Conformationally constrained analogues of diacylglycerol. 19. Synthesis and protein kinase C binding affinity of diacylglycerol lactones bearing an N-hydroxylamide side chain

Article abstract of DOI:10.1021/jm030082c

The structures of N-hydroxylamides la and lb, previously reported by Lee et al. in J. Med. Chem. 2001, 44, 4309-4312 as strong protein kinase C (PK-C) ligands, were incorrect and correspond instead to esters 2a and 2b, respectively. Here, we report the sy

Full text of DOI:10.1021/jm030082c

2790
J . Med. Chem. 2003, 46, 2790-2793
Brief Articles
Con for m a tion a lly Con str a in ed An a logu es of Dia cylglycer ol. 19. Syn th esis a n d
P r otein Kin a se C Bin d in g Affin ity of Dia cylglycer ol La cton es Bea r in g a n
N-Hyd r oxyla m id e Sid e Ch a in
Yongseok Choi,†,‡ J i-Hye Kang,†,‡ Nancy E. Lewin,§ Peter M. Blumberg,§ J eewoo Lee,# and Victor E. Marquez*,†
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of
Health, Frederick, Maryland 21702, Laboratory of Cellular Carcinogenesis & Tumor Promotion, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, and Laboratory of Medicinal Chemistry,
College of Pharmacy, Seoul National University, Shinlin Dong, Kwanak-ku, Seoul 151-742, South Korea
Received February 19, 2003
The structures of N-hydroxylamides 1a and 1b, previously reported by Lee et al. in J . Med.
Chem. 2001, 44, 4309-4312 as strong protein kinase C (PK-C) ligands, were incorrect and
correspond instead to esters 2a and 2b, respectively. Here, we report the synthesis and complete
characterization of 1a and 1b together with the associated biological activity in terms of PK-C
binding affinity.
With the intent of testing the limits of reducing the
log P in diacylglycerol (DAG) lactones known for their
high binding affinity toward protein kinase C (PK-C),
isomeric compounds 1a and 1b, where the typical ester
side chain was replaced by an N-hydroxylamide chain,
were designed.1 This structural change reduced the
log P to an unprecedented calculated value of 3.58,
almost matching the value of the prototypic phorbol
ester phorbol 12,13-dibutyrate (PDBU, calculated log P
) 3.43). The reported nanomolar binding affinities for
compounds 1a and 1b were considered exceptional and
informative regarding the precise mode of binding of
DAG-lactones to the C1 domain of PK-C.1 Unfortu-
nately, the structures of 1a and 1b were incorrect and
the PK-C binding affinities attributed to these com-
pounds should correspond instead to those of the esters
2a and 2b, also reported in the same manuscript.1 An
erratum for this manuscript appears in the same issue
as this manuscript.2
targets. The original synthesis of these compounds was
based on the strategy that aldehydes 6a and 6b (Scheme
1) would generate the desired N-hydroxylamines 7a and
7b after treatment with NH2OH‚HCl followed by in situ
reduction of the intermediate oximes with sodium
cyanoborohydride. Unfortunately, either the intermedi-
ate oximes were never formed or they hydrolyzed backto
aldehydes 6a and 6b under the reaction conditions, thus
regenerating the starting alcohols 5a and 5b after
hydride reduction. Consequently, the ensuing acylation
with pivaloyl chloride produced instead esters 2a and
2b.
In this new approach, we employed a tert-butyldimeth-
ylsilyl-protected hydroxylamine reagent to form the
intermediate oxime from the same aldehydes (6a and
6b), and the resulting alkylhydroxylamines (7a and 7b)
obtained after sodium cyanoborohydride reduction were
individually isolated and fully characterized. The tert-
butyldimethylsilyl ether was removed during the hy-
dride reduction step. Following the separation of Z- and
E-isomers at the olefination stage (4a and 4b), the
reaction sequence was performed separately on each
isomer. Acylation with pivaloyl chloride and final re-
moval of the benzyl protective group with BCl3 afforded
the desired targets 1a and 1b.
The 1H NMR spectra of these compounds deserve
some special comments. The variations in chemical shift
and multiplicity for certain peaks when changing from
CDCl3 to DMSO-d6 were remarkable and quite informa-
tive about the existence of an intramolecular H-bond
pattern associated with these molecules. In the case of
1a , the nonequivalent methylene protons on the CH2N-
(OH)COC(CH3)3 branch appeared as doublets (J ) 15.4
Hz) separated from each other by 1.14 ppm when the
solvent was CDCl3. On the other hand, in DMSO-d6 the
same two doublets (J ) 14.8 Hz) were just 0.31 ppm
apart. In CDCl3, the exchangeable primary alcohol
In the present manuscript, we correct this error and
report on the synthesis of the intended N-hydroxylactam
* To whom correspondence should be addressed. Phone: 301-846-
5954. Fax: 301-846-6033. E-mail: marquezv@dc37a.nci.nih.gov.
† Laboratory of Medicinal Chemistry, National Cancer Institute at
Frederick.
‡ These investigators contributed equally to this work.
§ Laboratory of Cellular Carcinogenesis & Tumor Promotion, Na-
tional Cancer Institute at Frederick.
#
Seoul National University.
10.1021/jm030082c CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/22/2003

Brief Articles
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2791
5
Sch em e 1a
Ta ble 1. PK-CR Binding Affinity and Calculated log P for
N-Hydroxylamides (1a and 1b) and Esters (2a and 2b)
Z/E
log P
Ki (nM)
1a
1b
2a
2b
Z
E
Z
E
3.58
3.58
5.03
5.03
6980 ( 110
6790 ( 190
2.90 ( 0.4
4.51 ( 0.5
vealed a dramatic drop in binding affinity of more than
3 orders of magnitude relative to the esters, suggesting
that the extra N-OH group is not directly involved in
binding the C1 domain of PK-C (Table 1).
Exp er im en ta l Section
(Z)-5-[(4-Met h oxyp h en oxy)m et h yl]-3-[5-m et h yl-3-(2-
m et h ylp r op yl)h exilid en e]-5-[(p h en ylm et h oxy)m et h yl]-
4,5-d ih yd r ofu r a n -2-on e (4a ) a n d (E)-5-[(4-Meth oxyp h en -
oxy)m eth yl]-3-[5-m eth yl-3-(2-m eth ylp r op yl)h exilid en e]-
5-[(p h en ylm eth oxy)m eth yl]-4,5-d ih yd r ofu r a n -2-on e (4b).
A stirred solution of 33,4 (4 g, 12 mmol) in THF (30 mL) was
cooled to -78 °C and treated dropwise with lithium bis-
(trimethylsilyl)amide (1 M in THF, 24 mL, 24 mmol). After
being stirred for 30 min at -78 °C, the mixture was treated
with a solution of aldehyde [(CH3)2CHCH2]2CHCH2CHO (2 g,
12 mmol) in THF (20 mL) and stirred for 2 h at the same
temperature. The reaction was quenched by the slow addition
of a saturated aqueous solution of NH4Cl and extracted several
times with ether. The combined organic extracts were washed
with H2O and brine, dried (MgSO4), and concentrated in vacuo.
The residue was purified by flash column chromatography on
silica gel with EtOAc/hexanes (1:4) as eluant to give the
intermediate â-hydroxylactone as an oil (5.6 g, 11 mmol). A
solution of the above compound in CH2Cl2 (30 mL) was cooled
to 0 °C and treated with Et3N (4.5 mL, 33 mmol) and CH3-
SO2Cl (1.3 mL, 17 mmol). The mixture was stirred at ambient
temperature for 10 min and then treated with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU, 4.9 mL, 33 mmol). After additional
stirring for 15 min, the reaction mixture was concentrated in
vacuo and the residue was purified by flash column chroma-
tography on silica gel with EtOAc/hexanes (1:10) as eluant to
give 4a (Z-isomer, 2.0 g, 4.2 mmol, 35%) and 4b (E-isomer,
2.0 g, 35%) as oils.
a
(a) [(CH3)3Si]2NLi (2 equiv), [(CH3)2CHCH2]2CHCH2CHO (1
equiv), THF, -78 °C, 2 h; (b) (i) Et3N (3 equiv), CH3SO2Cl (1.5
equiv), CH2Cl2, room temp, 10 min, (ii) DBU (3 equiv), room temp,
15 min; (c) (NH4)2Ce(NO3)6 (3 equiv), CH3CN/H2O (4:1), 0 °C, 30
min; (d) oxalyl chloride (1.5 equiv), DMSO (2.5 equiv), Et3N (3
equiv), room temp, 15 min; (e) (i) (CH3)3CSi(CH3)2ONH2 (1.5
equiv), pyridine, room temp, 3 h; (ii) NaBH3CN (1.7 equiv), AcOH,
room temp, 1 h; (f) Et3N (2 equiv), (CH3)CCOCl (1.2 equiv), CH2Cl2,
0 °C, 10 min; (g) BCl3 (3 equiv), CH2Cl2, -78 °C, 30 min.
4a : 1H NMR (CDCl3) δ 7.25-7.32 (m, 5 H, Ph), 6.80 (s, 4
H, PhOCH3), 6.18-6.23 (m, 1 H, >CdCH), 4.58 (AB q, 2 H, J
) 12.3, 14.5 Hz, OCH2Ph), 4.02 (AB q, 2 H, J ) 9.7, 28.4 Hz,
CH2OPhOCH3), 3.76 (s, 3 H, OCH3), 3.66 (AB q, 2 H, J ) 10.1,
22.4 Hz, CH2OCH2Ph), 2.82-2.98 (m, 2 H, H-4), 2.62-2.76 (m,
2 H, >CHdCHCH2), 1.58-1.69 (m, 3 H, 2 × CHMe2, CH(i-
Bu)2), 1.06-1.13 (m, 4 H, 2 × CHCH2CHMe2), 0.79-0.93 (m,
12 H, 4 × CH3); FABMS m/z (relative intensity) 494 (MH+,
35). Anal. (C31H42O5) C, H.
F igu r e 1. Proposed intramolecular H-bonding network for
compound 1a .
4b: 1H NMR (CDCl3) δ 7.25-7.35 (m, 5 H, Ph), 6.81 (s, 4 H,
PhOCH3), 6.76-6.81 (m, 1 H, >CdCH), 4.58 (AB q, 2 H, J )
12.4, 14.0 Hz, OCH2Ph), 4.02 (AB q, 2 H, J ) 9.7, 26.8 Hz,
CH2OPhOCH3), 3.76 (s, 3 H, OCH3), 3.66 (AB q, 2 H, J ) 10.4,
25.3 Hz, CH2OCH2Ph), 2.81-2.93 (m, 2 H, H-4), 2.11-2.14 (m,
2 H, >CHdCHCH2), 1.60-1.74 (m, 3 H, 2 × CHMe2, CH(i-
Bu)2), 1.04-1.15 (m, 4 H, 2 × CHCH2CHMe2), 0.81-0.93 (m,
12 H, 4 × CH3); FABMS m/z (relative intensity) 494 (MH+,
23). Anal. (C31H42O5‚0.1H2O) C, H.
(Z)-5-(Hydr oxym eth yl)-3-[5-m eth yl-3-(2-m eth ylpr opyl)-
h exyliden e]-5-(ph en ylm eth oxy)m eth yl]-4,5-dih ydr ofu r an -
2-on e (5a ). A solution of 4a (2.07 g, 4.2 mmol) in CH3CN/
H2O (4:1, 10 mL) was cooled to 0 °C and treated with
ammonium cerium(IV) nitrate (6.9 g, 12.6 mmol). After being
stirred for 30 min at 0 °C, the reaction mixture was diluted
with CH2Cl2. The organic layer was washed with H2O and
brine, dried (MgSO4), and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel with
EtOAc/hexanes (1:2) as eluant to give 5a as an oil (1.25 g,
76%): 1H NMR (CDCl3) δ 7.26-7.36 (m, 5 H, Ph), 6.17-6.21
(CH2OH) appeared as a doublet of doublets (J ) 10.4,
4.6 Hz) at δ 3.97, whereas in DMSO-d6 the same signal
appeared as a triplet (J ) 5.6 Hz) at δ 5.10. Finally,
the signal for the NOH proton resonated at δ 6.68 in
CDCl3 and at δ 9.49 in DMSO-d6. On the basis of these
results, we propose the existence of two strong intramo-
lecular H-bonds that keep the entire ensemble around
the two side chains fixed and unable to rotate freely and
that such a constrained system is more prevalent in
CDCl3 (Figure 1). The same changes were observed for
the isomeric compound 1b. These observations are
important and could explain how these molecules
behave in a lipid, nonpolar environment by adopting a
similar conformation as in CDCl3 that does not unfold
to a conformation required for efficient binding. Indeed,
this isosteric RC(O)O f RC(O)NOH replacement re-

2792 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13
Brief Articles
(m, 1 H, >CdCH), 4.56 (AB q, 2 H, J ) 12.1, 13.8 Hz, OCH2-
Ph), 3.64-3.76 (m, 2 H, CH2OH), 3.58 (AB q, 2 H, J ) 9.8,
17.6 Hz, CH2OCH2Ph), 2.81-2.82 (m, 2 H, H-4), 2.64-2.68 (m,
2 H, >CHdCHCH2), 1.57-1.68 (m, 3 H, 2 × CHMe2, CH(i-
Bu)2), 1.06-1.10 (m, 4 H, 2 × CHCH2CHMe2), 0.81-0.88 (m,
12 H, 4 × CH3); 13C NMR (CDCl3) δ 169.3, 144.2, 137.7, 128.6,
128.0, 127.8, 125.2, 83.4, 73.90, 72.00, 65.70, 44.1, 33.6, 33.4,
32.2, 25.3, 23.2, 22.9, 22.8; FABMS m/z (relative intensity) 389
(MH+, 48.7). Anal. (C24H36O4) C, H.
(Z)-N-H yd r oxy-N-({2-(h yd r oxym et h yl)-4-[5-m et h yl-3-
(2-m eth ylp r op yl)h exylid en e]-5-oxo(2-2,3-d ih yd r ofu r yl)}-
m eth yl)-2,2-d im eth ylp r op a n a m id e (1a ). A stirred solution
of 8a (175 mg, 0.36 mmol) in CH2Cl2 (4 mL) was cooled to -78
°C and treated dropwise with BCl3 (1 M CH2Cl2, 1.1 mL). After
the mixture was stirred for 30 min at - 78 °C, the reaction
was quenched with saturated NaHCO3 and the mixture was
immediately partitioned between ether and the NaHCO3
solution. The organic layer was washed with H2O and brine,
dried (MgSO4), and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel with
EtOAc/hexanes (1:2) as eluant to give 1a as a white solid: mp
(Z)-5-Ca r b on yl-3-[5-m et h yl-3-(2-m et h ylp r op yl)h exyl-
id en e]-5-(p h en ylm et h oxy)m et h yl]-4,5-d ih yd r ofu r a n -2-
on e (6a ). A cooled solution of DMSO (0.34 mL, 4.8 mmol) in
CH2Cl2 (5 mL) at -78 °C was treated with oxalyl chloride (0.25
mL, 2.9 mmol). After the mixture was stirred for 30 min at
-78 °C, a solution of 5a (728 mg, 1.9 mmol) in CH2Cl2 (5 mL)
was added, and the mixture was stirred for 2 h at the same
temperature. The reaction was quenched by the slow addition
of Et3N (0.79 mL, 5.7 mmol) followed by 30 min of stirring at
room temperature. After the addition of CH2Cl2 (20 mL), the
solution was washed with H2O and brine, dried (MgSO4), and
concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel with EtOAc/hexanes (1:
4) as eluant to give 6a as an oil (537 mg, 74%): 1H NMR
(CDCl3) δ 9.73 (s, 1 H, CHO), 7.26-7.36 (m, 5 H, Ph), 6.11-
6.28 (m, 1 H, >CdCH), 4.49-4.63 (m, 2 H, OCH2Ph), 3.61-
3.75 (AB m, 2 H, CH2OCH2Ph), 2.74-3.02 (m, 2 H, H-4), 2.64-
2.69 (m, 2 H, >CHdCHCH2), 1.57-1.67 (m, 3 H, 2 × CHMe2,
CH(i-Bu)2), 1.03-1.11 (m, 4 H, 2 × CHCH2CHMe2), 0.83-0.88
(m, 12 H, 4 × CH3). This compound was used immediately in
the following step without further purification.
1
100-101 °C (101 mg, 69%); H NMR (CDCl3) δ 6.68 (s, 1 H,
N(OH)CO, D2O exchangeable), 6.30-6.35 (m, 1 H, >CdCH),
4.54 (d, 1 H, J ) 15.4 Hz, CHHNCO), 3.97 (dd, 1H, J ) 4.6,
10.4 Hz, CH2OH, D2O exchangeable), 3.51 (dd, 1 H, J ) 4.4,
12.1 Hz, CHHOH), 3.41 (d, 1 H, J ) 15.4 Hz, CHHNCO), 3.34
(distorted triplet, 1 H, J ) 10.9, 11.3 Hz, CHHOH), 3.00-3.05
(dm, 1 H, J ) 16.4 Hz, 4-Ha), 2.58-2.75 (m, 3 H, 4-Hb, >CHd
CHCH2), 1.59-1.66 (m, 3 H, 2 × CHMe2, CH(i-Bu)2), 1.31 (s,
9 H, NCO(CH3)3), 1.04-1.14 (m, 4 H, 2 × CHCH2CHMe2),
1
0.85-0.87 (2 br doublets, 12 H, 4 × CH3); H NMR (DMSO-
d6) δ 9.49 (s, 1 H, N(OH)CO, D2O exchangeable), 6.11-6.13
(m, 1 H, >CdCH), 5.10 (t, 1 H, J ) 5.6 Hz, CH2OH, D2O
exchangeable), 3.72 (d, 1 H, J ) 14.8 Hz, CHHNCO), 3.51 (d,
1 H, J ) 14.8 Hz, CHHNCO), 3.31-3.41 (m, 2 H, CH2OH),
2.64-2.75 (m, 2 H, 4-Ha,b), 2.48-2.52 (m, 2 H, >CHdCHCH2),
1.47-1.61 (m, 3 H, 2 × CHMe2, CH(i-Bu)2), 1.11 (s, 9 H, NCO-
(CH3)3), 0.94-1.06 (m, 4 H, 2 × CHCH2CHMe2), 0.77-0.78 (br
d, 12 H, 4 × CH3); 13C NMR (CDCl3) δ 179.9, 168.7, 146.6,
123.6, 84.3, 63.6, 55.2, 44.1, 39.3, 35.4, 33.4, 32.4, 27.0, 25.3,
23.2, 23.1, 22.9, 22.8; 13C NMR (DMSO-d6) δ 182.3, 174.1,
145.8, 132.1, 89.6, 70.0, 58.0, 48.8, 43.8, 38.1, 36.5, 32.4, 30.1,
28.3, 28.0; FABMS m/z (relative intensity) 398 (MH+, 100).
Anal. (C22H39NO5) C, H, N.
(Z)-5-(Hyd r oxyla m in o)m eth yl)-3-[5-m eth yl-3-(2-m eth -
ylp r op yl)h exylid en e]-5-(p h en ylm eth oxy)m eth yl]-4,5-d i-
h yd r ofu r a n -2-on e (7a ). A solution of 6a (537 mg, 1.4 mmol)
in pyridine (5 mL) was treated with O-tert-(butyldimethylsilyl)-
hydroxylamine (265 mg, 1.8 mmol). After being stirred for 3 h
at ambient temperature, the reaction mixture was concen-
trated in vacuo. Following the complete removal of pyridine,
acetic acid (15 mL) was added and the resulting solution was
stirred for 1 h at room temperature. After treatment of this
solution with NaBH3CN (128 mg, 2.0 mmol) for 1 h, the
mixture was concentrated in vacuo and the residue was
purified by flash column chromatography on silica gel with
EtOAc/hexanes (1:2) as eluant to give 7a as a white solid: mp
(E)-5-(Hydr oxym eth yl)-3-[5-m eth yl-3-(2-m eth ylpr opyl)-
h exyliden e]-5-(ph en ylm eth oxy)m eth yl]-4,5-dih ydr ofu r an -
2-on e (5b). A solution of 4b (2.0 g, 4.0 mmol) in CH3CN/H2O
(4:1, 6 mL) was cooled to 0 °C and treated with ammonium
cerium(IV) nitrate (6.5 g, 12 mmol). Following a similar
procedure as for 5a , the E-isomer (5b) was obtained as an oil
(1.4 g, 92%): 1H NMR (CDCl3) δ 7.26-7.36 (m, 5 H, Ph), 6.73-
6.78 (m, 1 H, >CdCH), 4.56 (AB q, 2 H, J ) 12.1, 13.8 Hz,
OCH2Ph), 3.61-3.78 (m, 2 H, CH2OH), 3.58 (AB q, 2 H, J )
9.9, 27.3 Hz, CH2OCH2Ph), 2.68-2.79 (m, 2 H, H-4), 2.20 (t, 1
H, CH2OH), 2.09-2.13 (m, 2 H, >CHdCHCH2), 1.56-1.69 (m,
3 H, 2 × CHMe2, CH(i-Bu)2), 1.06-1.11 (m, 4 H, 2 × CHCH2-
CHMe2), 0.84-0.86 (m, 12 H, 4 × CH3); 13C NMR (CDCl3) δ
170.3, 140.6, 137.7, 128.6, 128.0, 127.8, 127.4, 84.3, 73.9, 72.1,
65.7, 44.0 34.9, 33.0, 30.3, 25.4, 23.1, 22.8; FABMS m/z
(relative intensity) 389 (MH+, 68). Anal. (C24H36O4) C, H.
(E)-5-Ca r b on yl-3-[5-m et h yl-3-(2-m et h ylp r op yl)h exyl-
id en e]-5-(p h en ylm et h oxy)m et h yl]-4,5-d ih yd r ofu r a n -2-
on e (6b). Following a similar method of oxidation as before,
6b was obtained as an oil (525 mg, 85%): 1H NMR (CDCl3) δ
9.73 (s, 1 H, CHO), 7.26-7.36 (m, 5 H, Ph), 6.73-6.78 (m, 1
H, >CdCH), 4.49-4.63 (m, 2 H, OCH2Ph), 3.61-3.75 (AB m,
2 H, CH2OCH2Ph), 2.74-3.02 (m, 2 H, H-4), 2.09-2.13 (m, 2
H, >CHdCHCH2), 1.57-1.67 (m, 3 H, 2 × CHMe2, CH(i-Bu)2),
1.03-1.11 (m, 4 H, 2 × CHCH2CHMe2), 0.83-0.88 (m, 12 H,
4 × CH3). This compound was used immediately in the
following step.
1
90-91 °C (300 mg, 54%); H NMR (CDCl3) δ 7.26-7.36 (m, 5
H, Ph), 6.17-6.20 (m, 1 H, >CdCH), 4.59 (s, 2 H, OCH2Ph),
3.57 (AB q, 2 H, J ) 9.9, 18.9 Hz, CH2OCH2Ph), 3.20 (AB q, 2
H, J ) 13.7, 25.6 Hz, CH2NHOH), 2.86-2.90 (m, 2 H, H-4),
2.65-2.69 (m, 2 H, >CHdCHCH2), 1.57-1.69 (m, 3 H, 2 ×
CHMe2, CH(i-Bu)2), 1.04-1.10 (m, 4 H, 2 × CHCH2CHMe2),
0.83-0.88 (m, 12 H, 4 × CH3); 13C NMR (CDCl3) δ 169.1, 143.7,
137.8, 128.6, 128.0, 127.8, 125.4, 82.7, 73.8, 73.0, 58.6, 44.1,
35.6, 33.4, 32.1, 25.3, 23.2, 22.8; FABMS m/z (relative inten-
sity) 404 (MH+, 2.4). Anal. (C24H37NO4) C, H, N.
(Z)-N-Hyd r oxy-2,2-d im eth yl-N-({4-[5-m eth yl-3-(2-m eth -
oxypr opyl)h exyliden e]-5-oxo-2-[(ph en ylm eth oxy)m eth yl]-
(2-2,3-d ih yd r ofu r yl)}m eth yl)p r op a n a m id e (8a ). A cooled
solution of 7a (200 mg, 0.5 mmol) in CH2Cl2 (3 mL) at 0 °C
was stirred with Et3N (0.14 mL, 1.0 mmol) and pivaloyl
chloride (74 µL, 0.6 mmol) for 10 min at 0 °C. The reaction
mixture was concentrated in vacuo, and the residue was
purified by flash column chromatography on silica gel with
EtOAc/hexanes (1:10) as eluant to give 8a as an oil (187 mg,
78%): 1H NMR (CDCl3) δ 7.26-7.36 (m, 5 H, Ph), 6.18-6.22
(m, 1 H, >CdCH), 4.48 (AB q, 2 H, J ) 11.7, 18.2 Hz, OCH2-
Ph), 3.99 (AB q, 2 H, J ) 15.0, 146.2 Hz, CH2N(OH)CO), 3.55
(AB q, 2 H, J ) 10.3, 25.4 Hz, CH2OCH2Ph), 2.80-2.91 (m, 2
H, H-4), 2.56-2.72 (m, 2 H, >CHdCHCH2), 1.56-1.68 (m, 3
H, 2 × CHMe2, CH(i-Bu)2), 1.23 (s, 9 H, NCO(CH3)3), 1.06-
1.09 (m, 4 H, 2 × CHCH2CHMe2), 0.83-0.86 (m, 12 H, 4 ×
CH3); 13C NMR (CDCl3) δ 178.7, 169.1, 144.6, 137.1, 128.7,
128.3, 127.9, 124.7, 83.6, 74.2, 73.4, 55.2, 44.1, 44.0, 39.2, 35.0,
33.4, 32.2, 27.2, 27.1, 25.3, 23.2, 22.9, 22.8; FABMS m/z
(relative intensity) 488 (MH+, 37). Anal. (C29H45NO5) C, H, N.
(E)-5-(Hyd r oxyla m in o)m eth yl)-3-[5-m eth yl-3-(2-m eth -
ylp r op yl)h exylid en e]-5-(p h en ylm eth oxy)m eth yl]-4,5-d i-
h yd r ofu r a n -2-on e (7b). The reaction of aldehyde 6b with
O-tert-(butyldimethylsilyl)hydroxylamine was performed in
the same manner as with 6a to give, after workup, 7b as a
1
white solid: mp 86-87 °C (283 mg, 54%); H NMR (CDCl3) δ
7.26-7.35 (m, 5 H, Ph), 6.72-6.77 (m, 1 H, >CdCH), 4.59 (s,
2 H, OCH2Ph), 3.57 (AB q, 2 H, J ) 10.1, 19.0 Hz, CH2OCH2-
Ph), 3.20 (AB q, 2 H, J ) 13.6, 32.2 Hz, CH2NHOH), 2.77-
2.87 (m, 2 H, H-4), 2.08-2.12 (m, 2 H, >CHdCHCH2), 1.58-
1.66 (m, 3 H, 2 × CHMe2, CH(i-Bu)2), 1.04-1.12 (m, 4 H, 2 ×
CHCH2CHMe2), 0.80-0.88 (m, 12 H, 4 × CH3); 13C NMR

Brief Articles
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2793
(CDCl3) δ 170.2, 140.3, 137.7, 128.6, 128.0, 127.8, 127.4, 83.4,
73.8, 73.2, 58.7, 44.0, 34.8, 33.0, 32.4, 25.4, 23.1, 22.8; FABMS
m/z (relative intensity) 404 (MH+, 19.2). Anal. (C24H37NO4) C,
H, N.
able), 3.90 (dd, 1 H, J ) 14.8 Hz, CHHNCO), 3.51 (d, 1 H, J )
14.8 Hz, CHHNCO), 3.39-3.45 (m, 2 H, CH2OH), 2.64 (s, 2
H, 4-H), 1.94-2.01 (m, 2 H, >CHdCHCH2), 1.55-1.58 (m, 3
H, 2 × CHMe2, CH(i-Bu)2), 1.11 (s, 9 H, NCO(CH3)3), 1.01-
1.06 (m, 4 H, 2 × CHCH2CHMe2), 0.79-0.81 (m, 12 H, 4 ×
CH3); 13C NMR (CDCl3) δ 180.0, 169.8, 143.1, 125.7, 85.0, 64.0,
55.4, 44.0, 39.3, 35.1, 32.9, 32.1, 27.0, 25.4, 23.2, 23.1, 22.8,
22.7; 13C NMR (DMSO-d6) δ 177.5, 170.0, 137.3, 129.7, 85.6,
65.3, 55.5, 44.1, 39.1, 34.6, 32.9, 30.2, 27.6, 25.4, 23.5, 23.2;
(E)-N-Hydr oxy-2,2-d im eth yl-N-({4-[5-m eth yl-3-(2-m eth -
oxypr opyl)h exyliden e]-5-oxo-2-[(ph en ylm eth oxy)m eth yl]-
(2-2,3-d ih yd r ofu r yl)}m eth yl)p r op a n a m id e (8b). Acyla-
tion of 7b with pivaloyl chloride was performed in the same
manner as with 7a to give, after workup, 8b as an oil (130
mg, 71%): 1H NMR (CDCl3) δ 7.25-7.36 (m, 5 H, Ph), 6.72-
6.78 (m, 1 H, >CdCH), 4.58 (AB q, 2 H, J ) 11.9, 15.6 Hz,
OCH2Ph), 4.00 (AB q, 2 H, J ) 14.8, 100.6 Hz, CH2NCO), 3.54
(AB q, 2 H, J ) 10.1, 21.1 Hz, CH2OCH2Ph), 2.77 (s, 2 H, H-4),
2.08-2.12 (m, 2 H, >CHdCHCH2), 1.56-1.68 (m, 3 H, 2 ×
CHMe2, CH(i-Bu)2), 1.23 (s, 9 H, NCO(CH3)3), 1.06-1.11 (m,
4 H, 2 × CHCH2CHMe2), 0.84-0.86 (m, 12 H, 4 × CH3); 13C
NMR (CDCl3) δ 178.8, 170.2, 141.0, 137.1, 128.7, 128.2, 127.9,
126.9, 84.6, 74.1, 73.3, 55.3, 44.0, 39.2, 34.9, 32.9, 31.7, 27.2,
27.1, 25.4, 23.1, 22.8, 22.7; FABMS m/z (relative intensity) 488
(MH+, 46.3). Anal. (C29H45NO5) C, H, N.
(Z)-N-H yd r oxy-N-({2-(h yd r oxym et h yl)-4-[5-m et h yl-3-
(2-m eth ylp r op yl)h exylid en e]-5-oxo(2-2,3-d ih yd r ofu r yl)}-
m eth yl)2,2-d im eth ylp r op a n a m id e (1b). Following an iden-
tical deprotection procedure, 1b was obtained as a white
solid: mp 95-96 °C (75 mg, 79%); 1H NMR (CDCl3) δ 7.05 (s,
1 H, NCO(OH), D2O exchangeable), 6.81-6.87 (m, 1 H, >Cd
CH), 4.50 (d, 1 H, J ) 15.2 Hz, CHHNCO), 4.04-4.07 (m, 1H,
CH2OH, D2O exchangeable), 3.56 (dd, 1 H, J ) 4.8, 9.3 Hz,
CHHOH), 3.48 (d, 1 H, J ) 15.4 Hz, CHHNCO), 3.30-3.35
(m, 1 H, CHHOH), 2.52-2.98 (m, 1 H, 4-H), 2.12-2.16 (m, 3
H, 4-H, >CHdCHCH2), 1.57-1.69 (m, 3 H, 2 × CHMe2, CH(i-
Bu)2), 1.31 (s, 9 H, NCO(CH3)3 ), 1.01-1.16 (m, 4 H, 2 ×
CHCH2CHMe2), 0.82-0.87 (m, 12 H, 4 × CH3); 1H NMR
(DMSO-d6) δ 9.49 (s, 1 H, NCO(OH), D2O exchangeable), 6.38-
6.45 (m, 1 H, >CdCH), 5.12 (t, 1H, CH2OH, D2O exchange-
FABMS m/z (relative intensity) 398 (MH+, 100). Anal. (C22H39
-
NO5) C, H, N.
Refer en ces
(1) Lee, J .; Han, K.-C.; Kang, J .-H.; Pearce, L. L.; Lewin, N. E.; Yan,
S.; Benzaria, S.; Nicklaus, M. C.; Blumberg, P. M.; Marquez, V.
E. Conformationally constrained analogues of diacylglycerol. 18.
The incorporation of a hydroxamate moiety into diacylglycerol-
lactones reduces lipophilicity and helps discriminate between
sn-1 and sn-2 binding modes to protein kinase
C (PK-C).
Implications for isozyme specificity. J . Med. Chem. 2001, 44,
4309-4312.
(2) Lee, J .; Han, K.-C.; Kang, J .-H.; Pearce, L. L.; Lewin, N. E.; Yan,
S.; Benzaria, S.; Nicklaus, M. C.; Blumberg, P. M.; Marquez, V.
E. J . Med. Chem. 2003, 46, 2794.
(3) Lee, J . Design and synthesis of bioisosteres of ultrapotent protein
kinase C (PKC) ligand, 5-acetoxymethyl-5-hydroxymethyl-3-
alkylidene tetrahydro-2-furanone. Arch. Pharmacal Res. 1998,
21, 452-457.
(4) Combustion analysis data for compound 3 in ref 3 were missing.
In this work, the following results were obtained: Anal. Calcd
for C20H22O5: C, 70.16; H, 6.48. Found: C, 70.13; H, 6.49.
(5) Meylan, W. M.; Howard, Ph. H. Atom fragment contribution
method for estimating octanol-water partition coefficients J .
Pharm. Sci. 1995, 84, 83-92 (KOWWIN, version 1.63; Syracuse
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J M030082C