Stereospecific, Stereoselective Rearrangement of Hexahydro-1,3-diazepin-2-ones to Tetrahydropyrimidin-2-ones and Imidazolidin-2-ones, a Useful Route for the Synthesis of HIV Protease Inhibitors

Article abstract of DOI:10.1021/jo980533e

We have discovered that hexahydro-5,6-dihydroxy-l,3-diazepin-2-ones can undergo a stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding tetrahydro-5-hydroxypyrimidin-2-ones. This reaction is very general and proceeds in excellent yields. The rearrangement proceeds through the formation of the aziridinium cationic intermediate I, which is subsequently opened by nucleophilic attack (S_N2) at the less hindered carbon to give the rearranged product. The X-ray structure determination of the rearranged product (17a; Figure 1) confirmed the structure and the stereochemical assignments and is consistent with the proposed mechanism. When the urea nitrogens are not substituted, the aziridine product can be isolated, and its structure (24; Figure 2) was also confirmed by X-ray analysis. The aziridine product can be used as a mono N-protecting group to synthesize differentially disubstituted N,N′-dialkylated tetrahydropyrimidin-2-one analogues. The tetrahydro-5-hydroxypyrimidin-2-ones can further undergo a second stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding imidazolidinones. This second rearrangement is also very general and proceeds in good yields. These tetrahydro-5-hydroxypyrimidin-2-ones and imidazolidinones have previously been shown to be potent HIVPR inhibitors.

Full text of DOI:10.1021/jo980533e

J . Org. Chem. 1998, 63, 4755-4766
4755
Ster eosp ecific, Ster eoselective Rea r r a n gem en t of
Hexa h yd r o-1,3-d ia zep in -2-on es to Tetr a h yd r op yr im id in -2-on es a n d
Im id a zolid in -2-on es, a Usefu l Rou te for th e Syn th esis of HIV
P r otea se In h ibitor s
George V. De Lucca*
Dupont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0500
Received March 20, 1998
We have discovered that hexahydro-5,6-dihydroxy-1,3-diazepin-2-ones can undergo a stereospecific,
stereoselective-rearrangement, ring-contraction reaction to give the corresponding tetrahydro-5-
hydroxypyrimidin-2-ones. This reaction is very general and proceeds in excellent yields. The
rearrangement proceeds through the formation of the aziridinium cationic intermediate I, which
is subsequently opened by nucleophilic attack (SN2) at the less hindered carbon to give the
rearranged product. The X-ray structure determination of the rearranged product (17a ; Figure 1)
confirmed the structure and the stereochemical assignments and is consistent with the proposed
mechanism. When the urea nitrogens are not substituted, the aziridine product can be isolated,
and its structure (24; Figure 2) was also confirmed by X-ray analysis. The aziridine product can
be used as a mono N-protecting group to synthesize differentially disubstituted N,N′-dialkylated
tetrahydropyrimidin-2-one analogues. The tetrahydro-5-hydroxypyrimidin-2-ones can further
undergo a second stereospecific, stereoselective-rearrangement, ring-contraction reaction to give
the corresponding imidazolidinones. This second rearrangement is also very general and proceeds
in good yields. These tetrahydro-5-hydroxypyrimidin-2-ones and imidazolidinones have previously
been shown to be potent HIVPR inhibitors.
In tr od u ction
HIVPR inhibitors.3 These C2-symmetric hexahydro-1,3-
diazepin-2-ones are complementary to the C2-symmetric
aspartic protease of HIV and are potent inhibitors of the
enzyme. This work resulted in the identification of two
clinical candidates in this series, DMP 3234 and DMP
450.5
The human immunodeficiency virus (HIV) encodes an
aspartyl protease that is responsible for the processing
of the gag and gag-pol gene products. This processing is
required for the production of mature, infectious virions
and has been a prime target for therapeutic intervention.1
Inhibition of this essential protease (PR) has been shown
to be an effective clinical treatment for AIDS.2 There are
currently four HIVPR inhibitors (saquinavir, ritonavir,
indinavir, and nelfinavir) that have been approved by the
FDA and are being used in AIDS therapy in combination
with reverse transcriptase (RT) inhibitors.
Lam and co-workers have previously described the
design and discovery of a novel class of cyclic urea based
* To whom correspondence should be addressed. E-mail:
George.V.DeLucca@dupontmerck.com.
(1) For recent reviews see: (a) De Clercq, E. J . Med. Chem. 1995,
38, 2491-2517. (b) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Ann.
Rep. Med. Chem. 1995, 30, 139-149. (c) Chong, K. T. Exp. Opin. Invest.
Drugs 1996, 5, 115-124. (d) Kempf, D. J .; Sham, H. L. Curr. Pharm.
Des. 1996, 2, 225-246. (e) De Lucca, G. V.; Erickson-Viitanen, S.; Lam,
P. Y. S. Drug Discovery Today 1997, 2, 6-18.
During our efforts to define the structure-activity
relationships (SAR) of these hexahydro-1,3-diazepin-2-
ones, we discovered that the seven-membered ring cyclic
urea has a tendency to undergo a series of rearrange-
(2) (a) Vacca, J . P.; Dorsey, B. D.; Schlief, W. A.; Levin, R. B.;
McDaniel, S. L.; Darke, P L.; Zugay, J .; Quintero, J . C.; Blahy, O. M.;
Roth, E.; Sardana, V. V.; Schlabach, A. J .; Graham, P. I.; Condra, J .
H.; Gotlib, L.; Holloway, M. K.; Lin, J .; Chen, I.-W.; Ostovic, D.;
Anderson, P. S.; Emini, E. A.; Huff, J . R. Proc. Natl. Acad. Sci. U.S.A.
1994, 91, 4096-4100. (b) Wei, X.; Ghosh, S. K.; Taylor, M. E.; J ohnson,
V. A.; Emini, E. A.; Deutsch, P.; Lifson, J . D.; Bonhoeffer, S.; Nowak,
M. A.; Hahn, B. H.; Saag, M. S.; Shaw, G. M. Nature 1995, 373, 117-
122. (c) Kempf, D.; Marsh, K. C.; Denissen, J . F.; McDonald, E.;
Vasavanonda, S.; Flentge, C. A.; Green, B. G.; Fino, L.; Park, C. H.;
Kong, X.-P.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham,
H. L.; Robins, T.; Stewart, K D.; Hsu, A.; Plattner, J . J .; Leonard, J .
M.; Norbeck, D. W. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484-2488.
(d) Ho, D. D.; Neumann, A. U.; Perelson, A. S.; Chen, W.; Leonard, J .
M.; Markowitz, M. Nature 1995, 373, 123-126. (e) Kitchen, V. S.;
Skinner, C.; Ariyoshi, K.; Lane, E. A.; Duncan, I. B.; Burckhardt, J .;
Burger, H. U.; Bragman, K.; Pinching, A. J .; Weber, J . N. Lancet 1995,
345, 952-955.
(3) Lam, P. Y. S.; J adhav, P. K.; Eyermann, C. J .; Hodge, C. N.; Ru,
Y.; Bacheler, L. T.; Meek, J . L.; Otto, M. J .; Rayner, M. M.; Wong, N.
Y.; Chang, C. H.; Weber, P. C.; J ackson, D. A.; Sharpe, T. R.; Erickson-
Viitanen, S. Science 1994, 263, 380-384.
(4) Lam, P. Y. S.; Ru, Y.; J adhav, P. K.; Aldrich, P. E.; De Lucca, G.
V.; Eyermann, C. J .; Chang, C.-H.; Emmett, G.; Holler, E. R.; Daneker,
W. F.; Li, L.; Confalone, P. N.; McHugh, R. J .; Han, Q.; Markwalder,
J . A.; Seitz, S. P.; Bacheler, L. T.; Rayner, M. M.; Klabe, R. M.; Shum,
L.; Winslow, D. L.; Kornhauser, D. M.; J ackson, D. A.; Erickson-
Viitanen, S.; Sharpe, T. R.; Hodge, C. N. J . Med. Chem. 1996, 39, 3514-
3525.
(5) Hodge, C. N.; Aldrich, P. E.; Bacheler, L. T.; Chang, C.-H.;
Eyermann, C. J .; Garber, S.; Grubb, M.; J ackson, D. A.; J adhav, P. K.;
Korant, B.; Lam, P. Y. S.; Maurin, M. B.; Meek, J . L.; Otto, M. J .;
Rayner, M. M.; Reid, C.; Sharpe, T. R.; Shum, L.; Winslow, D. L.;
Erickson-Viitanen, S. Chem. Biol. 1996, 3, 301-314.
S0022-3263(98)00533-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/20/1998

4756 J . Org. Chem., Vol. 63, No. 14, 1998
De Lucca
Sch em e 1a
a
Key: (a) 1 equiv of DAST/CH2Cl2; (b) MEM-Cl/Et3N; (c) DEAD/Ph3P/chloroacetic acid; (d) HCl/MeOH; (e) thiocarbonyldiimidazole; (f)
NaOH/MeOH; (g) Bu3SnH/AIBN.
ment, ring-contraction reactions to give sequentially, first
the tetrahydropyrimidinone6 and then the imidazolidi-
none.7 In this paper we wish to describe our findings in
detail.
the carbon fluorine bond (Scheme 1). The assignment
was based on the 1-D proton NMR, which seemed
consistent with this structure.
When the fluoro alcohol product was tested for HIVPR
activity, it was found to be more than 50-fold weaker than
the diol 1. The loss in activity was attributed to the
stereochemistry of the fluoro substituent, since, from
other SAR studies in our laboratory, it was known that
only one hydroxyl group was needed for full potency. To
obtain the fluoro analogue with the opposite configura-
tion, we used a double inversion procedure in which the
stereochemistry of one of the hydroxyls was first inverted
using Mitsunobu conditions and then treated with DAST
to give the fluoro alcohol with (it was expected) overall
retention of configuration. However, after implemention
of this tedious procedure, the fluoro alcohol that was
isolated was identical to the original product obtained
directly from the reaction of DAST with diol 1.
Resu lts a n d Discu ssion
While the seven-membered ring cyclic ureas, like DMP
323, are extremely potent inhibitors of HIV protease, the
symmetry of these molecules contributes to their high
crystallinity and low solubility. To improve solubility and
to determine the SAR of the diol functionality, we became
interested in substituting one of the hydroxyl groups with
a fluorine. In many cases, fluorine can be a good isostere
for hydroxyl groups and can have a significant impact
on pharmacological properties.8
When diol 14 was treated with 1 equiv of the fluorinat-
ing agent (diethylamino)sulfur trifluoride (DAST), we
obtained a fluoro alcohol as the major product. The
structure of the product was initially incorrectly assigned
as the expected corresponding (hexahydro-1,3-diazepin-
2-one) fluoro analogue with inversion of configuration of
To confirm the structure and the stereochemistry of
the fluoro alcohol, a series of 2-D NMR experiments were
1
carried out. Using a 2-D H COSY experiment, it was
obvious that the fluoro alcohol could not be a hexahydro-
1,3-diazepin-2-one. The COSY showed that one set of
benzyl protons were coupled to the proton R to the fluoro
and not R to the nitrogen, consistent with the rearranged
tetrahydropyrimidinone 2 (Scheme 1).
This implied that a rearrangement had also occurred
under the Mitsunobu conditions as outlined in Scheme
1. The diol 1 was first monoprotected as the mono-MEM
(6) De Lucca, G. V.; Liang, J .; Aldrich, P. E.; Calabrese, J .; Cordova,
B.; Klabe, R. M.; Rayner, M. M.; Chang, C.-H. J . Med. Chem. 1997,40,
1707-1719.
(7) De Lucca, G. V. Bioorg. Med. Chem. Lett. 1997, 7, 495-500.
(8) (a) Patani, G. A.; LaVoie, E. J . Chem. Rev. 1996, 96, 3146-3178.
(b) Cannon, J . G. Analogue Design. In Burger’s Medicinal Chemistry
and Drug Discovery, 5th ed.; Wolfe, M. E., Ed.; J ohn Wiley & Sons:
New York; 1995; Volume 1, Principles and Practice, pp 783-802.

Rearrangement of Hexahydro-1,3-diazepin-2-ones
J . Org. Chem., Vol. 63, No. 14, 1998 4757
Sch em e 2a
a
Key: (a) 1 equiv of DAST/CH2Cl2; (b) Ms-Cl/Et3N; (c) NaN3/DMF; (d) NaI/DMF; (e) 50 psi H2/10%Pd/C.
ether 3 by treatment with MEM-Cl. The free hydroxyl
of 3 was then treated under Mitsunobu conditions (Ph3P,
DEAD, chloroacetic acid) to give, not the expected inver-
sion product, but rather, the rearranged chloroacetate 4.
The structure of chloroacetate 4 was assigned by 2-D
NMR and by converting it into the known alcohol 9 as
outlined in Scheme 1. Ester 4 was hydrolyzed to the
alcohol 7, which was further converted to the thiocar-
bamate 6. Reduction of 6 (Bu3SnH, AIBN) followed by
removal of the MEM group (HCl/MeOH) gave 9, which
we previously obtained by total synthesis starting from
D-phenylalanine.6
The alcohol 7 was treated with DAST to give 5. The
MEM protecting group was removed (HCl/MeOH) to give
the fluoro alcohol 2, identical to that obtained directly
from the reaction of diol 1 with 1 equiv of DAST.
Alternatively, 7 was deprotected to give the non-C2-
symmetric diol 8. A 2-D COSY NMR showed it was the
rearranged tetrahydropyrimidinone analogue.
This rearrangement can be envisioned as proceeding
through the aziridinium cationic intermediate I (Scheme
1). In the case of the diol 1 and alcohol 7, the reaction
with DAST first converts the hydroxyl group into a good
leaving group. The urea nitrogen participates and
displaces the leaving group (in SN2 fashion) to give the
same intermediate I. The fluoride ion then opens up the
aziridine intermediate (SN2) to give the observed fluoro
alcohol 2. The stereochemical assignment of the fluoro
phenethyl side chain of 2 is based on this SN2 mechanism.
This assumption was subsequently supported by the
X-ray structure of the bromo analogue 17a (discussed
below).
was equally facile. For example, the reaction of the large
2-naphthyl substituted analogue 104 with 1 equiv of
DAST gave the corresponding tetrahydropyrimidinone
analogue 11 in good yield (Scheme 2).
The diol 10 was converted to the monomesylate 12.
Reaction of the mesylate with nucleophiles lead to
rearranged products. For example, the reaction of 12
with NaN3 gave the azido analogue 13. Treatment of 12
with NaI gave the trans olefin 14, presumably via the
phenethyl iodide. The structure of the olefin was further
confirmed by hydrogenation to give the phenethyl ana-
logue 15, which was also prepared independently.
We recently disclosed the design, synthesis, and evalu-
ation of tetrahydropyrimidinones, such as 9, and showed
these to be nearly equipotent inhibitors of HIVPR as the
seven-membered ring cyclic ureas.6 Thus, the discovery
of this rearrangement reaction offered an attractive
alternative synthesis of tetrahydropyrimidinones em-
ploying the seven-membered ring cyclic ureas4 as the
starting material. While the unsubstituted-phenethyl
tetrahydropyrimidinone analogues, such as 9, were nearly
equipotent to the diols (1), the substituted-phenethyl
compounds (such as 2, 8, 11, 13, and 14) were much
weaker inhibitors of HIVPR.
Taking advantage of this rearrangement, we developed
an efficient synthesis of the unsubstituted-phenethyl
tetrahydropyrimidinone analogues using 2-acetoxyisobu-
tyryl bromide, which has been used to convert diols to
bromo acetates via a cyclic oxonium ion intermediate.9
It was expected that, in our case, as the oxonium ion
intermediate II is formed, the urea nitrogen would
participate to give the aziridinium cationic intermediate
To explore the generality of this rearrangement, we
examined a variety of N-substituted seven-membered
ring cyclic urea analogues and found the ring contraction
(9) (a) Greenberg, S.; Moffatt, J . G. J . Am. Chem. Soc. 1973, 95,
4016-25. (b) Russell, A. F.; Greenberg, S.; Moffatt, J . G. J . Am. Chem.
Soc. 1973, 95, 4025-30.

4758 J . Org. Chem., Vol. 63, No. 14, 1998
De Lucca
Sch em e 3a
Sch em e 4a
a
Key: (a) 1 N NaOH/MeOH; (b) KOH(s)/MeOH; (c) H2/10%
Pd/C.
stereochemistry was consistent with (SN2) bromide attack
on the aziridinium cationic intermediate I as shown in
Scheme 3. By analogy, the stereochemistry of the other
substituted phenethyl compounds, such as 2, 8, 11, 13,
and 14, were then assigned.
The phenethyl bromide side chain of 17a was most
conveniently reduced using Zn (dust) in acetic acid to give
the phenethyl analogue 18a in nearly quantitative yield.
Finally, the hydrolysis of the acetate 18a gave the desired
alcohol 19 in excellent yield. Thus, the overall transfor-
mation of the diol 16 to the tetrahydropyrimidinone 19
was achieved efficiently with an overall yield of about
90%. This reaction sequence was quite general and was
used to synthesize many tetrahydropyrimidinone ana-
logues.6 For example, the naphthyl analogue 10 was
converted to the bromo acetate 17b and subsequently
reduced and hydrolyzed to give the tetrahydropyrimidi-
none analogue 15, identical to that obtained as shown
in Scheme 2.
a
Key: (a) acetoxyisobutyryl bromide;CH2Cl2; (b) Zn(dust)/acetic
acid; (c) NaOH/MeOH.
The bromo acetates 17a ,b were hydrolyzed to give the
bromo alcohols 20a ,b using mildly basic conditions (0.01
M NaOH/MeOH) as shown in Scheme 4. Under more
concentrated conditions (2 M NaOH or KOH in MeOH),
the olefinic alcohols 21 and 14 were obtained in excellent
yields. The olefin 14 was identical to that obtained from
the mesylate 12 in Scheme 2. Hydrogenation of 21 or
14 gave the corresponding tetrahydropyrimidinone ana-
logues 19 or 15 previously described above.
While the use of this three-step procedure (Scheme 3)
was a very efficient method to synthesize tetrahydropy-
rimidinones from the corresponding hexahydro-1,3-diaz-
epin-2-ones, it had some practical limitations. When the
two N,N′ substituents of the diazepin-2-one were not the
same, a mixture of the two possible regioisomeric tet-
rahydropyrimidinone products were obtained and their
separation sometimes required tedious chromatography.
In addition, the N,N′ substituents of the diazepin-2-one
had to be stable to the reaction conditions, namely stable
toward the following: acid bromides, reduction, and basic
hydrolysis. Thus, it was desirable to find a procedure
that used the parent N,N′-unsubstituted diazepin-2-one
as the starting material. This became possible when we
F igu r e 1.
I (Scheme 3). Bromide ion would then open the aziridine
to give the phenethyl bromide. We were gratified to find
that this was indeed the case. When diol 164 was treated
with 2-acetoxyisobutyryl bromide, a nearly quantitative
yield of the tetrahydropyrimidinone bromo acetate 17a
was obtained. Recrystallization of the bromo acetate 17a
gave crystals of sufficient quality for analysis by X-ray
crystallography (Figure 1). This analysis confirmed not
only the assigned structure but also the absolute config-
uration of the phenethyl bromide substituent.6 This

Rearrangement of Hexahydro-1,3-diazepin-2-ones
J . Org. Chem., Vol. 63, No. 14, 1998 4759
Sch em e 5a
Sch em e 6a
a
Key: (a) DHP/CHCl3/TsOH; (b) KO-t-Bu/THF; (c) HCl/MeOH
reflux.
Treatment of the aziridine 23 with HBr(gas) gave a
a
Key: (a) DAST/CH2Cl2; (b) NaOH/MeOH; (c) LAH/THF; (d)
nearly quantitative yield of the phenethyl bromide 25.
The bromide was reduced with zinc in acetic acid to give
the phenethyl analogue 26 in excellent yield. Hydrolysis
of 26 gave the unsubstituted tetrahydropyrimidinone 28
in excellent overall yield from the monoacetate 22.
Alternatively, the bromo acetate 25 was treated with
excess NaOH or KOH to give the olefinic alcohol 27 in
nearly quantitative yield. Hydrogenation of 27 gave the
tetrahydropyrimidinone 28, again in excellent yield.
HBr(gas)/dioxane; (e) Zn(dust)/acetic acid; (f) H2, 10%Pd/C.
The hydroxyl group of the N,N′-unsubstituted tetrahy-
dropyrimidinone 28 was most conveniently protected as
the THP ether to give 29 in quantitative yield (Scheme
6). The urea nitrogens were substituted using a variety
of alkylating agents under our standard conditions. For
example, treatment of 29 with 5-(bromomethyl)-1-SEM-
indazole12 and 1 M solution of KO-t-Bu (in THF) gave
the dialkylated tetrahydropyrimidinone 30. The protect-
ing groups were removed using acidic conditions (HCl/
MeOH) to give the indazole-substituted tetrahydropyri-
midinone 31 in good yield.
F igu r e 2.
discovered another unusual reaction of these hexahydro-
1,3-diazepin-2-ones with DAST.
Treatment of the N,N′-unsubstituted mono acetate 22
with DAST did not give a fluoro analogue and instead
provided the aziridine 23 in good yield (Scheme 5). The
aziridine 23 was not acid (silica gel) stable, but was
thermally stable and was purified by recrystallization
from ethyl acetate. It was also stable to basic conditions
and was hydrolyzed with NaOH/MeOH to give the alcohol
24. Alternatively, the acetate 23 was treated with LAH
to give the alcohol 24 in excellent yield. The structure
of alcohol 24 was confirmed by X-ray crystallography
(Figure 2). The crystal structure of 24 provides further
support for the intermediary aziridinium ion I in the
rearrangement reactions.
(10) Lam, P. Y.; J adhav, P. K.; Eyermann, C. J .; Hodge, C. N.; De
Lucca, G. V.; Rodgers, J . D. US 5,610,294, March 11, 1997.
(11) A literature search produced one example of a similar rear-
rangement of a tetrahydropyrimidinone to imidazolidinone via an
aziridine intermediate: Berges, D. A.; Schmidt, S. J . J . Org. Chem.
1984, 49, 4555-4557.
(12) (a) Rodgers, J . D.; J ohnson, B. L.; Wang, H.; Greenburg, R. A.;
Erickson-Viitanen, S.; Klabe, R. M.; Cordova, B. C.; Rayner, M. M.;
Lam, G. N.; Chang, C.-H. Bioorg. Med. Chem. Lett. 1996, 6, 2919-
2924. (b) Sun, J .-H.; Teleha, C. A.; Yan, J .-S.; Rodgers, J . D.; Nugiel,
D. A. J . Org. Chem. 1997, 62, 5627-5629.

4760 J . Org. Chem., Vol. 63, No. 14, 1998
De Lucca
Sch em e 7a
a
Key: (a) NaH/DMF/Bn-Br; (b) CF3COOH; (c) HBr(gas)/dioxane; (d) Zn(dust)/acetic acid; (e) NaOH/MeOH; (f) H2, 10%Pd/C.
The X-ray structural data of the aziridine 24 offers a
possible explanation of why only rearranged tetrahydro-
pyrimidinone products are obtained and none of the
possible hexahydro-1,3-diazepin-2-one products are ob-
served. When the aziridine cationic intermediate is
formed, the attacking nucleophile has a choice of the two
carbons of the aziridine ring. Examination of the X-ray
structure of 24 (Figure 2) suggests that attack at the
carbon that leads to diazepin-2-one products is sterically
congested by the presence of the vicinal hydroxyl (or
acetyl) group, whereas attack of the carbon leading to
the tetrahydropyrimidinone products is more accessible.
Thus, in every hexahydro-1,3-diazepin-2-one we have
examined, only rearrangement products are observed.
The aziridine 23 can also be considered a latent or
protected form of the desired tetrahydropyrimidinone
final product and was used to synthesize unsymmetri-
cally disubstituted N,N′ analogues as summarized in
Scheme 7. Alkylation of aziridine 23 with benzyl bromide
gave the N-benzylaziridine 32. The acetate of 32 was
removed under basic conditions to give alcohol 33, whose
structure was also confirmed by X-ray crystallography
(Figure 3). The aziridine 32 was sequentially treated
with HBr, zinc dust in acetic acid, and NaOH to give the
mono-N-alkylated tetrahydropyrimidinone 36.
The aziridine was also opened with other acids besides
HBr. For example, treatment of 32 with trifluoroacetic
acid gave the corresponding trifluoroacetate (Scheme 7).
Treatment with NaOH then gave the diol 34. The
aziridine 37, containing the N-3-(benzyloxy)benzyl group,
was hydrogenated, for a prolong period of time, to remove
not only the O-benzyl protecting groups but also reduce
the aziridine ring and gave the phenol 38.
F igu r e 3.
Suitably protected alcohols (such as 36 or 38) were
N-alkylated a second time to obtain unsymmetrical N,N′-
dialkylated tetrahydropyrimidinones with defined regio-
chemistry as shown in Scheme 8. For example, the
alcohol of 39 was protected as the MEM ether 40.
Alkylation of the urea nitrogen with cyclopropylmethyl
bromide under the usual conditions4 gave the dialkylated
product 41. The MEM group is removed under acidic
(HCl/dioxane) conditions, and the cyano group was
converted to the amidoxime with hydroxylamine to give
the desired unsymmetrical N,N′-dialkylated tetrahydro-
pyrimidinone 42.
The seven-membered ring cyclic sulfamides such as 43
are also potent inhibitors of HIVPR.10 To determine if
the same kind of rearrangement reaction occurs with
these compounds, we treated 43 with 2-acetoxybutyryl
bromide under our usual conditions (Scheme 9). The
reaction with sulfamides was not as efficient and pro-

Rearrangement of Hexahydro-1,3-diazepin-2-ones
J . Org. Chem., Vol. 63, No. 14, 1998 4761
Sch em e 8a
Sch em e 9a
a
Key: (a) MEM-Cl/Et3N/CH2Cl2; (b) NaH/DMF/cyclopropyl-
methyl bromide; (c) HCl/dioxane; (d) NH2OH‚HCl/Et3N/EtOH/
reflux.
duces a mixture of products. However, the major prod-
ucts obtained were the six- and seven-membered ring
bromo acetates 44 and 45 in about equal amounts.
The structure of the seven-membered ring cyclic sul-
famide 45 was deduced from its reaction with zinc dust
in acetic acid which cleanly gave the C2-symmetric olefin
46. The structure of the six-membered-ring compound
44 was deduced by 2-D COSY NMR and by the compari-
son of its NMR spectra to that of the analogous tetrahy-
dropyrimidinones 17a and 17b.
a
Key: (a) acetoxyisobutyryl bromide/CH2Cl2; (b) Zn(dust)/acetic
acid; (c) Bu3SnH/AIBN; (d) NaOH/MeOH.
The reduction of the bromide 44 with Zn gave the
phenethyl analogue 47 as the major product. This
reduction was not as clean as the urea analogues, and a
structurally undetermined olefin contamination was also
obtained under a variety of reduction conditions that
were explored. The product was purified by HPLC
chromatography, and NMR analysis (2-D COSY) showed
the familiar phenethyl group in the six-membered ring
analogues 47 and 48. The difference in behavior of the
cyclic sulfamide compared to the cyclic urea clearly points
to the importance of stereoelectronic effects in this
rearrangement reaction.
The tetrahydropyrimidinones can undergo a second
rearrangement as shown in Scheme 10, to give the
corresponding imidazolidinones.11 For example, when
the fluoro alcohol 2 (or 11) was treated with DAST, a
second rearrangement occurs to give the C2-symmetric
difluoroimidazolidin-2-one 49 in nearly quantitative yield.
Alternatively, the diol 1 (or 10) was treated with excess
DAST to give the same difluoro imidazolidin-2-one 49
directly.
symmetric difluoro imidazolidin-2-one product. None of
the possible 1,2-difluoro-3-phenylpropyl analogue was
observed.
The rearrangement of tetrahydropyrimidin-2-ones to
imidazolidin-2-one seems to be just as general as the
rearrangement of hexahydro-1,3-diazepin-2-ones to tet-
rahydropyrimidin-2-ones. For example, when the alcohol
50 was treated under Mitsunobu conditions (Ph3P, DEAD,
chloroacetic acid), the rearranged alcohol 51 was obtained
(Scheme 10). The structure of 51 was determined by
NMR and confirmed by reductive removal of the alcohol
(TCDI; Bu3SnH, AIBN) to give the C2-symmetrical phen-
ethyl imidazolidin-2-one 53. The alcohol 50 was also
treated with Ph3P/CBr4 to give the rearranged phenethyl
bromide 52. We have recently shown that these imida-
zolidin-2-ones are also HIVPR inhibitors.7 They are,
however, much weaker inhibitors since they lack the
important transition-state isostere needed for interaction
with the catalytic aspartic acid residues of HIVPR.
The fact that only one product was produced again
shows the importance of stereoelectronic effects and the
stereospecific, stereoselective nature of this rearrange-
ment reaction. Clearly, only one of the two urea nitro-
gens is properly aligned to participate and produce the
aziridinium cationic intermediate III (Scheme 10), which
can then be opened by fluoride ion to give only the C2-
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under
an atmosphere of dry nitrogen. Commercial reagents were
used without further purification. A general workup consisted
of diluting the reaction mixture with water and extracting into
an organic solvent (ethyl acetate, CH2Cl2, etc.). The organic
phase was washed sequentially with water (dilute acid or base

4762 J . Org. Chem., Vol. 63, No. 14, 1998
De Lucca
Sch em e 10a
3.30 (abx m, 2 H), 2.91-2.61 (m, 4 H), 2.49 (d, J ) 7 Hz, 1 H),
1.06 (m, 1 H), 0.96 (m, 1 H), 0.60-0.06 (m, 8 H); CIMS (NH3)
m/z 437.2 (M + H+, 100); HRMS calcd for C27H34N2O2F (M +
H+) 437.2604, found 437.2593.
(4R ,5S ,6S ,7R )-H e x a h y d r o -5-[(2-m e t h o x y e t h o x y )-
m eth oxy]-6-h yd r oxy-1,3-bis(cyclop r op ylm eth yl)-4,7-bis-
(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (3). A solution of
diol 1 (2.06 g, 4.7 mmol) in CH2Cl2 (20 mL) was treated with
MEM-Cl (0.71 g, 5.69 mmol) and diisopropylethylamine (1.53
g, 11.8 mmol), and the mixture was heated at reflux for 8 h.
After a general workup, the residue was chromatographed
(HPLC, Zorbax Sil, 5% MeOH/CHCl3) to give 1.3 g of 3 as an
oil; 1H NMR (CDCl3) δ 7.30-7.11 (m, 10 H), 4.95 (s, 2 H), 4.10
(m, 1 H), 3.89 (m, 3 H), 3.75-3.46 (m, 6 H), 3.41 (s, 3 H), 3.39-
2.97 (m, 5 H), 1.98 (m, 2 H), 0.90 (m, 2 H), 0.40 (m, 4 H), 0.03
(m, 4 H); CIMS (NH3) m/z 523 (M + H+, 100).
(4R,5S,6R)-Tet r a h yd r o-1,3-b is(cyclop r op ylm et h yl)-5-
(2-m et h oxyet h oxy)m et h oxy)-4-(1(S)-h yd r oxy-2-p h en yl-
eth yl)-6-(p h en ylm eth yl)-2(1H)-p yr im id in on e (7). To a
solution of 3 (1.0 g, 1.9 mmol) in THF were added triph-
enylphosphine (1.0 g, 3.8 mmol), DEAD (0.7 g, 4.0 mmol), and
chloroacetic acid (0.40 g, 4.2 mmol) and the mixture stirred
for 20 h at room temperature. The mixture was evaporated,
and the residue was chromatographed (MPLC, silica gel, 50%
EtOAc/hexane) to give 0.9 g of chloroacetate 4 as an oil: 1H
NMR (CDCl3) δ 7.27-7.21 (m, 10 H), 5.39 (m, 1 H), 4.95 (d, J
) 13 Hz, 1 H), 4.80 (d, J ) 13 Hz, 1 H), 4.70 (s, 1 H), 4.27 (m,
1 H), 4.19 (m, 2 H), 4.00-3.70 (m, 5 H), 3.93 (s, 2 H), 3.48 (dd,
J ) 7 Hz, J ) 15 Hz, 1 H), 3.37, (s, 3 H), 3.02-2.90 (m, 5 H),
1.90 (dd, J ) 7 Hz, J ) 15 Hz, 1 H), 1.22 (m, 2 H), 0.76 (m, 1
H), 0.57 (m, 2 H), 0.40-0.20 (m, 4 H), 0.0 (m, 1 H); CIMS (NH3)
m/z 599 (M + H+, 100).
A solution of the chloroacetate 4 (0.9 g, 1.5 mmol) in
methanol (15 mL) was treated with 4 mL of a 1 N NaOH
solution and stirred at room temperature for 1 h. After a
general workup, the residue was chromatographed (HPLC,
Zorbax Sil, 85% EtOAc/hexane) to give 0.4 g of alcohol 7 as a
viscous oil that slowly solidified over a few days: 1H NMR
(CDCl3) δ 7.33-7.13 (m, 10 H), 4.92 (d, J ) 7 Hz, 1 H), 4.84
(d, J ) 7 Hz, 1 H), 4.28 (m, 1H), 4.20 (m, 1 H), 3.91-3.79 (m,
5 H), 3.60 (m, 2 H), 3.50 (dd, J ) 7, 15 Hz, 1 H), 3.38 (s, 3 H),
3.06 (d, J ) 7 Hz, 2 H), 2.94 (dd, J ) 7, 15 Hz, 1 H), 2.82-2.62
(m, 2 H), 2.44 (d, J ) 7 Hz, 1 H), 1.91 (dd, J ) 7, 15 Hz, 1 H),
1.21 (m, 1 H), 0.81 (m, 1 H), 0.58 (m, 2 H), 0.45-0.25 (m, 4
H), 0.02 (m, 2 H); CIMS (NH3) m/z 523 (M + H+, 100).
(4S,5S,6R)-Tet r a h yd r o-1,3-b is(cyclop r op ylm et h yl)-5-
[(2-m eth oxyeth oxy)m eth oxy]-4-(1(S)-flu or o-2-p h en yleth -
yl)-6-(p h en ylm eth yl)-2(1H)-p yr im id in on e (5). A solution
of 7 (160 mg, 0.3 mmol) in CH2Cl2 (20 mL) was cooled to 0 °C
in an ice bath and treated with DAST (0.04 mL, 0.3 mmol)
via syringe. The solution was stirred at 0 °C for 30 min (TLC
showed complete conversion). After a general workup, the
residue was chromatographed (HPLC, Zorbax Sil, 50% EtOAc/
hexane) to give 100 mg of 5 as a thick oil: 1H NMR (CDCl3) δ
7.34-7.19 (m, 10 H), 5.00 (m, 0.5 H), 4.87 (d, J ) 7 Hz, 1 H),
4.81 (m, 0.5 H), 4.79 (d, J ) 7 Hz, 1 H), 4.23 (m, 1H), 3.94-
3.75 (m, 5 H), 3.59 (m, 2 H), 3.49 (dd, J ) 7, 15 Hz, 1 H), 3.39
(s, 3 H), 3.09 (d, J ) 7 Hz, 2 H), 3.08-2.78 (m, 3 H), 1.96 (dd,
J ) 7, 15 Hz, 1 H), 1.21 (m, 1 H), 0.79 (m, 1 H), 0.58 (m, 2 H),
0.50-0.25 (m, 4 H), 0.05 (m, 2 H); CIMS (NH3) m/z 525 (M +
H+, 100).
a
Key: (a) DAST/CH2Cl2; (b) DEAD/Ph3P/chloroacetic acid; (c)
NaOH/MeOH; (d) Ph3P/CBr4/CH2Cl2; (e) thiocarbonyldiimidazole/
THP; (f) Bu3SnH/AIBN.
as appropriate) and brine and then dried over MgSO4. The
drying agent was filtered, and the organic solvent was removed
under vacuum on a rotary evaporator. TLC was performed
on E. Merck 15710 silica gel plates. Medium-pressure liquid
chromatography (MPLC) was carried out using EM Science
silica gel 60 (230-400 mesh). HPLC chromatography was
carried out using Dupont Zorbax Sil or Zorbax NH2 1-in.
preparative columns. All final targets were obtained as
noncrystalline amorphous solids unless specified otherwise. 1H
NMR (300 MHz) spectra were recorded using tetramethylsi-
lane as an internal standard. Elemental analysis was per-
formed by Quantitative Technologies, Inc., Bound Brook, NJ .
For compounds where analysis was not obtained, HPLC
analysis was used, and purity was determined to be >98%
unless specified otherwise.
(4S,5S,6R)-Tet r a h yd r o-1,3-b is(cyclop r op ylm et h yl)-5-
h yd r oxy-4-(1(S)-flu or o-2-p h en yleth yl)-6-(p h en ylm eth yl)-
2(1H)-p yr im id in on e (2). Meth od 1 fr om 1. A solution of
(4R,5S,6S,7R)-hexahydro-5,6-dihydroxy-1,3-bis(cyclopropylm-
ethyl)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one (1)4 (0.112
g, 0.26 mmol) in CH2Cl2 (20 mL) was cooled to 0 °C in an ice
bath and treated with DAST (0.034 mL, 0.26 mmol) via
syringe. The solution was stirred at 0 °C for 30 min, at which
(4S,5S,6R)-Tet r a h yd r o-1,3-b is(cyclop r op ylm et h yl)-5-
h yd r oxy-4-(1(S)-flu or o-2-p h en yleth yl)-6-(p h en ylm eth yl)-
2(1H)-p yr im id in on e (2). Meth od 2 fr om 5. A solution of
5 (70 mg, 0.13 mmol) in methanol was cooled in an ice bath
while HCl gas was bubbled in for 20 min. The solution was
allowed to warm to room temperature and then stirred for 1
h. The solvent was removed under vacuum, and the residue
was chromatographed (HPLC, Zorbax Sil, 80% EtOAc/hexane)
to give 40 mg of 2 as a foam identical in every respect to the
product of diol 1 with DAST detailed above.
time TLC showed complete conversion. After
a general
workup, the residue was chromatographed (HPLC, Zorbax Sil,
65% EtOAc/hexane) to give 45 mg of 2 as a foam: 1H NMR
(CDCl3) δ 7.36-7.21 (m, 8 H), 7.08-7.06 (m, 2 H), 4.83 (m,
0.5 H), 4.73 (m, 0.5 H), 4.05 (dd, J ) 7, 15 Hz, 1 H), 3.86 (dd,
J ) 7, 15 Hz, 1 H), 3.81 (m, 1 H), 3.70 (m, 1 H), 3.61 (m, 1 H),
(4R,5S,6R)-Tet r a h yd r o-1,3-b is(cyclop r op ylm et h yl)-5-
h ydr oxy-4-(1(S)-h ydr oxy-2-ph en yleth yl)-6-(ph en ylm eth yl)-
2(1H)-p yr im id in on e (8). A solution of 7 (70 mg, 0.13 mmol)
in methanol was cooled in an ice bath while HCl gas was

Rearrangement of Hexahydro-1,3-diazepin-2-ones
J . Org. Chem., Vol. 63, No. 14, 1998 4763
bubbled in for 20 min. The solution was allowed to warm to
room temperature and stirred for 1 h. The solvent was
removed under vacuum, and the residue was chromatographed
(HPLC, Zorbax Sil, 80% EtOAc/hexane) to give 48 mg of 8 as
a white foam: 1H NMR (CDCl3) δ 7.36-7.17 (m, 10 H), 4.24
(m, 2 H), 3.98 (dd, J ) 8 Hz, J ) 15 Hz, 1 H), 3.80 (m, 1 H),
3.72 (m, 1 H), 3.68 (dd, J ) 8, 15 Hz, 1 H), 3.41 (d, J ) 3 Hz,
1 H), 3.15-2.96 (m, 2 H, abx), 2. 85 (dd, J ) 7, 15 Hz, 1 H),
2.79-2.51 (m, 2 H, abx), 2.19 (m, 1 H), 2.10 (dd, J ) 7, 16 Hz,
1 H), 1.09 (m, 1 H), 0.82 (m, 1 H), 0.58-0.25 (m, 6 H), 0.05
(m, 2 H); CIMS (NH3) m/z 435 (M + H+, 100).
(4R,5R,6R)-Tetr a h yd r o-1,3-bis(cyclop r op ylm eth yl)-5-
h yd r oxy-4-(2-p h en yleth yl)-6-(p h en ylm eth yl)-2(1H)-p yr i-
m id in on e (9). A solution of 7 (160 mg, 0.3 mmol) in THF
was treated with thiocarbonyldiimidazole (TCDI) (55 mg, 0.3
mmol) and the solution heated to reflux for 4 h. The solvent
was removed under vacuum, and the residue was chromato-
graphed (MPLC, silica gel, 50% EtOAc/hexane) to give 34 mg
of 6: 1H NMR (CDCl3) δ 8.23 (s, 1 H), 7.51 (bs, 1 H), 7.27-
7.21 (m, 10 H), 7.01 (bs, 1 H), 6.10 (m, 1 H), 4.83 (d, J ) 7 Hz,
1 H), 4.58 (d, J ) 6 Hz, 1 H), 4.28 (m, 1 H), 3.97-3.81 (m, 3
H), 3.65-3.40 (m, 5 H), 3.38 (s, 3 H), 3.22-2.91 (m, 5 H), 1.90
(dd, J ) 7, 15 Hz, 1 H), 1.20 (m, 1 H), 0.87 (m, 1 H), 0.65-
0.25 (m, 6 H), 0.03 (m, 2 H).
(m, 5 H), 2.50 (s, 3 H), 2.26 (d, J ) 4 Hz, 1 H); CIMS (NH3)
m/z 685 (M + H+, 100).
(4R,5S,6R)-Tet r a h yd r o-1,3-b is(2-n a p h t h ylm et h yl)-5-
h yd r oxy-4-(1(S)-a zid o-2-p h en yleth yl)-6-(p h en ylm eth yl)-
2(1H)-p yr im id in on e (13). A solution of 12 (100 mg, 0.15
mmol) in DMF was treated with NaN3 (100 mg, 1.5 mmol) and
heated at 80 °C for 2 h and then at 40 °C overnight. After a
general workup, the solid residue was chromatographed
(HPLC, Zorbax Sil, 50% EtOAc/hexane) to give 80 mg of 13 as
a white solid: IR 2114; 1H NMR (CDCl3) δ 7.93-7.78 (m, 7
H), 7.63-7.39 (m, 8 H), 7.25-7.05 (m, 7 H), 6.73 (d, J ) 7 Hz,
2 H), 5.76 (d, J ) 7 Hz, 1 H), 5.68 (d, J ) 7 Hz, 1 H), 4.10 (d,
J ) 7 Hz, 1 H), 3.78 (d, J ) 7 Hz, 1 H), 3.62 (m, 1 H), 3.52 (m,
1 H), 3.29 (m, 2 H), 3.07-2.85 (abx m, 2 H), 2.56-2.31 (abx
m, 2 H), 1.97 (d, J ) 7 Hz, 1 H); DCI MS (NH3) m/z 632 (M +
H+, 100); HRMS calcd for C41H38N5O2 (M + H+) 632.3025,
found 632.3023. Anal. Calcd for C41H37N5O2‚0.4(EtOAc)‚
0.4(hexane): C, 77.05; H, 6.58; N, 9.98. Found: C, 77.17; H,
6.27; N, 9.81.
(4R,5S,6R)-Tetr a h yd r o-1,3-bis(2-n a p h th a len ylm eth yl)-
5-h yd r oxy-4-(â-styr en e)-6-(p h en ylm eth yl)-2(1H)-p yr im i-
d in on e (14). Meth od 1. A solution of 12 (100 mg, 0.15 mmol)
in DMF was treated with NaI (100 mg, 1.5 mmol) and heated
at 80 °C for 2 h and then at 40 °C overnight. After a general
workup, the solid residue was chromatographed (HPLC,
Zorbax Sil, 50% EtOAc/hexane) to give 50 mg of 14 as a white
solid: 1H NMR (CDCl3) δ 7.93-7.65 (m, 6 H), 7.59 (m, 1 H),
7.55-7.40 (m, 6 H), 7.40-7.20 (m, 9 H), 7.12 (d, J ) 8 Hz, 2
H), 6.55 (d, J ) 16 Hz, 1 H), 5.91 (dd, J ) 8, 16 Hz, 1 H), 5.70
(d, J ) 15 Hz, 1 H), 5.55 (d, J ) 15 Hz, 1 H), 4.14 (d, J ) 15
Hz, 1 H), 3.80 (m, 1 H), 3.53 (d, J ) 15 Hz, 1 H), 3.53 (m, 2 H),
2.98-2.70 (abx m, 2 H), 1.85 (d, J ) 5 Hz, 1 H); DCI MS (NH3)
m/z 589 (M + H+, 100). Anal. Calcd for C41H36N2O2‚0.5H2O:
C, 82.38; H, 6.24; N, 4.69. Found: C, 82.52; H, 6.33; N, 4.56.
(4R,5S,6R)-Tetr a h yd r o-1,3-bis(2-n a p h th a len ylm eth yl)-
5-h yd r oxy-4-(â-styr en e)-6-(p h en ylm eth yl)-2(1H)-p yr im i-
d in on e (14). Meth od 2. 1-bromo-2-phenylethyl acetate 17b
(100 mg, 0.14 mmol) was dissolved in MeOH (10 mL) and
treated with solid KOH (1.0 g, 17.8 mmol) at room temperature
for 1 h. After a general workup, 50 mg of 14 was obtained as
a white solid identical to that obtained using method 1 above.
(4R,5R,6R)-Tetr ah ydr o-1,3-bis(2- n aph th alen ylm eth yl)-
5-h yd r oxy-4-(2-p h en yleth yl)-6-(p h en ylm eth yl)-2(1H)-p y-
r im id in on e (15). Meth od 1. A solution of 14 (30 mg) in
dioxane was treated with 10% Pd/C (30 mg) and hydrogenated
at 50 psi for 3 h. The solution was filtered, the solvent
removed under vacuum, and the residue chromatographed
(HPLC, Zorbax Sil, 70% EtOAc/hexane) to give 10 mg of 15 as
a white solid: 1H NMR (CDCl3) δ 7.87-7.77 (m, 6 H), 7.67 (s,
1 H), 7.61 (s, 1 H), 7.54-7.40 (m, 6 H), 7.26-7.16 (m, 6 H),
7.03-6.93 (m, 4 H), 5.66 (d, J ) 15 Hz, 1 H), 5.63 (d, J ) 15
Hz, 1 H), 4.06 (d, J ) 15 Hz, 1 H), 4.01 (d, J ) 15 Hz, 1 H),
3.41-3.34 (m, 2 H), 3.20 (m, 1 H), 3.08-2.81 (abx m, 2 H),
2.42 (m, 2 H), 1.90 (m, 1 H), 1.65 (m, 1 H), 1.60 (bs, 1 H); DCI
MS (NH3) m/z 591.5 (M + H+, 100). Anal. Calcd for
A solution of 6 (34 mg, 0.05 mmol) in toluene was heated to
reflux and treated with Bu3SnH (0.03 mL, 0.1 mmol) and AIBN
(4 mg). The mixture was heated at reflux for 1 h, the solvent
was removed under vacuum, and the residue was chromato-
graphed (HPLC, Zorbax Sil, 60% EtOAc/hexane) to give 20 mg
of the reduced product as a film. The film was dissolved in
methanol and cooled in an ice bath, and HCl gas was bubbled
in for 20 min and then warmed to room temperature over 1 h.
The solvent was removed under vacuum, and the residue was
chromatographed (HPLC, Zorbax Sil, 10% MeOH/CHCl3) to
give 10 mg of alcohol 9 identical to the product previously
reported:6 1H NMR (CDCl3) δ 7.38-7.12 (m, 8 H), 7.05 (d, J )
7 Hz, 2 H), 3.87 (dd, J ) 7, 14 Hz 2 H), 3.72 (m, 1 H), 3.62 (m,
1 H), 3.40 (m, 1 H), 3.11 (dd, J ) 6, 13 Hz, 1 H, abx), 2.95 (dd,
J ) 10, 12 Hz, 1 H, abx), 2.85 (dd, J ) 7, 14 Hz, 1 H) 2.67 (dd,
J ) 7, 14 Hz, 1 H), 2.51 (m, 2 H), 2.30 (d, J ) 10 Hz, 1 H),
1.96 (m, 1 H), 1.70 (m, 1 H), 1.03 (m, 2 H), 0.60-0.15 (m, 8
H); CIMS (NH3) m/z 419 (M + H+, 100); HRMS calcd for
C
27H34N2O2 (M + H+) 419.2699, found 419.2704.
(4S,5S,6R)-Tet r a h yd r o-1,3-b is(2-n a p h t h ylm et h yl)-5-
h yd r oxy-4-(1(S)-flu or o-2-p h en yleth yl)-6-(p h en ylm eth yl)-
2(1H)-p yr im id in on e (11). A solution of (4R,5S,6S,7R)-
h exa h ydr o-5,6-dih ydr oxy-1,3-bis(2-n a ph t h ylm et h yl)-4,7-
bis(phenylmethyl)-2H-1,3-diazepin-2-one (10)4 (0.10 g, 0.16
mmol) in CH2Cl2 (20 mL) was treated with DAST (0.026 mL,
0.16 mmol) as described above and chromatographed (HPLC,
Zorbax Sil, 50% EtOAc/hexane) to give 35 mg of 11 as a foam:
1H NMR (CDCl3) δ 8.00-7.80 (m, 8 H), 7.68-7.54 (m, 6 H),
7.34-7.19 (m, 6 H), 7.06 (m, 2 H), 6.88 (d, J ) 7 Hz, 2 H), 5.83
(d, J ) 15 Hz, 1 H), 5.81 (d, J ) 15 Hz, 1 H), 4.80 (m, 0.5 H),
4.63 (m, 0.5 H), 4.24 (d, J ) 15 Hz, 1 H), 4.18 (d, J ) 15 Hz,
1 H), 3.57 (m, 2 H), 3.31 (m, 1 H), 3.20 (m, 1 H, abx), 2.98 (m,
1 H, abx), 2.80-2.55 (m, 2 H), 1.95 (d, J ) 8 Hz, 1 H); CIMS
(NH3) m/z 609 (M + H+, 100); HRMS calcd for C41H38N2O2F
(M + H+) 609.2917, found 609.2911. Anal. Calcd for
C
41H38N2O2: C, 83.36; H, 6.48; N, 4.74. Found: C, 83.06; H,
6.48; N, 4.50.
(4R,5R,6R)-Tet r a h yd r o-1,3-b is(2-n a p h t h ylm et h yl)-5-
h yd r oxy-4-(2-p h en yleth yl)-6-(p h en ylm eth yl)-2(1H)-p yr i-
m id in on e (15). Meth od 2. To a solution of (4R,5S,6S,7R)-
hexahydro-5,6-dihydroxy-1,3-bis(2-naphthyl-methyl)-4,7-bis-
(phenylmethyl)-2H-1,3-diazepin-2-one (10)4 (2.0 g, 3.3 mmol)
in CH2Cl2 (40 mL) at room temperature was added
2-acetoxyisobutyryl bromide (2.0 g, 10 mmol), and the
solution was stirred at room temperature for 10 min. The
solution was quenched with saturated NaHCO3, and after
a general workup the residue was chromatographed (MPLC
C
41H37N2O2F‚0.2H2O: C, 80.42; H, 6.16; N, 4.57. Found: C,
80.41; H, 6.16; N, 4.43.
(4R,5S,6S,7R)-Hexa h yd r o-5-(m esyloxy)-6-h yd r oxy-1,3-
bis(2-n a p h th ylm eth yl)-4,7-bis(p h en ylm eth yl)-2H-1,3-d i-
a zep in -2-on e (12). A solution of (4R,5S,6S,7R)-hexahydro-
5,6-dihydroxy-1,3-bis(2-naphthylmethyl)-4,7-bis(phenylmethyl)-
2H-1,3-diazepin-2-one (10)4 (0.60 g, 1.0 mmol) in pyridine was
treated with methanesulfonyl chloride (0.17 g, 1.5 mmol) and
stirred at room temperature for 3 h. After a general workup,
the solid residue was chromatographed (MPLC, silica gel, 40%
EtOAc/hexane) to give 420 mg of 12 as a white solid: 1H NMR
(CDCl3) δ 7.84-7.76 (m, 6 H), 7.58-7.40 (m, 6 H), 7.40-7.21
(m, 8 H), 7.09 (m, 4 H), 5.05 (d, J ) 14 Hz, 1 H), 5.03 (d, J )
14 Hz, 1 H), 4.45 (dd, J ) 4.5, 10 Hz, 1 H), 3.91 (m, 1 H), 3.78
(m, 1 H), 3.66 (m, 1 H), 3.44 (d, J ) 14 Hz, 1 H), 3.22-2.85
silica gel 30% EtOAc/hexane) to give 1.3
g of the
1-bromo-2-phenylethyl acetate tetrahydropyrimidinone 17b:
1H NMR (CDCl3) δ 7.89-7.78 (m, 6 H), 7.74 (m, 2 H),
7.60 (m, 1 H), 7.56-7.46 (m, 5 H), 7.19-7.13 (m, 4 H),
7.04 (m, 2 H), 6.47-6.74 (m, 2 H), 6.67 (d, J ) 8 Hz,
2 H), 5.72 (d, J ) 15 Hz, 1 H), 5.66 (d, J ) 15 Hz,
1 H), 4.67 (m, 1 H), 4.28 (d, J ) 15 Hz, 1 H), 4.13 (d,
J
) 15 Hz, 1 H), 4.06 (m, 1 H), 3.77 (dd, J ) 4, 8 Hz,

4764 J . Org. Chem., Vol. 63, No. 14, 1998
De Lucca
1 H), 3.59 (m, 1 H), 3.20 (dd, J ) 5, 13 Hz, 1 H), 2.85
(abx m, 2 H), 2.68 (dd, J ) 5, 13 Hz, 1 H), 1.26 (s, 3
H); CIMS (NH3) m/z 713 (M + H+, 100) 711 (M + H+,
95). Anal. Calcd for C43H39N2O3Br: C,72.57; H, 5.52; N,
3.95. Found: C, 72.24; H, 5.55; N, 3.72.
(dd, J ) 4, 15 Hz, 1 H), 3.16 (dd, J ) 4, 14 Hz, 1 H), 3.00-2.84
(m, 3 H), 2.65 (dd, J ) 8, 15 Hz, 1 H), 2.10 (s, 3 H); DCI MS
(NH3) m/z 351 (M + H+, 100). Anal. Calcd for C21H22N2O3:
C, 71.98; H, 6.34; N, 7.99; Found: C, 72.06; H, 6.34; N, 7.84.
(4R,5S,6R,7R)-1,3-Dia za -4,7-b is(p h en ylm et h yl)-5-(h y-
d r oxy)[4.1.0]bicycloh ep ta n -2-on e (24). Meth od 1. A solu-
tion of acetate 23 (100 mg, 0.29 mmol) in methanol (5 mL)
was treated with 1 N NaOH (10 drops from 2 mL disposable
pipet) and stirred at room temperature for 30 min. After a
general workup, 30 mg of 24 was obtained as a white solid.
Anal. Calcd for C21H22N2O3‚0.25CH3OH: C, 73.08; H, 6.69;
N, 8.85. Found: C, 73.23; H, 6.63; N, 8.49.
Meth od 2. A solution of acetate 23 (350 mg, 1.0 mmol) in
THF was cooled in an ice bath, treated with LAH (76 mg, 2.0
mmol), and stirred while allowing the solution to warm to room
temperature for 3 h. After a general workup, 300 mg of 24
was obtained as a white solid recrystallized from EtOAc/
hexane: mp 170-176 °C dec; 1H NMR (CDCl3/CD3OD) δ 7.38-
7.16 (m, 10 H), 3.97 (dd, J ) 5 Hz, J ) 7 Hz, 1 H), 3.52 (m, 1
H), 3.40-3.20 (m, 2 H), 3.00-2.74 (m, 3 H), 2.51 (dd, J ) 10
Hz, J ) 15 Hz, 1 H); DCI MS (NH3) m/z 309 (M + H+, 100).
Anal. Calcd for C21H22N2O3‚0.2(EtOAc)‚0.2(hexane): C, 73.49;
H, 7.17; N, 8.16. Found: C, 73.62; H, 6.93; N, 8.16.
(4R,5S,6R)-Tetr a h yd r o-5-(a cetyloxy)-4-(1(S)-br om o-2-
p h en yleth yl)-6-(p h en ylm eth yl)-2(1H)-p yr im id in on e (25).
A solution of aziridine 23 (1.0 g, 2.9 mmol) in dioxane was
cooled in an ice bath while HBr(gas) was bubbled into the
solution for 10 min. The ice bath was removed and the
solution stirred at room temperature for 20 min. The solvent
was removed under vacuum, and the residue was chromato-
graphed (MPLC, silica gel, EtOAc) to give 900 mg of 25 as a
white solid: 1H NMR (CDCl3) δ 7.36-7.11 (m, 10 H), 5.85 (bs,
1 H), 5.07 (bs, 1 H), 5.05 (m, 1 H), 4.23 (m, 1 H), 3.95 (m, 1 H),
3.61 (m, 1 H), 3.23 (d, J ) 7 Hz, 2 H), 2.70 (abx m, 2 H), 2.12
(s, 3 H); CIMS (NH3) m/z 433, 431 (M + H+, 35).
(4R,5R,6R)-Tetr ah ydr o-5-(acetyloxy)-4-(2-ph en yleth yl)-
6-(p h en ylm eth yl)-2(1H)-p yr im id in on e (26). A solution of
bromo acetate 25 (900 mg, 2.1 mmol) in acetic acid was treated
with 10 g of Zn dust as described above to give after chroma-
tography (MPLC, silica gel, EtOAc-10% MeOH/EtOAc) 600
mg of 26 as a white solid: 1H NMR (CDCl3) δ 7.35-7.10 (m,
10 H), 6.08 (bs, 1 H), 5.28 (bs, 1 H), 4.80 (m, 1 H), 3.80 (m, 1
H), 3.42 (m, 1 H), 2.83 (abx m, 2 H), 2.77 (m, 1 H), 2,62 (m, 1
H), 2.12 (s, 3 H), 1.74 (m, 2 H); 13C NMR (CDCl3) δ 170.2, 156.3,
140.26, 135.40, 129.0, 128.9, 128.5, 128.3, 127.3, 126.2, 67.1,
53.5, 51.2, 36.9, 31.4, 20.9; CIMS (NH3) m/z 353 (M + H+, 100).
(4S,5R,6R)-Tetr a h yd r o-5-h yd r oxy-4-(â-styr en e)-6-(p h e-
n ylm eth yl)-2(1H)-p yr im id in on e (27). Crude bromoacetate
25 (10.7 g, 25 mmol) was dissolved in MeOH, treated with 10
g of KOH, and stirred at room temperature overnight. After
a general workup, 7.0 g of 27 was obtained as a white solid:
mp 231-233 °C; 1H NMR (CDCl3/CD3OD) δ 7.36-7.21 (m, 10
H), 6.56 (d, J ) 16 Hz, 1 H), 6.06 (dd, J ) 5, 16 Hz, 1 H), 5.74
(bs, 1 H, exchanges), 4.95 (bs, 1 H, exchanges), 4.18 (m, 1 H),
3.75 (m, 1 H), 3.58 (m, 1 H), 3.01 (abx dd, J ) 6, 14 Hz, 1 H),
2.81 (abx dd, J ) 6, 14 Hz, 1 H); CIMS (NH3) m/z 309 (M +
H+, 100). Anal. Calcd for C19H20N2O2‚0.2H2O: C, 71.90; H,
6.67; N, 8.83. Found: C, 71.63; H, 6.41; N, 8.71.
The 1-bromo-2-phenylethyl acetate 17b (0.4 g, 0.6 mmol))
was dissolved in 50 mL of acetic acid, treated with Zn(dust)
(1 g), and vigorously stirred at room temperature until TLC
analysis showed complete conversion. The mixture was
filtered and the solid washed thoroughly with EtOAc. The
filtrate was washed with water, saturated NaHCO3, and brine.
The solvent was removed under vacuum to give the phenethyl
acetate 18b. The crude phenethyl acetate was dissolved in
MeOH, treated with 1 N NaOH (5 mL), and stirred at room
temperature. After a general workup, the resulting residue
was chromatographed (MPLC silica gel 50% EtOAc/hexane)
to give 170 mg of 15 identical to that obtained using method
1 above.
(4R,5R,6R)-Tet r a h yd r o-1,3-b is(p h en ylm et h yl)-5-h y-
d r oxy-4-(2-p h en yleth yl)-6-(p h en ylm eth yl)-2(1H)-p yr im i-
din on e (19). Following the proceedure for 17b, (4R,5S,6S,7R)-
hexahydro-5,6-dihydroxy-1.3-bis(phenylmethyl) -4,7-bis(phenyl-
methyl)-2H-1,3-diazepin-2-one (16)4 (1.3 g, 2.6 mmol) was
treated with 2-acetoxyisobutyryl bromide (1.7 g, 8.1 mmol) to
give after chromatography (MPLC silica gel 30% EtOAc/
hexane) 1.4 g of 17a . A fraction of the eluent from this
chromatography was allowed to evaporate slowly to give
crystals of the bromo acetate 17a that were of sufficient quality
for single-crystal X-ray analysis. For 17a : mp 178-180 °C;
1H NMR (CDCl3) δ 7.42-7.16 (m, 16 H), 6.89-6.79 (m, 4 H),
5.50 (d, J ) 15 Hz, 1 H), 5.43 (d, J ) 15 Hz, 1 H), 4.71 (t, J )
4 Hz, 1 H), 4.10 (d, J ) 15 Hz, 1 H), 4.02 (m, 1 H), 3.87 (d, J
) 15 Hz, 1 H), 3.71 (dd, J ) 4, 7 Hz, 1 H), 3.58 (m, 1 H), 3.10
(dd, J ) 6, 13 Hz, 1 H), 2.95 (dd, J ) 3, 15 Hz, 1 H), 2.77 (dd,
J ) 10, 15 Hz), 2.65 (dd, J ) 10, 13 Hz, 1 H), 1.61 (s, 3 H).
Anal. Calcd for C35H35N2O3Br‚0.2C6H14: C, 69.15; H, 6.06; N,
4.45. Found: C, 69.26; H, 5.79; N, 4.31.
The bromo acetate 17a (1.0 g) was treated with Zn(dust) (7
g) as described above for 15 to give after chromatography
(MPLC silica gel 65% EtOAc/hexane) 820 mg of the acetate
18a as a white foam. The acetate 18a (400 mg, 0.68 mol) was
dissolved in MeOH, treated with 1 N NaOH (5 mL), and stirred
at room temperature. After a general workup, the residue was
chromatographed (MPLC silica gel 65% EtOAc/hexane) to give
300 mg of 19 as a foam: 1H NMR (CDCl3) δ 7.37-7.15 (m, 16
H), 6.97 (m, 4 H), 5.46 (d, J ) 15 Hz, 1 H), 5.42 (d, J ) 14 Hz,
1 H), 3.89 (d, J ) 14 Hz, 1 H), 3.82 (d, J ) 15 Hz, 1 H), 3.41
(m, 1 H), 3.33 (m, 1 H), 3.17 (m, 1 H), 2.95 (m, 2 H), 2.85 (m,
2 H), 2.40 (t, J ) 8 Hz, 2 H), 1.9 (m, 1 H), 1.61 (m, 2 H); CIMS
(NH3) m/z 491 (M + H+, 100). Anal. Calcd for C33H34N2O2:
C, 80.78; H, 6.98; N, 5.71. Found: C, 80.46; H, 6.97; N, 5.66.
(4S,5S,6R)-Tet r a h yd r o-1,3-b is(2-n a p h t h ylm et h yl)-5-
h yd r oxy-4-(1(S)-br om o-2-p h en yleth yl)-6-(p h en ylm eth yl)-
2(1H)-p yr im id in on e (20b). 1-Bromo-2-phenylethyl acetate
17b (100 mg, 0.14 mmol) was dissolved in MeOH (5 mL) and
treated with 1 N NaOH (1 mL, 1.0 mmol) at room temperature
for 1 h. After a general workup, 80 mg of 20b was obtained
as a white solid: mp 85 °C dec; 1H NMR (CDCl3) δ 7.89-7.78
(m, 7 H), 7.64 (m, 2 H), 7.50 (m, 4 H), 7.40-7.00 (m, 9 H),
6.67 (d, J ) 8 Hz, 2 H), 5.60 (d, J ) 15 Hz, 1 H), 5.56 (d, J )
15 Hz, 1 H), 4.21 (d, J ) 15 Hz, 1 H), 3.76 (m, 1 H), 3.62 (d, J
) 15 Hz, 1 H), 3.36 (m, 1 H), 3.01-2.90 (m, 3 H), 2.68 (dd, J
) 5, 13 Hz, 1 H), 2.00 (d, J ) 7 Hz, 1 H); CIMS (NH3) m/z
669.2 (M + H+, 67), 671.2 (M + H+, 72), 589.2 ((M - HBr +
H+, 100). Anal. Calcd for C41H37N2O2Br‚0.2H2O: C, 73.14;
H, 5.60; N, 4.16. Found: C, 73.09; H, 5.63; N,3.99.
(4R,5R,6R)-Tetr a h yd r o-5-h yd r oxy-4-(2-p h en yleth yl)-6-
(p h en ylm eth yl)-2(1H)-p yr im id in on e (28). Meth od 1. A
solution of 27 (7.0 g, 23 mmol) in THF/MeOH was treated with
3 g of 10% Pd/C and hydrogenated at 50 psi for 3 h at room
temperature. The solution was filtered through Celite and the
solvent removed under vacuum to give 6.3 g of 28. Product
was identical to that previously described.6
Meth od 2. A solution of 26 (0.5 g, 1.4 mmol) in methanol
was treated with 5 mL of 1 N NaOH solution and stirred at
room temperature for 8 h. After a general workup, 0.3 g of
28 was obtained identical to that previously described:6 mp
162-163 °C; 1H NMR (CDCl3) δ 7.38-7.19 (m, 10 H), 6.69 (bs,
1 H), 5.00 (bs, 1 H), 4.61 (d, J ) 8 Hz, 1 H), 3.60 (t, J ) 7 Hz,
1 H), 3.49 (bm, 1 H), 3.38 (bm, 1 H), 3.30 (dd, J ) 7, 14 Hz, 1
H, abx), 2.82 (dd, J ) 7, 14 Hz, 1 H, abx), 2.78 (m, 1 H, abx)
2.57 (m, 1 H, abx), 1.62 (m, 2 H); 13C NMR (CDCl3) δ 157.1,
141.7, 137.2, 129.7, 129.2, 128.8, 128.8, 127.3, 126.4, 65.9, 57.1,
(4R ,5S ,6R ,7R )-1,3-D ia za -4,7-b is (p h e n y lm e t h y l)-5-
(a cetyloxy)[4.1.0]bicycloh ep ta n -2-on e (23). A solution of
monoacetate 224 (2.0 g, 5.0 mmol) in CH2Cl2 (30 mL) was
cooled to 0 °C in an ice bath and treated with DAST (0.8 mL,
6.0 mmol) via syringe. The solution was stirred at 0 °C for 30
min. After a general workup, 1.9 g of 23 was obtained as a
white solid. The solid was recrystallized from ethyl acetate:
mp 222 °C; 1H NMR (CDCl3) δ 7.38-7.00 (m, 10 H), 5.54 (d, J
) 6 Hz, 1 H), 4.97 (dd, J ) 5, 7 Hz, 1 H), 3.81 (m, 1 H), 3.26

Rearrangement of Hexahydro-1,3-diazepin-2-ones
J . Org. Chem., Vol. 63, No. 14, 1998 4765
53.5, 38.4, 37.7, 32.4; CIMS (NH3) m/z 311 (M + H+, 100). Anal.
Calcd for C19H22N2O2: C, 73.52; H, 7.14; N, 9.04. Found: C,
73.49; H, 7.03; N, 8.92.
1 H), 1.96 (m, 1 H), 1.73 (m, 1 H); DCI MS (NH3) m/z 401 (M
+ H+, 100). Anal. Calcd for C26H28N2O2: C, 77.97; H, 7.06;
N, 6.99. Found: C, 78.06; H, 7.19; N, 6.97.
(4R,5R,6R)-Tetr a h yd r o-5-(tetr a h yd r op yr a n -2-yloxy)-4-
(2-p h en ylet h yl)-6-(p h en ylm et h yl)-2(1H )-p yr im id in on e
(29). A solution of alcohol 28 (6.2 g, 20 mmol) in chloroform
was treated with dihydropyran (12.0 g, 140 mmol) and TsOH‚
H2O (0.4 g, 2 mmol) and stirred overnight at room tempera-
ture. After a general workup, 7.8 g of 29 was obtained as white
(4R,5R,6R)-Tet r a h yd r o-1-[(3-cya n op h en yl)m et h yl]-6-
(p h en ylm eth yl)-5-h yd r oxy-4-(2-p h en yleth yl)-2(1H)-p yr i-
m id in on e (39). By using the same procedure detailed above
for the synthesis of 36, the aziridine 23 was converted to 39:
1H NMR (CDCl3) δ 7.48 (d, J ) 7 Hz, 1 H), 7.35-7.10 (m, 13
H), 5.35 (s, 1 H), 5.00 (d, J ) 15 Hz, 1 H), 3.53 (m, 1 H), 3.38
(m, 2 H), 3.20 (d, J ) 15 Hz, 1 H), 3.12 (dd, J ) 5, 13 Hz, 1 H),
2.87-2.58 (m, 3 H), 2.29 (bs, 1 H), 2.05 (m, 1 H), 1.77 (m, 1
H); DCI MS (NH3) m/z 426 (M + H+, 100); HRMS calcd for
1
solid: mp 182-184 °C; H NMR (CDCl3) δ 7.38-7.19 (m, 10
H), 4.83 (bs, 0.5 H), 4.78 (bs, 0.5 H), 4.69 (bs, 1 H), 4.45 (bs, 1
H), 3.97-3.42 (m, 5 H), 3.09-2.57 (m, 4 H), 1.92-1.51 (m, 8
H); CIMS (NH3) m/z 395.3 (M + H+, 100). Anal. Calcd for
C
27H28N3O2 (M + H+) 426.2181, found 426.2159.
C
24H30N2O3: C, 73.09; H, 7.68; N, 7.10. Found: C, 72.76; H,
(4R,5R,6R)-Tet r a h yd r o-1,6-b is(p h en ylm et h yl)-5-h y-
7.51; N, 6.91.
d r oxy-4-(1-h yd r oxy-2-p h en ylet h yl)-2(1H )-p yr im id in o-
n e (34). The aziridine 32 (30 mg, 0.07 mmol) was dissolved
in 1 mL of trifluoroacetic acid for 1 h. After a general workup,
the trifluoroacetate obtained was redissolved in methanol (5
mL), treated with 1 N NaOH (1 mL), and stirred at room
temperature for 2 h. The solution was acidified with 1 N HCl
(4R,5R,6R)-Tetr a h yd r o-5-h yd r oxy-1,3-bis(1H-in d a zol-
5-ylm et h yl)-4-(2-p h en ylet h yl)-6-(p h en ylm et h yl)-2(1H )-
p yr im id in on e (31). A solution of 29 (2.47 g, 6.3 mmol) and
5-(bromomethyl)-1-SEM-indazole12 (4.70 g, 13.8 mmol) in THF
was treated dropwise with a 1 M solution of KO-t-Bu (in THF)
via syringe. The resulting solution was stirred at room
temperature for 30 min. The solvent was removed and the
residue chromatographed (MPLC, silica gel, 25% EtOAc/
hexane) to give 4.3 g of 30 (75% yield). A solution of 30 (4.3
g, 4.6 mmol) in MeOH (150 mL) was treated with 50 mL of
concentrated HCl and heated at reflux for 2 h. The solution
was concentrated to half its volume on a rotary evaporator
and made basic with 1 N NaOH. After a general workup, the
residue was chromatographed (MPLC, silica gel, 1.5% MeOH/
EtOAc) to give 2.3 g (88% yield) of 31: mp 130-134 °C; 1H
NMR (CDCl3) δ 10.95 (bs, 1H), 10.87 (bs, 1 H), 7.84 (s, 1 H),
7.72 (s, 1 H), 7.50 (s, 1 H), 7.47 (s, 1 H), 7.35-7.15 (m, 10 H),
7.07 (2 overlapping d, J ) 7 Hz, 2 H), 6.95 (2 overlapping d, J
) 7 Hz, 2 H), 5.51 (d, J ) 15 Hz, 1 H), 5.48 (d, J ) 15 Hz, 1
H), 4.10 (d, J ) 16 Hz, 1 H), 3.94 (d, J ) 15 Hz, 1 H), 3.53 (m,
1 H), 3.42 (m, 1 H), 3.32 (m, 1 H), 2.94 (m, 2 H), 2.42 (m, 2 H),
1.90 (m, 1 H), 1.76 (m, 1 H), 1.62 (bs, H); CIMS (NH3) m/z 571
(M + H+, 100). Anal. Calcd for C35H34N6O2: C, 73.66; H, 6.00;
N, 14.73. Found: C, 73.38; H, 5.95; N, 14.50.
(4R ,5S ,6R ,7R )-1,3-Dia za -1,4,7-t r is(p h e n ylm e t h yl)-5-
(a cetyloxy)[4.1.0]bicycloh ep ta n -2-on e (32a ). A solution of
23 (0.20 g, 0.57 mmol) in DMF was cooled in an ice bath,
treated with NaH (30 mg, 0.7 mmol, 60% oil dispersion), and
stirred for 30 min. Then benzyl bromide (0.12 g, 0.69 mmol)
was added, and the solution was allowed to warm to room
temperature for 1 h. After a general workup, the residue was
chromatographed (HPLC, Zorbax Sil, 50% EtOAc/hexane) to
give 80 mg of 32a as a white solid. An additional 30 mg of
the 5-benzyl ether compound was also obtained. For 32a : 1H
NMR (CDCl3) δ 7.40-7.20 (m, 13 H), 7.08 (m, 2 H), 5.05 (d, J
) 15 Hz, 1 H), 4.53 (dd, J ) 5, 7 Hz, 1 H), 3.77 (m, 1 H), 3.28
(dd, J ) 4, 15 Hz, 1 H), 3.22 (abx m, 1 H), 3.05 (abx m, 1 H),
2.94 (m, 1 H), 2.83 (m, 1 H), 2.83 (d J ) 15 Hz, 1 H), 2.55 (dd,
J ) 8, 15 Hz, 1 H), 1.95 (s, 3 H); DCI MS (NH3) m/z 441 (M +
H+, 100).
and extracted into methylene chloride. After
a general
workup, 15 mg of 34 was obtained as a white solid: mp 193-
194 °C; 1H NMR (CDCl3) δ 7.41-7.15 (m, 13 H), 6.95 (m, 2
H), 5.89 (bs, 1 H), 5.05 (d, J ) 15 Hz, 1 H), 4.90 (m, 2 H), 3.41
(m, 2 H), 3.18-2.65 (m, 7 H); DCI MS (NH3) m/z 417 (M +
H+, 100). Anal. Calcd for C26H28N2O3‚0.66(CH3OH): C, 73.16;
H, 7.06; N, 6.40. Found: C, 73.33; H, 6.88; N, 6.07.
(4R,5R,6R)-Tetr a h yd r o-1-[(3-h yd r oxyp h en yl)m eth yl]-
5-h yd r oxy-4-(2-p h en yleth yl)- 6-(p h en ylm eth yl)-2(1H)-p y-
r im id in on e (38). A solution of 23 (1.4 g, 4.1 mmol) in DMF
was alkylated with 3-benzyloxybenzyl bromide (1.4 g, 6.2
mmol) as described above to give after chromatography
(MPLC, silica gel, 50% EtOAc/hexane) 1 g of 37 (mixture of R
) OAc and R ) 3-benzyloxybenzyl) as a white solid. An
additional 0.5 g of pure 37 (R ) OH) was also obtained. For
37 (R ) OH): mp 184-185 °C. Anal. Calcd for C33H32N2O3:
C, 78.55 H, 6.39 N, 5.55 Found: C, 78.34 H, 6.34 N, 5.35.
A solution of 37 (mixture of R ) OAc and R ) 3-benzyloxy-
benzyl) (1 g) in methanol was treated with 1 N NaOH and
stirred at room temperature for 1 h. After a general workup,
the residue was chromatographed (MPLC, silica gel, 50%
EtOAc/hexane) to give 800 mg of 37 (mixture of R ) OH and
R ) 3-benzyloxybenzyl) as a white solid. A solution of 37
(mixture of R ) OH and R ) 3-benzyloxybenzyl) (800 mg) in
ethanol was treated with 10% Pd/C (800 mg) and hydrogenated
at 50 psi for 2 days. The solution was filtered through Celite
and the filtrate concentrated. The residue was chromato-
graphed (HPLC, Zorbax Sil, 3% MeOH/CHCl3) to give 230 mg
of 38 as a white solid. The 2-D COSY was consistent with
assigned structure: 1H NMR (CDCl3) δ 9.13 (s, 1H), 7.35-
7.12 (m, 9 H), 6.83-6.80 (m, 4 H), 6.39 (d, J ) 7 Hz, 1 H), 5.19
(bs, 1 H), 5.00 (d, J ) 15 Hz, 1 H), 3.36 (m, 1 H), 3.16 (m, 2
H), 3.02 (abx m, 1 H), 2.98 (d, J ) 15 Hz, 1 H), 2.70 (abx m, 1
H), 2.45 (m, 2 H), 1.86 (m, 1 H), 1.74 (d, J ) 5 Hz, 1 H), 1.30
(m, 1 H); DCI MS (NH3) m/z 417 (M + H+, 100); HRMS calcd
for C26H29N2O3 (M + H+) 417.2178, found 417.2163.
(4R,5R,6R)-Tetrahydro-1-[3-(N-hydroxycarboximidamido)-
p h e n y lm e t h y l]-3-(c y c lo p r o p y lm e t h y l)-6-(p h e n y l-
m eth yl)-5-h ydr oxy-4-(2-ph en yleth yl)-2(1H)-pyr im idin on e
(42). The alcohol 39 (0.5 g, 1.2 mmol) in methylene chloride
was treated with MEM-Cl (0.29 g, 2.4 mmol), and DIEA (0.3
g, 2.4 mmol), and the solution was heated at reflux overnight.
The solvent was removed under vacuum and the residue
chromatographed (MPLC, silica gel, EtOAc) to give 400 mg of
the MEM ether 40 as an oil: DCI MS (NH3) m/z 514.2 (M +
H+, 100).
(4R ,5S ,6R ,7R )-1,3-Dia za -1,4,7-t r is(p h e n ylm e t h yl)-5-
h yd r oxy[4.1.0]bicycloh ep ta n -2-on e (33). A solution of 32a
(20 mg) in methanol was treated with 5 mL of 1 N NaOH and
stirred at room temperature for 1 h. After a general workup,
the residue was chromatographed (HPLC, Zorbax Sil, 70%
EtOAc/hexane) to give 15 mg of 33 as a white solid. The solid
was recrystallized from ethyl acetate to give crystals suitable
for X-ray analysis: 1H NMR (CDCl3) δ 7.41-7.21 (m, 13 H),
6.96 (m, 2 H), 5.08 (d, J ) 15 Hz, 1 H), 3.63 (m, 1 H), 3.58-
3.34 (m, 3 H), 3.04 (m, 1 H), 2.95 (m, 1 H), 2.81 (m, 1 H), 2.56
(d, J ) 15 Hz, 1 H), 2.38 (dd, J ) 10, 15 Hz, 1 H), 2.25 (bs, 1
H); DCI MS (NH3) m/z 399 (M + H+, 100).
(4R,5R,6R)-Tet r a h yd r o-1,6-b is(p h en ylm et h yl)-5-h y-
d r oxy-4-(2-p h en yleth yl)-2(1H)-p yr im id in on e (36). By us-
ing the same procedure detailed above for the sequence 25/
The MEM ether 40 (0.25 g, 0.5 mmol) was alkylated with
cyclopropylmethyl bromide (0.39 g, 3.0 mmol; DMF, NaH (0.11
g, 3.0 mmol, 60% dispersion, 70 °C for 1 h) as described above
to give after chromatography (HPLC, Zorbax Sil, EtOAc) 41:
1H NMR (CDCl3) δ 7.50 (m, 1 H), 7.37-7.10 (m, 13 H), 4.84
(d, J ) 15 Hz, 1 H), 4.69 (dd, J ) 7, 22 Hz, 2 H), 3.90 (dd, J )
7, 15 Hz, 1 H), 3.80-3.60 (m, 5 H), 3.52 (m, 2 H), 3.36 (s, 3 H),
3.20 (d, J ) 15 Hz, 1 H), 3.20 (d, J ) 15 Hz, 1 H), 3.06-2.88
1
26/28, the aziridine 32a was converted to 36: mp 180 °C; H
NMR (CDCl3) δ 7.36-7.15 (m, 13 H), 7.03 (m, 2 H), 5.16 (d, J
) 15 Hz, 1 H), 4.98 (s, 1 H), 3.49 (m, 1 H), 3.36 (m, 2 H), 3.17
(d, J ) 15 Hz, 1 H), 3.08 (dd, J ) 5, 13 Hz, 1 H), 2.83 (dd, J )
9, 13 Hz, 1 H), 2.77 (m, 1 H), 2.62 (m, 1 H), 2.09 (d, J ) 7 Hz,

4766 J . Org. Chem., Vol. 63, No. 14, 1998
De Lucca
(m, 3 H), 2.52 (m, 2 H), 2.05 (m, 2 H), 1.07 (m, 1 H), 0.54 (m,
2 H), 0.32 (m, 2 H).
2 H); CIMS (NH3) m/z 439 (M + H+, 100). Anal. Calcd for
C
27H32N2OF2‚0.2H2O: C, 73.34; H, 7.39; N, 6.34. Found: C,
The MEM group was removed (4 N HCl/dioxane, room
temperature, 3 h), and 41 (40 mg) was converted to the
amidoxime (NH2OH‚HCl (60 mg), Et3N (80 mg), EtOH, reflux,
2 h). After a general workup, the residue was chromato-
graphed (HPLC, Zorbax NH2, 15% MeOH/CH2Cl2) to give 42
73.44; H, 7.43; N, 6.18.
(3S,4S)-1,3-Bis(n aph th alen ylm eth yl)-4,5-bis(1(S)-flu or o-
2-p h en ylm eth yl)-2-im id a zolid in on e (49b). The tetrahy-
dropyrimidinone 11 (or the diazepin-2-one 10) was treated with
excess DAST as described above to give the C2-symmetric
imidazolidinone 49b: 1H NMR (CDCl3) δ 7.83 (m, 3 H), 7.33
(s, 1 H0, 7.49 (m, 3 H), 7.10 (m, 3 H), 6.62 (m, 2 H), 5.15 (d, J
) 15 Hz, 2 H), 4.36 (d, J ) 15 Hz, 2 H), 4.57-4.42 (dm, J ) 46
Hz, 2 H), 3.50 (m, 2 H), 2.66-2.25 (m, 4 H); CIMS (NH3) m/z
611 (M + H+, 100). Anal. Calcd for C41H36N2OF2‚0.25H2O:
C, 80.04; H, 5.98; N, 4.55. Found: C, 79.98; H, 6.02; N, 4.46.
(4S,5R)-Dim eth yl-3,3′-[[4-(1(S)-br om o-2-p h en yleth yl)-
2-oxo-5-(2-ph en yleth yl)-1,3-im idazolidin yl]bis(m eth ylen e)]-
bis(ben zoa te) (52). The tetrahydropyrimidinone 506 (45 mg)
was treated with triphenylphosphine (135 mg) and CBr4 (145
mg) in methylene chloride at room temperature for 48 h. The
solvent was removed under vacuum and the residue chro-
matographed (MPLC silica gel 50% EtOAc/hexane) to give 20
mg of 52: 1H NMR (CDCl3) δ 7.98 (m, 4 H), 7.59 (d, J ) 8 Hz,
1 H), 7.41 (m, 3 H), 7.21 (m, 6H), 7.01 (m, 2 H), 6.80 (m, 2 H),
5.08 (d, J ) 15 Hz, 1 H), 4.86 (d, J ) 15 Hz, 1 H), 4.36 (d, J )
15 Hz, 1 H), 4.07 (d, J ) 15 Hz, 1 H), 4.07 (m, 1 H), 3.85 (s, 3
H), 3.75 (s, 3 H), 3.67 (m, 1 H), 3.58 (m, 1 H), 3.07 (dd, J ) 2,
15 Hz, 1 H), 2.50 (m, 1 H), 2.32 (m, 2 H), 1.88 (m, 2 H); CIMS
(NH3) m/z 688 (M + NH4+, 100) 686 (M + NH4+, 92) 671 (M +
H+, 82) 669 (M + H+, 75).
(4S,5R)-Dim eth yl-3,3′-[[4-(1(S)-h ydr oxy-2-ph en yleth yl)-
2-oxo-5-(2-ph en yleth yl)-1,3-im idazolidin yl]bis(m eth ylen e)]-
bis(ben zoa te) (51). The tetrahydropyrimidinone 506 (500
mg) was treated under the Mitsunobu and hydrolysis condi-
tions described for the synthesis of 8 to give 400 mg of 51: 1H
NMR (CDCl3) δ 7.98 (m, 4 H), 7.59 (d, J ) 8 Hz, 1 H), 7.41 (m,
3 H), 7.21 (m, 6H), 6.96 (m, 2 H), 6.89 (m, 2 H), 5.00 (d, J ) 15
Hz, 1 H), 4.93 (d, J ) 15 Hz, 1 H), 4.34 (d, J ) 15 Hz, 1 H),
4.05 (d, J ) 15 Hz, 1 H), 3.84 (s, 3 H), 3.80 (m, 1 H), 3.78 (s,
3 H), 3.48 (m, 1 H), 3.38 (m, 1 H), 2.66 (dd, J ) 2, 15 Hz, 1 H),
2.43 (m, 1 H), 2.30 (m, 1 H), 2.17 (dd, J ) 10, 14 Hz, 1 H),
1.92 (bs, 1 H), 1.78 (m, 2 H); CIMS (NH3) m/z 607 (M + H+,
100).
1
as a foam: mp 130-134 °C; H NMR (CDCl3) δ 7.50-6. 95
(m, 14 H), 5.15 (d, J ) 15 Hz, 1 H), 4.84 (bs, 2 H), 3.90 (dd, J
) 7, 15 Hz, 1 H), 3.90 (bs, 1 H), 3.76 (d, J ) 15 Hz, 1 H), 3.57
(m, 1H), 3.43 (m, 1 H), 3.38 (m, 1 H), 3.52 (m, 2 H), 2.96 (m,
3 H), 2.78 (dd, J ) 7, 15 Hz, 1 H), 2.42 (m, 2 H), 1.87 (m, 1 H),
1.64 (m, 1 H), 1.07 (m, 1 H), 0.54 (m, 2 H), 0.32 (m, 2 H); ESI
MS (NH3) m/z 513.3 (M + H+, 100). Anal. Calcd for
C31H36N4O3: C, 72.63; H,7.09; N, 10.93. Found: C, 73.01; H,
6.97; N, 10.16.
Rea ction of Su lfa m id e 43 w ith 2-Acetoxybu tyr yl Br o-
m id e. Syn th esis of 44 a n d 45. To a solution of sulfamide
439 (5.3 g, 10 mmol) in CH2Cl2 (40 mL) at room temperature
was added 2-acetoxyisobutyryl bromide (4.2 g, 20 mmol), and
the solution was stirred at room temperature for 10 min. After
a general workup, the residue was chromatographed (MPLC
silica gel 30% EtOAc/hexane) to give 1.0 g of the seven-
membered ring analogue 45 and 2.5 g of a mixture of 45 and
1-bromo-2-phenylethyl six-membered-ring analogue 44. The
mixture was further purified by HPLC (Zorbax Sil, 30% EtOAc/
hexane) to obtain a pure sample of 44.
For 44: 1H NMR (CDCl3) δ 7.49-7.15 (m, 16 H), 7.02 (d, J
) 7 Hz, 2 H), 6.89 (m, 2 H), 4.89 (d, J ) 15 Hz, 1 H), 4.83 (m,
1 H), 4.66 (d, J ) 15 Hz, 1 H), 4.61 (m, 1 H), 4.53 (d, J ) 15
Hz, 1 H), 4.41 (m, 1 H), 4.23 (d, J ) 15 Hz, 1 H), 3.94 (dd, J )
4, 9 Hz, 1 H), 3.06 (dd, J ) 3, 15 Hz, 1 H), 2.94 (dd, J ) 5, 14
Hz, 1 H), 2.90 (dd, J ) 10, 15 Hz), 2.68 (dd, J ) 10, 14 Hz, 1
H), 1.75 (s, 3 H); CIMS (NH3) m/z 649 (M + H+, 100) 647 (M
+ H+, 92). Anal. Calcd for C34H35N2O4SBr: C,63.06; H, 5.46;
N, 3.34. Found: C, 63.05; H, 5.42; N, 4.20.
For 45: mp 103-105 °C; 1H NMR (CDCl3) δ 7.49-7.15 (m,
18 H), 7.00 (m, 2 H), 5.20 (m, 1 H), 5.00-4.20 (m, 6 H), 4.05
(m,1 H), 3.25-2.98 (m, 3 H), 2.75 (m, 1 H), 1.91 (s, 3 H); CIMS
(NH3) m/z 649 (M + H+, 100) 647 (M + H+, 95). Anal. Calcd
for C34H35N2O4SBr: C,63.06; H, 5.46; N, 3.34. Found: C,
63.07; H, 5.45; N, 4.23.
(4R,5R)-Dim et h yl-3,3′-[[2-oxo-4,5-b is(2-p h en ylet h yl)-
1,3-im id a zolid in ed iyl]bis(m eth ylen e)]bis(ben zoa te) (53).
Compound 51 (300 mg) was treated with TCDI and reduced
with Bu3SnH as described for the synthesis of 9 to give 50 mg
of the C2-symmetric imidazolidinone 53: 1H NMR (CDCl3) δ
7.95 (m, 4 H), 7.52 (d, J ) 8 Hz, 2 H), 7.43 (m, 2 H), 7.21 (m,
6H), 6.93 (m, 4 H), 5.01 (d, J ) 15 Hz, 2 H), 4.11 (d, J ) 15
Hz, 2 H), 3.85 (s, 6 H), 3.23 (m, 2 H), 2.42 (m, 2 H), 2.30 (m,
2 H), 1.78 (m, 4 H); CIMS (NH3) m/z 591 (M + H+, 100). Anal.
Calcd for C34H38N2O5‚0.33H2O: C, 74.48; H, 6.53; N, 4.70.
Found: C, 74.66; H, 6.39; N, 4.35.
Syn th esis of Com p ou n d 46. Reduction of 45 (200 mg,
0.31 mmol) with Zn/AcOH as described above gave (MPLC
silica gel 50% EtOAc/hexane) 70 mg of 46 as a white solid:
mp 149-151 °C; 1H NMR (CDCl3) δ 7.41-7.15 (m, 18 H), 7.00
(m, 2 H), 5.55 (s, 2 H), 4.81 (d, J ) 15 Hz, 2 H), 4.42 (m, 2 H),
4.38 (d, J ) 15 Hz, 2 H), 2.98 (dd, J ) 5, 14 Hz, 2 H), 2.75 (dd,
J ) 10, 14 Hz, 2 H); CIMS (NH3) m/z 509 (M + H+, 100);
HRMS calcd for C32H33N2O2S (M + H+) 509.2262, found
509.2238. Anal. Calcd for C32H32N2O2S‚0.033CDCl3: C, 75.05;
H, 6.29; N, 5.46. Found: C, 75.09; H, 6.31; N, 5.29.
Syn th esis of Com p ou n d 48. The same procedure as
outlined for the synthesis of 19 above was used to convert 44
1
Ack n ow led gm en t. The author thanks Drs. J . Ca-
labrese and N. J ones (Dupont CR&D) for the X-ray
crystal structure determinations of 17a , 24, and 33.
to 48: mp 170-172 °C; H NMR (CDCl3) δ 7.37-7.15 (m, 18
H), 6.82 (m, 2 H),4.8-4.6 (m, 3 H), 4.23 (s, J ) 15 Hz, 1 H),
3.54-3.21 (m, 3 H), 2.98 (m, 2 H), 2.39-2.00 (m, 3 H), 1.92
(bs, 1 H), 1.70 (m, 1 H); CIMS (NH3) m/z 527 (M + H+, 100).
Anal. Calcd for C32H34N2O3S: C, 72.97; H, 6.52; N, 5.33.
Found: C, 72.94; H, 6.42; N, 5.28.
Su p p or tin g In for m a tion Ava ila ble: Summary of crystal
data and structure refinement, atomic coordinates, bond
lengths and angles, anisotropic thermal parameters, and
intramolecular nonbonding distances for compounds 24 and
33 (17 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
(3S,4S)-1,3-Bis(cyclop r op ylm eth yl)-4,5-bis(1(S)-flu or o-
2-p h en ylm eth yl)-2-im id a zolid in on e (49a ). The tetrahy-
dropyrimidinone 2 (or the diazepin-2-one 1) was treated with
excess DAST as described above to give the C2-symmetric
imidazolidinone 49a : 1H NMR (CDCl3) δ 7.37-7.11 (m, 20 H),
4.93-4.71 (dm, J ) 48 Hz, 2 H), 4.04 (m, 2 H), 3.49 (dd, J )
7, 15 Hz, 2 H), 3.03 (m, 4 H), 2.96 (dd, J ) 7, 15 Hz, 2 H), 0.95
(m, 2 H), 0.59 (m, 2 H), 0.48 (m, 2 H), 0.29 (m, 2 H), 0.21 (m,
J O980533E