 (d, J CP ) 143.0
Hz), 54.75 (d, J CP ) 7.3 Hz), 54.01 (d, J CP ) 7.5 Hz), 37.00 (d,
J CP ) 8.2 Hz), 33.60, 27.71; 31P NMR (162 MHz, CDCl3) δ
22.89; HRMS calcd for C14H26O5PS (M + H)+ required 337.1239,
found 337.1242.
Cyclic r-Th iop h osp h on oa ceta te 15. The starting R-thio-
homoallylicphosphonoacetate 14 (0.59 g, 1.8 mmol) was sub-
jected to general metathesis conditions utilizing Grubbs
catalyst (88 mg, 0.07 mmol) in CH2Cl2 (35 mL). Flash chro-
matography (1.5:1 hexanes/EtOAc) afforded 540 mg (99%) of
15 as a yellow oil. FTIR 1725, 1457, 1391, 1368, 1255 cm-1
;
1H NMR (400 MHz, CDCl3) δ 5.88-5.79 (m, 2H), 3.88 (d, J HP
) 10.7 Hz, 3H), 3.81 (d, J HP ) 10.9 Hz, 3H), 3.29-3.19 (m,
2H), 2.88-2.75 (m, 2H), 1.46 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 167.20 (d, J CP ) 3.3 Hz), 125.70 (d, J CP ) 8.6 Hz),
123.01, 82.98, 54.91 (d, J CP ) 7.0 Hz), 54.03 (d, J CP ) 7.2 Hz),
50.89 (d, J CP ) 136.8 Hz), 29.69 (d, J CP ) 2.1 Hz), 27.62, 25.55
(d, J CP ) 4.7 Hz), 31P NMR (162 MHz, CDCl3) δ 22.89; HRMS
calcd for C12H22O5PS (M + H)+ required 309.0926, found
309.0902.
Ack n ow led gm en t. This investigation was gener-
ously supported by partial funds provided by the Her-
man Frasch Foundation (442-HF97, administered by the
American Chemical Society) and the National Institutes
of Health (National Institute of General Medical Sci-
ences, RO1-GM58103). The authors also thank Dr.
David Vander Velde for assistance with NMR measure-
ments, Dr. Todd Williams for HRMS analysis, and Dr.
Douglas Powell for X-ray crystallographic analysis.
r-Acyla zid o P h osp h on a te 16. tert-Butylphosphonoacetate
15 (70 mg, 0.23 mmol) was dissolved in HCO2H (5 mL). Once
hydrolysis was complete, the reaction was concentrated under
reduced pressure. The crude acid (46 mg, 0.18 mmol) was
dissolved in CH2Cl2 (1 mL) and the solution was cooled to 0
°C. Oxalyl chloride (46 mg, 0.37 mmol) was added followed by
the addition of 1 drop of DMF. Once gas extrusion subsided,
the reaction mixture was concentrated under reduced pressure.
The resulting red oil was dissolved in CH3CN (1 mL) and
cooled to 0 °C. A saturated aqueous solution of NaN3 (59 mg,
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and 31P
NMR spectra of new compounds as well as X-ray data for
compounds 2, 4, and 11. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0262208
J . Org. Chem, Vol. 67, No. 23, 2002 8129