A temporary phosphorus tether/ring-closing metathesis strategy to functionalized 1,4-diamines

Article abstract of DOI:10.1021/ol016828n

equation presented The synthesis of 1,4-diamines containing the (Z)-1,4-diaminobut-2-ene subunit via a temporary phosphorus tether/RCM strategy is described. We have developed a new method utilizing phosphorus nuclei as suitable temporary tethers for the

Full text of DOI:10.1021/ol016828n

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3939-3942
A Temporary Phosphorus Tether/
Ring-Closing Metathesis Strategy to
Functionalized 1,4-Diamines
Kevin T. Sprott, Matthew D. McReynolds, and Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582
phanson@ku.edu
Received September 27, 2001
ABSTRACT
The synthesis of 1,4-diamines containing the (Z)-1,4-diaminobut-2-ene subunit via a temporary phosphorus tether/RCM strategy is described.
We have developed a new method utilizing phosphorus nuclei as suitable temporary tethers for the coupling of nonracemic allylic amines.
This approach allows for the generation of C -symmetric and unsymmetric 1,4-diamines 1−3, which may have considerable synthetic and
2
biological utility. This represents the first synthetic pathway for the expedient coupling of two amines via a temporary tether approach.
Recently, nonracemic 1,4-diamines have served as key
synthetic intermediates in the development of potent cyclic
HIV protease inhibitors.1 In addition, the potential of
nonracemic 1,4-diamines to serve as biologically active
agents2 and asymmetric ligands3 warrants continued efforts
toward an efficient route to their synthesis. Previous methods
reported for the generation of nonracemic 1,4-diamines
include intermolecular pinacol coupling of R-amino alde-
hydes4 and several chiral pool syntheses starting from
tartrate1b or mannitol.1d Our interest in the ring-closing
metathesis5 (RCM) reaction on phosphorus templates6 has
led us to investigate a temporary phosphorus tether (P-tether)/
RCM strategy to the synthesis of 1,4-diamines.
(1) (a) Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru,
Y.; Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y. N.;
Chang, C.-H.; Weber, P. C.; Jackson, D. A.; Sharpe, T. R.; Erickson-
Vittanen, S.; Science 1994, 263, 380-384. (b) Patel, M.; Kaltenbach, R.
F., III; Nugiel, D. A.; McHugh, R. J., Jr.; Jadhav, P. K.; Bacheler, L. T.;
Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S.; Garber, S.; Reid, C.;
Seitz, S. P. Bioorg. Med. Chem. Lett. 1998, 8, 1077-1082. (c) De Lucca,
G. V J. Org. Chem. 1998, 63, 4755-4766. (d) Hulte´n, J.; Bonham, N. M.;
Nillroth, U.; Hansson, T.; Zuccarello, G.; Bouzide, A.; Åqvist, J.; Classon,
B.; Danielson, U. H.; Karle´n, A.; Kvarnstro¨m, I.; Samuelsson, B.; Hallberg,
A. J. Med. Chem. 1997, 40, 885-897.
(2) For examples of biologically active 1,4-diamines, see: (a) Rische,
T.; Eilbracht, P. Tetrahedron 1999, 55, 3917-3922 and refs 1-4 cited
therein. (b) He, Z.; Nadkarni, D. V.; Sayre, L. M.; Greenaway, F. T. Biochim.
Biophys. Acta 1995, 1253, 117-127. For the use of 1,4-diamines as
dipeptide isosteres, see: (c) Baker, W. R.; Condon, S. L. J. Org. Chem.
1993, 58, 3277-3284.
Although temporary tethers7 have been extensively utilized
in organic synthesis,8,9 examples of P-tethers have been
(4) Konradi, A. W.; Pedersen, S. F. J. Org. Chem. 1992, 57, 28-32.
(5) For recent reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3013-3043. (c) Wright, D. L. Curr. Org. Chem. 1999, 3, 211-240. (d)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (e) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388.
(6) (a) Stoianova, D. S.; Hanson, P. R. Org. Lett. 2000, 2, 1769-1772.
(b) Sprott, K. T.; McReynolds, M. D.; Hanson, P. R. Synthesis 2001, 612-
620 and references therein. (c) Stoianova, D. S.; Hanson, P. R. Org. Lett.
2001, 3, 3285-3288.
(3) For examples of 1,4-diamines and their derivatives serving as ligands
for metals, see: (a) Nivorozhkin, A. L.; Toftlund, H.; Jøergensen, P. L.;
Nivorozhkin, L. E. J. Chem. Soc., Dalton Trans. 1996, 1215-1221. (b)
Fritsky, I. O.; Kozlowski, H.; Prisyazhnaya, E. V.; Karaczyn, A.; Kalibab-
chuk, V. A.; Glowiak, T. J. Chem. Soc., Dalton Trans. 1998, 1535-1536.
(c) Codina, G.; Caubet, A.; Lopez, C.; Moreno, V.; Molins, E. HelV. Chim.
Acta 1999, 82, 1025-1037.
(7) For a comprehensive review on disposable tethers, see: Gauthier,
D. R., Jr.; Zandi, K. S.; Shea, K. J. Tetrahedron 1998, 54, 2289-2338.
(8) For a review on temporary silicon-tethered (Si-tethered) reactions,
see: (a) Fensterbank, L.; Malacria, M.; Sieburth, S. M. Synthesis 1997, 8,
813-854. For additional references on Si-tethered reactions, see: (b)
Ishikawa, T.; Kudo, T.; Shigemori, K.; Saito, S. J. Am. Chem. Soc. 2000,
122, 7633-7637. (c) Shuto, S.; Yahiro, Y.; Ichikawa, S.; Matsuda, A. J.
10.1021/ol016828n CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/27/2001

limited.10 We now report a new strategy that allows for the
rapid coupling of nonracemic allylic amines via a P-tether/
RCM sequence11,12 to derive Z-olefinic, C2-symmetric 1,4-
diamines 1 and 2 and unsymmetric, differentially substituted
1,4-diamines 3 (Scheme 1).13
Scheme 1
Figure 1.
diazaphosphepine 2-oxides such as A and B (Figure 1).6b,12c
These compounds and analogues thereof are similar in
structure to DMP-323 and other potent HIV-1 protease
inhibitors developed at DuPont Merck Laboratories.1a-c We
determined that in order to generate phosphonamides such
as A (R3 ) alkyl, aryl), containing exocyclic R-amino
substitution, it is necessary to overcome steric congestion
imposed by an R-branched secondary amine by first syn-
thesizing the 1,4-diamine 1,14 coupling it with R3PCl2, and
oxidizing at phosphorus.12c
Our initial strategy for the synthesis of A was to couple 2
equiv of an R-branched secondary allylic amine, such as 7,
with either a P(V)- or P(III)-dichloride, followed by RCM
(Scheme 2). However, we found that, due to steric congestion
Our new method employs both intermediate phosphorous
acid diamide 4 and phosphonamide species 5 and 6 contain-
ing P(III)- and P(V)-nuclei, respectively, as the central lynch-
pins for subsequent RCM (Scheme 1). The temporary cyclic
P-tethers can be quantitatively hydrolyzed under mild acidic
conditions to derive the title 1,4-diamines 1-3 containing
the (Z)-1,4-diaminobut-2-ene subunit.
Scheme 2a
Our primary interest in C2-symmetric 1,4-diamines 1 was
rooted in our efforts to synthesize amino acid-derived 1,3,2-
Org. Chem. 2000, 65, 5547-5557. (d) Miyata, O.; Nishiguchi, A.;
Ninomiya, I.; Aoe, K.; Okamura, K.; Naito, T. J. Org. Chem. 2000, 65,
6922-6931. (e) Rubinstenn, G.; Mallet J.-M.; Sinay, P. Tetrahedron Lett.
1998, 39, 3697-3700.
(9) For examples of metal-derived temporary tethers, see the following.
Mg and Al tethers: (a) Stork, G.; Chan, T. Y. J. Am. Chem. Soc. 1995,
117, 6595-6596. Boron tethers: (b) Batey, R. A.; Thadani, A. N.; Lough,
A. J. J. Am. Chem. Soc. 1999, 121, 450-451. Al and Zn tethers: (c)
Bertozzi, F.; Olsson, R.; Frejd, T. Org. Lett. 2000, 2, 1283-1286.
(10) For an example of a phosphoramidic P(V) temporary tether, see:
Rubinstenn, G.; Esnault, J.; Mallet, J.-M.; Sinay, P. Tetrahedron: Asymmetry
1997, 8, 1327-1336. To the best of our knowledge, there are no examples
in the literature of utilizing P(III) as a temporary tether.
(11) For examples of silicon tethers utilized in the RCM reaction, see:
(a) Evans, P. A.; Murthy, V. S. J. Org. Chem. 1998, 63, 6768-6769. (b)
Hoye, T. R.; Promo, M. A. Tetrahedron Lett. 1999, 40, 1429-1432. (c)
Gierasch, T. M.; Chytil, M.; Didiuk, M. T.; Park, J. Y.; Urban, J. J.; Nolan,
S. P.; Verdine, G. L. Org. Lett. 2000, 2, 3999-4002. (d) Lobbel, M.; Koll,
P. Tetrahedron: Asymmetry 2000, 11, 393-396.
a Reagents and conditions: (a) i. PCl3, Et3N, DMAP, CH2Cl2,
reflux, ii. H2O, 80-90%; (b) i. 9, benzene, reflux, >95%, ii.
methanolic HCl, rt, >95%.
(12) For other tethers utilized in the RCM reaction, see the following.
Catechol tethers: (a) O’Leary, D. J.; Miller, S. J.; Grubbs, R. H. Tetrahedron
Lett. 1998, 39, 1689-1690. Ketone tethers: (b) Rodriguez, J. R.; Castedo,
L.; Mascarenas, J. L. Org. Lett. 2000, 2, 3209-3212. Phthalamide tethers:
(c) Sprott, K. T.; Hanson, P. R. J. Org. Chem. 2000, 65, 7913-7918.
(13) For other methods of producing simple, unsaturated 1,4-diamines,
see: (a) Radhakrishnan, U.; Al-Masum, M.; Yamamoto, Y. Tetrahedron
Lett. 1998, 39, 1037-1040. (b) Courtois, G.; Desre, V.; Miginiac, L. J.
Organomet. Chem. 1999, 580, 178-187. For a recent method of producing
saturated 1,4-diamines, see ref 2a. (c) To the best of our knowledge, no
general method exists for the preparation of nonracemic, differentially
substituted 1,4-diamines.
imposed by 7, the only phosphorus reagent which allowed
the bis-coupling event to occur was phosphorus trichloride.6b
Hydrolysis to 8, followed by RCM with the first generation
Grubbs catalyst,15a,b afforded 1,3,2-diazaphosphepine 2-oxide
10.
(14) We have reported the synthesis of 1,4-diamine 1a (Scheme 2) via
a phthalamide tether/RCM/hydrolysis sequence. RCM yielded predominantly
the Z-isomer (10:1 Z:E), see ref 12c.
3940
Org. Lett., Vol. 3, No. 24, 2001

Due to the lability of the P-N bond to hydrolysis in cyclic
species 10,16 we reasoned that we could employ the
phosphorous acid diamide moiety as a P(III)-temporary tether
in a one-pot RCM/hydrolysis procedure (Scheme 2). Opti-
mization of the previously reported conditions6b provides
acyclic RCM precursors 8 in 80-90% yield. Subsequent
RCM utilizing the second generation Grubbs catalyst 915c,17
in refluxing benzene, followed by facile cleavage18 of the
P-tether with methanolic HCl, results in quantitative yields
of C2-symmetric 1,4-diamine 1 with complete stereochemical
and geometrical integrity. Furthermore, the RCM reaction
is complete within several minutes, reaction scale is a
nonissue, and the RCM/hydrolysis sequence is a single-pot
event.
Scheme 3a
a Reagents and conditions: (a) RP(O)Cl2 (12a,R ) OPh; 12b,
R ) Ph), Et3N, DMAP, CH2Cl2, reflux, R ) OPh, >95%, R ) Ph,
84%; (b) i. 9, benzene, reflux, ii. HCl/H2O/THF, 50 °C, R ) OPh,
91%, R ) Ph, 70%.
A number of other temporary tethers were also investi-
gated,19 including various metals9a,c (Cu, Fe, Mn, Mg, and
Ni), as well as carbon (CO) and boron9b (BPh). Thus far,
none have allowed this facile “di-amine” binding/metathesis
sequence to occur. Our group previously reported an RCM
strategy to generate cyclic sulfamides analogous to 10;20
however, the inability to effectively cleave the sulfamide
linkage (R2NSO2NR2) under mild conditions limits their
utility in the production of 1,4-diamines such as 1-3.
Moreover, while temporary silicon tethers11 have been
employed in the RCM reaction to access 1,4-diols, all of
our attempts to prepare 1 from 7 utilizing silicon tethers
(SiPh2, SiMe2, and SiCl2) have been unsuccessful. We have
found that not only does phosphorus appear to be the sole
nucleus in which this 1,4-diamine chemistry is successful
but the efficiency and ease of the sequence is extraordinary.
With this temporary bridging strategy in hand, we turned
our attention to the synthesis of C2-symmetric 1,4-diamine
2, containing branching at the allylic positions (Scheme 3).
Previously, we found that less sterically encumbering
R-branched primary amines, such as L-valine-derived 11,21
readily couple twice with P(V)-dichloride 12a to give 13a
in high yield.6b In addition, we and others22 have shown that
the reaction between phosphorus oxychloride (POCl3) and
3 equiv of an R-branched primary amine, such as 11, is facile
to afford the corresponding phosphoramide.23 Therefore, it
was crucial in the synthesis of diamine 2 to use RP(O)Cl2
(R * Cl), where R serves as an ancillary blocking group to
prevent the formation of the triply coupled product. Subse-
quent RCM using catalyst 9, followed by in situ hydrolysis
of the P(V)-tether under slightly more forcing conditions (50
°C), generates 1,4-diamine 2.
To extend the scope of utilizing temporary P-tethers, we
directed our efforts toward the synthesis of unsymmetric,
differentially substituted 1,4-diamines such as 3 (Scheme 4).
Scheme 4a
(15) For the first generation Grubbs catalyst, see: (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. For the second generation Grubbs catalyst, see: (c)
Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-
956.
a Reagents and conditions: (a) 7a, Et3N, DMAP, CH2Cl2, reflux,
>95%, ds ) 1.1:1.0;24 (b) 11, Et3N, DMAP, CH2Cl2, 0 °C, 88%,
ds ) 6.6-13.2:1.0; (c) i. 17, CH2Cl2, reflux, ii. methanolic HCl,
50 °C, 97%.
(16) 1,3,2-Diazaphosphepine 2-oxide 10 hydrolyzed after prolonged
storage at 0 °C (2-3 weeks).
(17) RCM with the traditional Grubbs benzylidene catalyst15a,b occurs
in excellent yields with most substrates if the reaction was performed on
small scale (<500 mg). Reaction times varied from 1 to 24 h.
(18) No transesterification was observed during the tether cleavage
procedure when benzyl esters were employed, as in 1c and 1d.
(19) Details of the unsuccessful attempts with other tethers are provided
in the Supporting Information.
(20) Dougherty, J. M.; Probst, D. A.; Robinson, R. E.; Moore, J. D.;
Klein, T. A.; Snelgrove, K. A.; Hanson, P. R. Tetrahedron 2000, 56, 9781-
9790 and references therein.
Prior work in our laboratory revealed that only 1 equiv of
an N-allylated, R-branched amino ester, such as 7a, couples
with P(V)-dichlorides, such as methylphosphonic dichloride
(14), to give an ∼1.1:1.0 diastereomeric mixture of phos-
phonamidic monochloridates 15.24 We reasoned that this
monochloridate, 15, would serve as an ideal intermediate in
the production of the differentially substituted 1,4-diamine
3. Therefore, addition of primary amine 11 to the diastere-
(21) (a) Fehrentz, J.-A.; Castro, B. Synthesis 1983, 676-678. (b) Saari,
W. S.; Fisher, T. E. Synthesis 1990, 453-454.
(22) (a) Unpublished results from our laboratory. Our findings are in
agreement with Wills and co-workers who have reported that 3 equiv of
(R)-R-methyl benzylamine couple readily with POCl3 to provide the
corresponding phosphoramide, see: (b) Burns, B.; Studley, J. R.; Wills,
M. Tetrahedron Lett. 1993, 34, 7105-7106.
(23) This is in sharp contrast with our report that the addition of
R-branched secondary amines such as 7 to POCl3 occurs only once to give
the phosphonamidic dichloridate, see ref 6b.
(24) Sprott, K. T.; Hanson, P. R. J. Org. Chem 2000, 65, 4721-4728.
Org. Lett., Vol. 3, No. 24, 2001
3941

omeric mixture of 15 produces the unsymmetric metathesis
precursor 16 in high yield and with good to high diastereo-
selectivity (ds 6.6-13.2:1.0).25 Metathesis utilizing the first
generation Grubbs catalyst15a,b 17, followed by in situ acid-
mediated methanolic cleavage of the P(V)-tether, affords
unsymmetric 1,4-diamine 3 in near quantitative yield.
The strengths of this new P-tether strategy are reflected
in the ease in which the chiral, nonracemic 1,4-diamines can
be synthesized. Not only is the RCM/hydrolysis sequence a
single-pot event but chromatography is required only after
the initial phosphorus/amine coupling. Moreover, the 1,4-
diamines 1-3 can be obtained in high purity by simple acid/
base extraction following the cleavage of the temporary
P-tether (>99% purity as determined by GC and >95%
diamines 1-3 via a P-tethered RCM/hydrolysis sequence,
of which the P(III)-tether represents the first of its kind.10
To our knowledge, this approach represents the first synthetic
pathway that allows for the expedient coupling of two amines
via a facile temporary tether approach. Furthermore, we have
demonstrated the P-tether strategy to be an effective route
to the synthesis of unsymmetric, differentially substituted
1,4-diamines. The synthetic and biological potential of the
1,4-diamines and analogues thereof is currently being
investigated and will be reported in due course.
Acknowledgment. This investigation was generously
supported by funds provided by the National Institutes of
Health (National Institute of General Medical Sciences, RO1-
GM58103). The authors also thank Dr. Martha Morton and
Dr. David Vander Velde for their assistance with NMR
measurements and Dr. Todd Williams for HRMS analysis.
1
purity as determined by H, 13C, and 31P NMR analysis).
We have demonstrated the efficacy of this sequence by
generating as much as 10 g of 1,4-diamines 1b in a single
afternoon starting from N-allylated amino esters 7b.
In summary, we have developed an efficient method to
synthesize C2-symmetric and unsymmetric, nonracemic 1,4-
Supporting Information Available: Experimental pro-
cedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
(25) The unambiguous assignment of the major diastereomer, as well as
mechanistic rationale for the observed selectivity, is currently being
investigated.
OL016828N
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Org. Lett., Vol. 3, No. 24, 2001