A Concise Route to Structurally Diverse DMP 323 Analogues via Highly Functionalized 1,4-Diamines

Article abstract of DOI:10.1021/ol027074v

(Matrix Presented) The utility of functionalized 1,4-diamines, produced via a temporary phosphorus tether (P-tether)/ring-closing metathesis (RCM)/hydrolysis sequence, is demonstrated in the synthesis of structurally diverse DMP 323 analogues. These 1,4-d

Full text of DOI:10.1021/ol027074v

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4673-4676
A Concise Route to Structurally Diverse
DMP 323 Analogues via Highly
Functionalized 1,4-Diamines
Matthew D. McReynolds, Kevin T. Sprott, and Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582
phanson@ku.edu
Received October 10, 2002
ABSTRACT
The utility of functionalized 1,4-diamines, produced via a temporary phosphorus tether (P-tether)/ring-closing metathesis (RCM)/hydrolysis
sequence, is demonstrated in the synthesis of structurally diverse DMP 323 analogues. These 1,4-diamines are transformed into various
seven-membered heterocycles via insertion of the appropriate nuclei “X”. Subsequent derivatization generates heterocyclic diols that are
similar in structure to DMP 323, a notable member of a class of highly potent inhibitors of HIV protease.
Temporary tethers have become powerful tools in organic
synthesis to expedite the assembly of complex molecules.1,2
Our interest in the development of new methods involving
organophosphorus compounds3 has led us to explore the
utility of temporary phosphorus tethers (P-tethers) toward
the synthesis of biologically relevant targets. We have
recently described a highly efficient method employing
P-tethers in conjunction with ring-closing metathesis4 (RCM)
to assemble functionalized 1,4-diamines containing the (Z)-
1,4-diamino-but-2-ene subunit.5 Although temporary tethers
have been used in a wide variety of synthetic applications,1,2
to our knowledge this report was the first example of the
rapid tethering and subsequent coupling of two amines using
a mononuclear tether.6 In the report described herein, the
utility of various 1,4-diamines produced using our temporary
P-tether protocol is demonstrated in the synthesis of an array
of seven-membered heterocycles analogous to DMP 323.
Cyclic ureas DMP 323 and DMP 450 are notable members
of a promising class of highly potent HIV protease inhibitors
initially developed at DuPont Merck Laboratories (Scheme
(1) For a comprehensive review on disposable tethers, see: (a) Gauthier,
D. R., Jr.; Zandi, K. S.; Shea, K. J. Tetrahedron 1998, 54, 2289-2338. For
recent examples of temporary tethers used in organic synthesis, see: (b)
Crimmins, M. T.; Hauser, E. B. Org. Lett. 2000, 2, 281-284. (c) Bertozzi,
F.; Olsson, R.; Frejd, T. Org. Lett. 2000, 2, 1283-1286. (d) Sukeda, M.;
Shuto, S.; Sugimoto, I.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2000, 65,
8988-8996. (e) Chebolu, R.; Zhang, W.; Galoppini, E.; Gilardi, R.
Tetrahedron Lett. 2000, 41, 2831-2834.
(2) For use of tethers in RCM reactions, see: (a) O’Leary, D. J.; Miller,
S. J.; Grubbs, R. H. Tetrahedron Lett. 1998, 39, 1689-1690. (b) Evans, P.
A.; Murthy, V. S. J. Org. Chem. 1998, 63, 6768-6769. (c) Hoye, T. R.;
Promo, M. A. Tetrahedron Lett. 1999, 40, 1429-1432. (d) 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) Rodriguez, J. R.; Castedo, L.;
Mascarenas, J. L. Org. Lett. 2000, 2, 3209-3212. (e) Sprott, K. T.; Hanson,
P. R. J. Org. Chem. 2000, 65, 7913-7918. (f) Sakamoto, Y.; Okazaki, M.;
Miyamoto, K.; Nakata, T. Tetrahedron Lett. 2001, 42, 7633-7636. (g)
Micalizio, G. C.; Schreiber, S. L. Angew. Chem., Int. Ed. 2002, 41, 152-
154.
(4) 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) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-
4450. (d) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-
388.
(3) Moore, J. D.; Sprott, K. T.; Wrobleski, A. D.; Hanson, P. R. Org.
Lett. 2002, 4, 2357-2360. (b) Stoianova, D. S.; Hanson, P. R. Org. Lett.
2001, 3, 3285-3288. (c) Sprott, K. T.; McReynolds, M. D.; Hanson, P. R.
Synthesis 2001, 612-620 and references therein. (d) Stoianova, D. S.;
Hanson, P. R. Org. Lett. 2000, 2, 1769-1772.
(5) Sprott, K. T.; McReynolds, M. D.; Hanson, P. R. Org. Lett. 2001, 3,
3939-3942. All 1,4-diamines described in this manuscript were prepared
using this protocol.
(6) We have also reported the synthesis of 1,4-diamines via a phthalamide
tether/RCM/hydrolysis sequence; see ref 2e.
10.1021/ol027074v CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/04/2002

diverse set of heterocycles analogous to DMP 323, including
cyclic ureas 1, phosphonamides 2, and sulfamides 3 (Scheme
1). The seven-membered heterocyclic diols 1-3 are derived
from 1,4-diamines 4 via insertion of the appropriate nuclei
“X,” followed by osmium-mediated dihydroxylation. As
previously demonstrated, 1,4-diamines 4 are accessed via a
RCM/hydrolysis sequence upon P-tethered amines 5, which
can be constructed following appropriate choice of both the
P-tether [P(III) or P(V)] and the allylic amines.5 For the initial
studies contained in this report, the more readily available,
L-amino acid derived allylic amines were employed to
establish our new method.10
Scheme 1
To this end, we applied the strategy above to the synthesis
of both C2-symmetric and unsymmetric14 cyclic ureas en
route to DMP 323 analogues (Scheme 2). Following the
Scheme 2a
1).7 The synthesis of these compounds involved the use of
a 1,4-diamine synthon of the general structure A as the key
synthetic intermediate.8 Carbonylation, followed by N-
benzylation, provided cyclic ureas with substituents occupy-
ing the P1/P1′/P2/P2′ positions. Extensive investigations were
carried out to elucidate the effects of varying P1/P1′/P2/P2′
residues,9 as well as P1/P1′ and hydroxyl group stereochem-
istry.10 It was found that each of these factors significantly
influence inhibitor potency by accentuating hydrophobic (P1/
P1′), hydrogen bonding (P2/P2′), and catalytic aspartate (diol
functionality) interactions with the enzyme. Although cyclic
ureas have been the most widely examined, independent
studies by DuPont Merck,11 Hallberg and co-workers,12 and
Karle´n and co-workers13 have also shown that sulfamide
analogues of DMP 323 display high inhibitory activity.
With each of these points in mind, we reasoned our
P-tether strategy would allow for the rapid assembly of a
a Reagents and conditions: (a) CDI, CH2Cl2, reflux, 69% 6a;
(b) CDI, tetrachloroethane, reflux, 71% 6b; (c) BnBr, KOtBu, THF,
78% 7a, 81% 7b; (d) (Cl3CO)2CO, Et3N, CH2Cl2, -78 °C, 38%;
(e) CDI, CH2Cl2, reflux, 46%; (f) BnBr, KHMDS, 18-crown-6,
THF, -78 to 0 °C, 71%.
(7) Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru,
Y.; Bachelor, 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) De Lucca, G. V.; Lam, P. Y.
S. Drugs Future 1998, 23, 987-994 and references therein.
(8) Nugiel, D. A.; Jacobs, K.; Worley, T.; Patel, M.; Kaltenbach, R. F.,
III; Meyer, D. T.; Jadhav, P. K.; De Lucca, G. V.; Smyser, T. E.; Klabe, R.
M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. J. Med. Chem. 1996, 39,
2156-2169. (b) Pierce, M. E.; Harris, G. D.; Islam, Q.; Radesca, L. A.;
Storace, L.; Waltermire, R. E.; Wat, E.; Jadhav, P. K.; Emmett, G. C. J.
Org. Chem. 1996, 61, 444-450. (c) Confalone, P. N.; Waltermire, R. E. In
Process Chemistry in the Pharmaceutical Industry; Gadamasetti, K. G.,
Ed.; Marcel Dekker: New York, 1999; pp 201-219.
DuPont Merck protocol,8 C2-symmetric cyclic ureas 7 with
substituents occupying P1/P1′/P2/P2′ positions were gener-
ated by carbonylation and subsequent N-benzylation of
primary 1,4-diamines 4a,b.15 Optimal conditions for carbo-
nylation of secondary 1,4-diamine 4c involved the use of
triphosgene to furnish C2-symmetric urea 8 where R-amino
substitution occupies the exocyclic P2/P2′ positions.16 In a
(12) 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. (b) Hulte´n, J.; Andersson, H. O.; Schaal, W.; Danielson, H. U.; Classon,
B.; Kvarnstro¨m, I.; Karle´n, A.; Unge, T.; Samuelsson, B.; Hallberg, A. J.
Med. Chem. 1999, 42, 4054-4061.
(13) Schaal, W.; Karlsson, A.; Ahlsen, G.; Lindberg, J.; Andersson, H.
O.; Danielson, U. H.; Classon, B.; Unge, T.; Samuelsson, B.; Hulte´n, J.;
Hallberg, A.; Karle´n, A. J. Med. Chem. 2001, 44, 155-169.
(14) Unsymmetric DMP 323 derivatives are of particular interest due to
their potential to exhibit different solubility and inhibitory profiles relative
to their C2-symmetric counterparts; see: (a) Wilkerson, W. W.; Dax, S.;
Cheatham, W. W. J. Med. Chem. 1997, 40, 4079-4088. (b) De Lucca, G.
V.; Kim, U. T.; Liang, J.; Cordova, B.; Klabe, R. M.; Garber, S.; Bacheler,
L. T.; Lam, G. N.; Wright, M. R.; Logue, K. A.; Erickson-Viitanen, S.;
Ko, S. S.; Trainor, G. L. J. Med. Chem. 1998, 41, 2411-2423. (c) 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.
(9) For evalutation of P1/P1′ substituents, see: (a) Nugiel, D. A.; Jacobs,
K.; Cornelius, L.; Chang, C.-H.; Jadhav, P. K.; Holler, E. R.; Klabe, R.
M.; Bacheler, L. T.; Cordova, B.; Garber, S.; Reid, C.; Logue, K. A.; Gorey-
Feret, L. J.; Lam, G. N.; Erickson-Vittanen, S.; Seitz, S. P. J. Med. Chem.
1997, 40, 1465-1474. (b) Patel, M.; Bacheler, L. T.; Rayner, M. M.;
Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S.; Seitz, S. P. Bioorg.
Med. Chem. Lett. 1998, 8, 823-828. For evalutation of P2/P2′ substituents,
see: (c) Han, Q.; Chang, C.-H.; Li, R.; Ru, Y.; Jadhav, P. K.; Lam, P. Y.
S. J. Med. Chem. 1998, 41, 2019-2028. (d) Rodgers, J. D.; Johnson, B.
L.; Wang, H.; Erickson-Viitanen, S.; Klabe, R. M.; Bacheler, L.; Cordova,
B. C.; Chang, C.-H. Bioorg. Med. Chem. Lett. 1998, 8, 715-720.
(10) DuPont Merck concluded that the optimal stereochemical config-
uration of endocyclic substituted ureas is (4R,5S,6S,7R), as demonstrated
in DMP 323 (Scheme 1). However, a model study (Ar ) Ph) revealed that
the analogous cis-diol (RSRR) exhibited comparable HIV protease binding
affinity (Ki ) 6.0 nM) relative to the trans-diol (RSSR, Ki ) 3.6 nM); see:
Kaltenbach, R. F., III; Nugiel, D. A.; Lam, P. Y. S.; Klabe, R. M.; Seitz,
S. P. J. Med. Chem. 1998, 41, 5113-5117.
(11) De Lucca, G. V J. Org. Chem. 1998, 63, 4755-4766.
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Org. Lett., Vol. 4, No. 26, 2002

manner similar to the synthesis of 6a, unsymmetric cyclic
urea 10 was prepared from unsymmetric 1,4-diamine 4d.
Although a direct RCM approach to seven-membered cyclic
ureas 6-10 would be ideal, our repeated attempts to affect
RCM upon acyclic urea dienes were unsuccessful. A detailed
account of these findings is forthcoming.
Scheme 4a
Our interest in P-heterocycles has recently driven our
efforts toward phosphorus-containing analogues of DMP 323,
where the phosphonyl group serves as a carbonyl surrogate.
P-Heterocycles 11 were initially targeted, where exocyclic
R-amino substitution occupies the P2/P2′ positions (Scheme
3). We previously reported that a direct RCM approach to
a Reagents and conditions: (a) SOCl2, Et3N, CH2Cl2, 68%; (b)
SO2Cl2, Et3N, CH2Cl2, no reaction; (c) H2NSO2NH2, pyridine,
reflux, no reaction using 4c, >95% using 4d; (d) BnBr, K2CO3,
CH3CN, 70 °C, 92%.
Scheme 3
4c in the formation of unsymmetric sulfamide 13. As
anticipated, subjection of 4d to a solution of sulfamide in
refluxing pyridine smoothly yields 13. N-Benzylation pro-
vides unsymmetric seven-membered sulfamide 14.
We next focused our attention on metathesis product 16a
in order to produce unsymmetric phosphorus-containing
analogues of DMP 323 (Scheme 5). While initially utilizing
1,3,2-diazaphosphepine-2-oxides 11 (R3 * H) is not feasible
because of the inability to generate the corresponding acyclic
phosphonamide diene precursors.2e,3c Consequently, it is
necessary to first synthesize the C2-symmetric 1,4-diamines
4c,e-g, followed by coupling with a phosphorus dichloride.
As a result of the steric demands imposed by R-branched,
secondary 1,4-diamines 4c,e-g, coupling with P(V)-dichlo-
rides was unsuccessful to give 11. To overcome this steric
congestion, P(III)-dichlorides (R3PCl2) were implemented.
Subsequent oxidization at phosphorus yielded 11 containing
R-amino substitution at P2/P2′.
Scheme 5
In an attempt to utilize 1,4-diamines 4c,e-g in the
synthesis of sulfamide analogues of 11, we observed a
reactivity profile comparable to that described in Scheme 3.
Whereas 1,4-diamine 4c coupled successfully with thionyl
chloride (SOCl2) to yield pseudo-C2-symmetric 1,2,7-thia-
diazepane-1-oxide 12, 4c did not react with sulfuryl dichlo-
ride17 (SO2Cl2) or sulfamide12a (H2NSO2NH2) to yield the
analogous C2-symmetric sulfamide (Scheme 4).18,19 We
surmised that unsymmetric 1,4-diamine 4d, being less
sterically hindered due to the presence of a primary amino
group, would exhibit different reactivity relative to that of
16a as a temporary P-tethered substrate en route to 4d,5 we
found that good levels of diastereoselectivity (ca. 7-13:1)
were achieved in the formation of acyclic phosphonamide
15a; however, the absolute stereochemistry at phosphorus
was not immediately determined. We deemed it necessary
to first determine the stereochemistry at phosphorus prior to
dihydroxylation.20 As a result, the (S)-configuration at
phosphorus (PS) was unambiguously assigned to the major
diastereomer using X-ray crystallographic analysis of the
crystalline derivative major-16c.21
Conversion of the cyclic olefin to the diol via cis-
dihydroxylation is the final step toward the title DMP 323
analogues.10 Thus, osmium-mediated dihydroxylation was
carried out on various seven-memberd heterocyclic alkenes,
(15) We have developed a direct RCM route to both sulfamide and
phosphonamide analogues of 6. For sulfamide derivative, see: 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. For phosphonamide
derivative, see ref 3c.
(16) Since 4c was completely consumed during the course of this reaction,
the low isolated yield of 8 could be attributed to competing oligomer
formation; see: McCusker, J. E.; Grasso, C. A.; Main, A. D.; McElwee-
White, L. Org. Lett. 1999, 1, 961-964.
(17) Although SO2Cl2 reacts with primary amines to afford sulfamides
(see ref 15), SO2Cl2 is a notoriously poor electrophile toward secondary
amines; see: Barluenga, J.; Lopez-Ortiz, J. F.; Tomas, M.; Gotor, V. J.
Chem. Soc., Perkin Trans. 1 1981, 1891-1895.
(18) We postulate that the steric congestion of the 1,4-diamines 4c,e-g,
as well as subtle steric and electronic differences in the electrophiles,
contribute to the failure of this reaction. See refs 2e and 17.
(19) For our direct RCM strategy to generate cyclic sulfamides analogous
to 12 and related to 14, see ref 15.
(20) We initially believed that the phosphonyl moiety could serve as a
stereodirecting group to augment the inherent diastereofacial bias for
dihydroxylation anti to the isopropyl group.
(21) While major-16c exists as colorless crystals, 15a-c and major-
16a,b exist as colorless oils. Consequently, the unambiguous assignment
of the (S)-configuration at phosphorus for major-16a was accomplished
using the following 31P NMR correlation experiment: the major diastereo-
mers in both the acyclic and cyclic phosphonamides 15 and 16, respectively,
exhibit a downfield chemical shift in the 31P NMR relative to the minor
diastereomers. This evidence supports the PS assignment for major-16a.
See Table 2 in the Supporting Information for details of the 31P NMR
correlation experiment, as well as X-ray data for major-16c.
Org. Lett., Vol. 4, No. 26, 2002
4675

reoselective osmylation (entries 3, 4, and 7-10).22 Dihy-
droxylation of both N-H cyclic urea 9 and N-benzyl cyclic
urea 10 provided diols 1c and 1d, respectively, each as a
single diastereomer by NMR (entries 3 and 4), with osmy-
lation occurring anti to the isopropyl group as evidenced by
crystallographic analysis of 1d.23 Conversely, while N-H
sulfamide 13 gave high selectivity (11.0:1.0, entry 9),
diastereoselection diminished for N-benzyl sulfamide 14 (5.9:
1.0, entry 10).24 We were surprised to find that minor-16a,
where the phosphonyl oxygen resides anti to the isopropyl
group, gave lower selectivity (1.8:1.0, entry 8) relative to
that of major-16a (7.6:1.0, entry 7). Contrary to our
hypothesis,20 it is obvious that a cooperative directing effect
of the phosphonyl oxygen and the isopropyl group is not
the major factor governing diastereoselectivity.25
Table 1a
In conclusion, the synthetic utility of 1,4-diamines pro-
duced via temporary P-tethers has been demonstrated in the
synthesis of a number of structurally diverse seven-membered
heterocyclic diols analogous to DMP 323. Future work
involves the use of D-amino acid derived allylic amines,10
as well as utilizing other methods for functionalizing the
cyclic olefin moiety. Preliminary biological evaluation of the
analogues described has been promising 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) and a DoD Breast Cancer Research Program
Predoctoral Fellowship for M.D.M. The authors also thank
Dr. Douglas R. Powell for X-ray crystallographic analysis
and Dr. Gerald H. Lushington for preliminary molecular
modeling studies.
Supporting Information Available: Experimental pro-
cedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
a General reaction conditions: 3 mol % OsO4 (4 wt % solution in H2O),
OL027074V
1.2 equiv NMO‚H2O, acetone/H2O. b Isolated yields after flash chroma-
tography. c Various attempts using 7a were unsuccessful, presumably
because of steric hindrance about the cyclic olefin caused by the vicinal
iPr groups. d 1.2 equiv of citric acid was added to facilitate the reaction.26
(22) These unsymmetric heterocycles differ only in the type of nuclei
connecting the two amino functionalities [C(O), P(O)Me, or SO2].
(23) X-ray data for 1d can be found in the Supporting Information.
(24) Preliminary molecular modeling experiments (SYBYL v. 6.8 using
MMFF94 force field; see Supporting Information) suggest that N-substitution
effects the orientation of the endocyclic isopropyl group in cyclic sulfamide
14, leading to diminished diastereoselectivity.
1H NMR was employed to determine the diastereoselectivity. f 31P NMR
e
was employed to determine the diastereoselectivity. g The stereochemistry
at phosphorus was not unambiguously determined. h Product 2d was not
isolated.
(25) Molecular modeling experiments similar to those described in ref
24 suggest that significant conformational changes in the seven-membered
ring may lead to the observed differences in diastereoselectivity between
major-16a and minor-16a.
(26) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K.
B. AdV. Synth. Catal. 2002, 344, 421-433.
the results of which are summarized in Table 1. Oxidation
of unsymmetric seven-membered heterocycles is of particular
stereochemical interest because of the potential for diaste-
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Org. Lett., Vol. 4, No. 26, 2002