Synthesis of caprazamycin analogues and their structure - Activity relationship for antibacterial activity

Article abstract of DOI:10.1021/jo702264e

(Chemical Equation Presented) Synthesis of palmitoyl caprazol 7, which possesses a simple fatty acyl side chain at the 3?-position of the diazepanone moiety, was carried out and their antibacterial activity was evaluated. The key elements of our approach include the improved synthesis of the key 5′-β-O-aminoribosyl-glycyluridine derivative, installation of the palmitoyl side chain to the cyclization precursor, and the construction of the diazepanone by an intramolecular reductive animation. The second generation synthesis of (+)-caprazol was also established. Palmitoyl caprazol 7 exhibited antibacterial activity against Mycobacterium smegmatis ATCC607 (MIC = 6.25 μg/mL) with potency similar to that of the caprazamycins (CPZs). Palmitoyl caprazol 7 and N^6′-desmethyl palmitoyl caprazol 28 also exhibited antibacterial activity against drug-resistant bacteria including methyciline-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains (MIC = 3.13-12.5 μg/mL).

Full text of DOI:10.1021/jo702264e

Synthesis of Caprazamycin Analogues and Their Structure-Activity
Relationship for Antibacterial Activity
Shinpei Hirano, Satoshi Ichikawa,* and Akira Matsuda*
Faculty of Pharmaceutical Sciences, Hokkaido UniVersity, Sapporo 060-0812, Japan
matuda@pharm.hokudai.ac.jp; ichikawa@pharm.hokudai.ac.jp
ReceiVed October 19, 2007
Synthesis of palmitoyl caprazol 7, which possesses a simple fatty acyl side chain at the 3′′′-position of
the diazepanone moiety, was carried out and their antibacterial activity was evaluated. The key elements
of our approach include the improved synthesis of the key 5′-â-O-aminoribosyl-glycyluridine derivative,
installation of the palmitoyl side chain to the cyclization precursor, and the construction of the diazepanone
by an intramolecular reductive amination. The second generation synthesis of (+)-caprazol was also
established. Palmitoyl caprazol 7 exhibited antibacterial activity against Mycobacterium smegmatis
ATCC607 (MIC ) 6.25 µg/mL) with potency similar to that of the caprazamycins (CPZs). Palmitoyl
caprazol 7 and N6′-desmethyl palmitoyl caprazol 28 also exhibited antibacterial activity against drug-
resistant bacteria including methyciline-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant
Enterococcus (VRE) strains (MIC ) 3.13-12.5 µg/mL).
Introduction
class of naturally occurring 6′-N-alkyl-5′-â-O-aminoribosyl-
glycyluridine antibiotics including liposidomycins5 (LPMs, 2)
and FR-9004936 (3), which have been shown to exhibit excellent
antimicrobial activity against Gram-positive bacteria. In par-
Tuberculosis (TB) is a disease primarily of the respiratory
system from which two million people die each year.1 With
resistant strains continuing to emerge,2 the need for better anti-
TB agents possessing new mechanisms of action remains
critical.3 Caprazamycins (CPZs) (Figure 1, 1) were isolated from
a culture broth of the Actinomycete strain Streptomyces sp.
MK730-62F2 in 20034 and represent the newest members of a
(4) (a) Igarashi, M.; Nakagawa, N.; Doi, N.; Hattori, S.; Naganawa, H.;
Hamada, M. J. Antibiot. 2003, 56, 580-583. (b) Igarashi, M.; Takahashi,
Y.; Shitara, T.; Nakamura, H.; Naganawa, H.; Miyake, T.; Akamatsu, Y.
J. Antibiot. 2005, 58, 327-337. (c) Takeuchi, T.; Igarashi, M.; Naganawa,
H.; Hamada, M. JP 2003012687, 2001. (d) Miyake, M.; Igarashi, M.;
Shidara, T.; Takahashi, Y. WO 2004067544, 2004.
(5) (a) Isono, K.; Uramoto, M.; Kusakabe, H.; Kimura, K.; Izaki, K.;
Nelson, C. C.; McCloskey, J. A. J. Antibiot. 1985, 38, 1617-1621. (b)
Ubukata, M.; Kimura, K.; Isono, K.; Nelson, C. C.; Gregson, J. M.;
McCloskey, J. A. J. Org. Chem. 1992, 57, 6392-6403. (c) Ubukata, M.;
Isono, K. J. Am. Chem. Soc. 1988, 110, 4416-4417. (d) Kimura, K.; Ikeda,
Y.; Kagami, S.; Yoshihama, M.; Suzuki, K.; Osada, H.; Isono, K. J. Antibiot.
1998, 51, 1099-1104. (e) Muroi, M.; Kimura, K.; Osada, H.; Inukai, M.;
Takatsuki, A. J. Antibiot. 1997, 50, 103-104. (f) Kimura, K.; Ikeda, Y.;
Kagami, S.; Yoshihama, M.; Ubukata, M.; Esumi, Y.; Osada, H.; Isono,
K. J. Antibiot. 1998, 51, 647-654. (g) Kimura, K.; Kagami, S.; Ikeda, Y.;
Takahashi, H.; Yoshihama, M.; Kusakabe, H.; Osada, H.; Isono, K. J.
Antibiot. 1998, 51, 640-646. (h) Kimura, K.; Miyata, N.; Kawanishi, G.;
Kamio, Y.; Izaki, K.; Isono, K. Agric. Biol. Chem. 1989, 53, 1811-1815.
* Address correspondence to this author. A.M.: phone (+81) 11-706-3228;
fax (+81) 11-706-4980. S.I.: phone (+81) 11-706-3763; fax (+81) 11-706-
4980.
(1) Barry, C.; Cole, S.; Fourie, B.; Geiter, L.; Gosey, L.; Grosset, J.;
Kanyok, T.; Laughon, B.; Mitchison, D.; Numnn, P.; O’Brienn, R.;
Robinson, T. Scientific Blueprint for Tuberculosis Drug DeVelopment, 2001;
see: http://www.tballiance.org/.
(2) (a) Russell, D. G. Nature 2001, 2, 1-9. (b) Espinal, M. A.
Tuberculosis 2003, 83, 44-51. (c) Perri, G. D.; Bonora, S. J. Antimicrob.
Chemther. 2004, 54, 593-602.
(3) (a) Nayyar, A.; Jain, R. Curr. Med. Chem. 2005, 12, 1873-1886.
(b) Duncan, K.; Barry, C. E., III Curr. Opin. Microbiol. 2004, 7, 460-
465.
10.1021/jo702264e CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/20/2007
J. Org. Chem. 2008, 73, 569-577
569

Hirano et al.
TB agents as well as general antibacterial agents.7 To keep pace
with the serious public health problem due to multiantibiotic
resistant bacterial pathogens arising from the extensive use of
antibiotics,8 new antibiotics to treat multidrug-resistant Myco-
bacterium tuberculosis, methyciline-resistant Staphylococcus
aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and
vancomycin-resistant Staphylococcus aureus (VRSA) are ur-
gently needed. Therefore, the CPZs including the LPMs, a target
of which is MraY, are promising leads for novel antibacterial
agents, too. We designed a palmitoyl caprazol 7 (Figure 3),
which possesses a simple fatty acyl side chain at the 3′′′-position
of the diazepanone moiety, as an initial study for the structure-
activity relationship of the 6′-N-alkyl-5′-â-O-aminoribosyl-
glycyluridine class of antibiotics. Here we described the
synthesis of simplified CPZ analogues and their antibacterial
activity. The key elements of our approach include the improved
synthesis of the key 5′-â-O-aminoribosyl-glycyluridine deriva-
tive, installation of the palmitoyl side chain to the cyclization
precursor, and construction of the diazepanone by an intramo-
lecular reductive amination. The second generation synthesis
of (+)-caprazol was also established.
Results and Discussion
Synthesis of Palmitoylcaprazol. We have recently completed
the total synthesis of (+)-caprazol (4), which is a deacylated
CPZs.9 To understand the impact on the fatty acyl side chain,
we embarked on the synthesis of palmitolyl caprazol 7, in which
the fatty acyl side chain of the CPZs has been replaced with a
simple palmitoyl residue. Initially, we attempted to derive the
palmitoly caprazol from 5, which is a key intermediate of the
synthesis of 4, as shown in Scheme 1. Namely, protecting group
manipulation of 59 followed by acylation with palmitic acid and
deprotection of the temporal tert-butyldiphenylsilyl (TBDPS)
group gave 6. Oxidation of the primary alcohol of 6 was
conducted with several conditions such as Dess-Martin perio-
dinane and NaIO4. However, the desired carboxylic acid was
not obtained at all because the intermediate aldehyde derivative
was susceptible to â-elimination of the palmitoyloxy group.
An alternative to this approach, employing the more acces-
sible amino acid derivative 14 derived from 9 (Scheme 2) to
minimize transformations at a later stage of the synthesis, was
developed as shown in Figure 3. In addition to this modification,
the synthesis was conducted without the benzyloxymethyl
(BOM) protection at the N-3-position of the uracil moiety
because the presence of the BOM group complicated the
construction of the diazepanone moiety, as described in the total
synthesis of caprazol,9 and removal of the BOM group was
sometimes problematic.10 Preparation of the amino acid deriva-
tive 14 is outlined in Scheme 2. Deprotection of the Boc group
of 99 (80% aqueous TFA) followed by protection of the resulting
amino group (2 equiv of 2,2,2-trichloroethoxycarbonyl chloride
FIGURE 1. Structures of nucleoside antibiotics possessing the 6′-N-
alkyl-5′-O-aminoribosyl-glycyluridine.
ticular, the CPZs have shown excellent anti-mycobacterial
activity in vitro against drug-susceptible (MIC ) 3.13 µg/mL)
and multi-drug-resistant Mycobacterium tuberculosis strains
(MIC ) 3.13 µg/mL), and exhibit no significant toxicity in mice.
With such excellent biological properties, CPZs are expected
to become promising leads for the development of anti-
tuberculosis agents with a novel mode of action. A biological
target of the 6′-N-alkyl-5′-â-O-aminoribosyl-glycyluridine class
of antibiotics is believed to be the phospho-MurNAc-pentapep-
tide translocase (MraY, translocase I, Figure 2), and it is known
that this class of antibiotics strongly inhibits MraY (E. coli
translocase, IC50 ) 0.05 µg/mL for LPMs).5h Because of their
complex structural and biological similarities, it has been
suggested that the CPZs may possess the same mode of action
as the LPMs. Peptide glycan biosynthesis consists of three
stages, including the formation of uridine diphosphate N-
acetylmuraminylpentapeptide (UDP-MurNAc-pentapeptide) in
cytoplasm, the membrane-anchored synthesis of lipid I and lipid
II, a precursor to the peptide glycan, and polymerization of the
resulting lipid II by transpeptidation and transglycosidation. The
second and the third stages are involved in a lipid cycle, and
the MraY catalyzes the first step of the lipid-linked cycle of
the reactions, where UDP-MurNAc-pentapeptide is attacked by
the undecaprenol monophosphate in the bacterial cell membrane
providing lipid I (Figure 2). Lipid I anchored to the cell
membrane is further glycosylated by N-acetylglucosamine to
afford lipid II. Since MraY is an essential enzyme among
bacteria, it is potentially a target for the development of anti-
(7) (a) Dini, C. Curr. Top. Med. Chem. 2005, 5, 1221-1236. (b) Kimura,
K.; Bugg, T. D. H. Nat. Prod. Rep. 2003, 20, 252-273. (c) Ichikawa, S.;
Matsuda, A. Expert Opin. Ther. Pat. 2007, 17, 487-498.
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Chemother. 1994, 38, 1225-1229. (c) Wootton, M.; Howe, R. A.; Walsh,
T. R.; Bannett, P. M.; MacGowan, A. P. J. Antimicrob. Chemother. 2002,
50, 760-761. (d) Hiramatsu, K. Infect. Dis. 2001, 1, 147-155.
(9) (a) Hirano, S.; Ichikawa, S.; Matsuda, A. Angew. Chem., Int. Ed.
2005, 44, 1854-1856. (b) Hirano, S.; Ichikawa, S.; Matsuda, A. J. Org.
Chem., published Nov 21, http://dx.doi.org/10.1021/jo701699h.
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2804.
(6) (a) Ochi, K.; Ezaki, M.; Morita, I.; Komori, T.; Kohsaka, M. ER
0333177, 1989, A2. (b) Yoshida, Y.; Yamanaka, H.; Sakane, K. JP H05-
78385, 1993.
570 J. Org. Chem., Vol. 73, No. 2, 2008

Synthesis of Caprazamycin Analogues
FIGURE 2. Formation of lipid I catalyzed by MraY (translocase I).
of 16 resulted in superb improvement of the yield, regioselec-
tivity, and stereoselectivity compared to our original synthesis
to afford 17 (15 mol % of K2[Os2(OH)4], 15 mol % of
hydroquinidine (anthraquinone-1,4-diyl) diether ((DHQD)2AQN),
3 equiv of benzyl carbamate, 2.6 equiv of NaOH, iPrOH-H2O,
15 °C, 96% yield, 98% de). â-Selective ribosylation of 17 with
the 3-pentylidene-protected ribosyl donor 189 gave the desired
19 with excellent â-selectivity (1.2 equiv of BF3‚OEt2, CH2-
Cl2, -30 °C, 81%, â/R ) 24.0/1). Thus, it was revealed that
protection of the N-3-position of the uracil moiety was un-
necessary in the ribosylation step. Further crystallization of the
mixture gave the pure 19 (â/R ) >99/1). The azide group in
19 was reduced to the corresponding amine (3 equiv of PPh3,
5 equiv of H2O, benzene-THF, 50 °C), which was protected
with a Boc group to give 20 (2 equiv of Boc2O, 2 equiv of
NaHCO3, 90% overall). The yield of the hydrolysis of the
methyl ester 20 giving 21 (1 equiv of Ba(OH)2, aqueous THF,
73%) was also improved, as was the case with the Sharpless
aminohydroxylation. Coupling of 21 with the secondary amine
14 using 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-
one (DEPBT)17 (4 equiv, 1.5 equiv of 14, 4 equiv of NaHCO3,
THF, 0 °C, 66%) gave the amide 22, the TBDPS deprotection
of which afforded 23 (5 equiv of TBAF, AcOH, THF, 78%).
Acylation of the resulting secondary alcohol of 23 with palmitic
acid (3 equiv, 3 equiv of 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide hydrochloride (EDCI), 0.3 equiv of DMAP, CH2-
Cl2) and conversion of the terminal olefin of 24 to the aldehyde
with the two-step sequence provided the precursor 25 for the
cyclization (0.5 mol % of OsO4, 2.5 equiv of NMO, acetone-
H2O; 2.7 equiv of NaIO4, acetone-phosphate buffer (pH 7),
FIGURE 3. Synthetic strategy of palmitoyl caprazol.
(TrocCl), CH2Cl2, 90% overall) gave 10, protecting group
manipulation of which was further carried out to afford 11 (30
equiv of NH4F, MeOH; 1.5 equiv of 4,4′-dimethoxytrityl
chloride (DMTrCl), pyridine; 3 equiv of TBDPSCl, 6 equiv of
imidazole, DMF, 68% overall). Compound 11 was successively
N-methylated (2.5 equiv of MeI, 2 equiv of NaH, DMF) and
deprotected (aqueous AcOH, 74% overall) to afford the second-
ary amine derivative 12. The primary alcohol of 12 was oxidized
(0.5 equiv of 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO),
2.4 equiv of PhI(OAc)2, aqueous MeCN), and the resulting
t
carboxylic acid was protected as a Bu ester to afford 13 (10
equiv of tBuOC(NH)CCl3, 0.3 equiv of BF3‚OEt2, CH2Cl2, 89%
overall). Finally, the Troc group of 13 was removed by Zn (10
equiv, 30 equiv of NH4Cl, MeOH, 91%) to give 14.
With the secondary amine 14 in hand, the synthesis of the
palmitoyl caprazol 7 was undertaken as shown in Scheme 3.
Oxidation of 1511 with 2-iodoxybenzoic acid (IBX)12 (3 equiv,
MeCN, 80 °C) followed by a two-carbon elongation with
Ph3PdCHCO2Me (1.2 equiv, CH2Cl2, -20 °C, 91% overall)
provided 16 (trans/cis ) 37/1). The aminohydroxylation13-16
(15) Tao, B.; Schlingloft, G.; Sharpless, K. B. Tetrahedron Lett. 1998,
39. 2507-2510.
(11) Asakura, J.; Matsubara, Y.; Yoshihara, M. J. Carbohydr. Chem.
1996, 15, 231-239.
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1952.
(12) More, J. D.; Finny, N. S. Org. Lett. 2002, 4, 3001-3003.
(13) Rudolph, J.; Sennhenn, P. C.; Vlaar, C. P.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2810-2817.
(17) Jiang, H.; Li, X.; Fan, Y.; Ye, C.; Romoff, T.; Goodman, M. Org.
Lett. 1999, 1, 91-93.
(18) Brandish, P. E.; Burnham, M. K.; Lonsdale, J. T.; Southgate, R. S.;
Ibukai, M.; Bugg, T. D. H. J. Biol. Chem. 1996, 271, 7609-7614.
(14) O’Brlen, P.; Osborne, S. A.; Parkaer, D. D. Tetrahedron Lett. 1998,
39, 4099-4102.
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Hirano et al.
SCHEME 1. Initial Attempts to Prepare 3′′′-O-palmitoyl Caprazol Derivative
SCHEME 2. Preparation of N-Methyl-2-amino-3-hydroxyl-4-pentonoate
83% overall). Then, the intramolecular reductive amination was
synthetic strategy enabled us to prepare 7 in 10.5% over 16
steps starting from uridine. Several analogues of the CPZs,
where the fatty acyl side was modified, had already been
semisynthesized from (+)-caprazol, which was obtained by
hydrolysis of the naturally occurring CPZs. Therefore, our
second generation synthesis of (+)-caprazol would provide a
full chemical process toward the preparation of the CPZs
analogues.
applied to 25, and the desired diazepanone 26 was obtained in
i
excellent yield (H2, Pd black, PrOH, then 4 equiv of NaBH-
(OAc)3, AcOH, AcOEt, 96% overall). Spectrometric analysis
by NMR unambiguously confirmed the structure of 26. There-
fore, no epimerization had occurred despite the two-step
diazepanone construction at the R-palmitoyloxy formyl moiety,
which should be sensitive to epimerization. Methylation of 26
gave 27 (5 equiv of (CH2O)n, 4 equiv of NaBH(OAc)3, AcOH,
AcOEt, 77%). Finally, a global deprotection of 27 (80% aqueous
TFA, quant.) provided the palmitoyl caprazol 7. The diaz-
epanone derivative 26 was also deprotected to give N6′-
desmethyl palmitoyl caprazol 28 (80% aqueous TFA, quant.).
This modified synthetic strategy enabled us to prepare 7 in
10.2% over 16 steps, starting from uridine, in a highly concise
manner.
Second Generation Synthesis of (+)-Caprazol. Improve-
ment of the number of steps and total chemical yield of the
preparation of (+)-caprazol were also accomplished with this
modified synthesis as shown in Scheme 4. Thus, protection of
the allylic alcohol of the amide derivative 23 with a triethylsilyl
(TES) group (TESCl, imidazole, DMF) and conversion of the
terminal olefin of 29 to an aldehyde with the two-step sequence
provided 30 (0.5 mol % of OsO4, 2.5 equiv of NMO, acetone-
H2O; 2.7 equiv of NaIO4, acetone-phosphate buffer (pH 7),
69% overall) to afford a precursor for the cyclization reaction.
The intramolecular reductive amination of 30 gave the diaz-
epanone 31 (H2, Pd black, iPrOH, then 4 equiv of NaBH(OAc)3,
AcOH, AcOEt, 78% overall). After N-methylation at the
diazepanone moiety (5 equiv of (CH2O)n, 4 equiv of NaBH-
(OAc)3, AcOH, AcOEt, 91%), a global deprotection of 32 (80%
aqueous TFA, quant.) provided (+)-(7). This second generation
Evaluation of the Antibacterial Activity. Antibacterial
activity of the synthetic compounds was evaluated against a
range of bacterial strains including Mycobacterium sp, and the
minimum inhibitory concentrations (MIC, µg/mL) are sum-
marized in Table 1. Palmitoyl caprazol 7, which possesses a
simple fatty acyl side chain, exhibited antibacterial activity
against Mycobacterium smegmatis ATCC607 (MIC ) 6.25 µg/
mL) with a potency similar to that of the CPZs. Consistent with
these observations and with previous studies,4e simplification
of the fatty acyl side chain in the CPZs to the palmitoyl group,
lacking substituents and stereocenters, was tolerated for anti-
bacterial activity. Removal of the methyl group at the N6-
position had a relatively high impact on anti-Mycobacterium
activity, and 28 resulted in a modest 4-fold reduction in potency.
Clinically used â-lactams and vancomycin inhibit peptidoglycan
biosynthesis; their mode of action is inhibition of the polym-
erization of the lipid II at the bacterial surface. The CPZs may
have a similar mode of action as the LPMs, which also inhibit
peptidoglycan biosynthesis, but they would inhibit MraY in a
different manner from those of the â-lactams and vancomycin.
Since the reaction catalyzed by MraY is located upstream of
the lipid II polymerization and is the essential step for the growth
of most bacteria, it is expected that MraY inhibitors would
exhibit antibacterial activity against drug-resistant strains. As
572 J. Org. Chem., Vol. 73, No. 2, 2008

Synthesis of Caprazamycin Analogues
SCHEME 3. Synthesis of Palmitoyl Caprazol 7 and Its Des-N-methyl Analogue 28
expected, 7 and 28 exhibited antibacterial activity against drug-
resistant bacteria including MRSA and VRE strains (MIC )
3.13-12.5 µg/mL). Different from the case with Mycobacterium
smegmatis, the desmethyl analogue 28 exhibited a similar
potency to 7 in antibacterial activity against MRSA and VRE
strains. Mycobacteria have an extra cell wall structure that is
extraordinarily thick and tight, located outside the peptidoglycan
layer. This cell wall structure contains the characteristic long
chain fatty acid, mycolic acid.19 The difference in antibacterial
activity between 7 and 28 observed in Mycobacterium sp. might
be correlated to the subtle difference in lipophilicity introduced
by the methyl group at the diazepanone moiety. Of significance
is the antibacterial activity against drug-resistant bacteria
including MRSA and VRE strains. Therefore, the CPZs includ-
ing the LPMs and the MRYs, a target of which is MraY, are
promising leads for the novel antibacterial agents against drug-
resistant bacteria. More precise optimization (simplification) of
the lipophilic side chain is, however, necessary to improve the
TABLE 1. Antibacterial Activity of CPZ Analogues
MIC (µg/mL)
strain
4
7
28
25
1.56
3.13
6.25
6.25
6.25
M. smegmatis ATCC607
S. aureus FDA 209P
>100
>100
>100
>100
>100
>100
>100
>100
6.25
1.56
3.13
6.25
6.25
6.25
6.25
S. aureus MS9610 (MDR)
S. aureus MRSA No. 5 (MRSA)
S. aureus MRSA No. 17 (MRSA)
S. aureus MS16526 (MRSA)
S. aureus TY04282 (MRSA)
E. faecalis NCTC 12201 (VRE)
12.5
12.5
(19) (a) Crick, D. C.; Mahapatra, S.; Brennan, P. J. Glycobiology 2001,
11, 107R-118R. (b) Hong, X.; Hopfinger, A. J. Biomacromolecular 2004,
5, 1052-1065.
12.5
J. Org. Chem, Vol. 73, No. 2, 2008 573

Hirano et al.
SCHEME 4. The Second Generation Synthesis of
(+)-Caprazol (4)
phenyl), 7.47-7.37 (m, 6H, phenyl), 5.91 (m, 1H, H-4), 5.67 (d,
1H, TrocNH, JNH,2 ) 8.0 Hz), 5.43 (d, 1H, H-5a, J5a,4 ) 17.1 Hz),
5.28 (d, 1H, H-5b, J5b,4 ) 10.3 Hz), 4.71 (m, 2H, CH2CCl3), 4.36
(m, 1H, H-3), 3.96 (dd, 1H, H-1a, J1a,1b ) 10.8 Hz, J1a,2 ) 3.4
Hz), 3.79 (dd, 1H, H-1b, J1b,1a ) 10.8 Hz, J1b,2 ) 3.4 Hz), 3.76
(m, 1H, H-2), 1.07 (s, 9H, tert-butyl); 13C NMR (CDCl3, 125 MHz)
δ 154.4, 137.1, 136.5, 135.5, 135.4, 135.4, 132.3, 132.2, 130.3,
130.2, 130.1, 128.0, 128.0, 127.9, 127.9, 116.7, 95.5, 74.6, 74.1,
63.7, 55.2, 26.8, 26.8, 19.1; FABMS-HR (NBA) calcd for C24H31-
Cl3NO4Si 530.1088, found 530.1097.
(2R,3S)-3-O-tert-Butyldiphenylsilyl-1-O-(4,4′-dimethoxytrityl)-
2-(2,2,2-trichloroethoxycarbonylamino)-4-pentene-1,3-diol (11).
Compound 10 (1.24 g, 2.35 mmol) in MeOH (25 mL) was treated
with NH4F (2.5 g) at 45 °C for 2 h. The reaction mixture was diluted
with AcOEt and the insoluble materials were filtered off though a
Celite pad. The filtrate was concentrated in vacuo. The residue in
pyridine (20 mL) was treated with DMTrCl (1.19 g, 3.53 mmol) at
room temperature for 24 h. The reaction mixture was concentrated
in vacuo, and the residue was partitioned between AcOEt and H2O.
The organic phase was washed with saturated aqueous NaCl, dried
(Na2SO4), and concentrated in vacuo. The residue in DMF (20 mL)
was treated with imidazole (1.4 g, 21 mmol) and TBDPSCl (1.8
mL, 7.1 mmol) at room temperature for 24 h. The reaction mixture
was partitioned between AcOEt and H2O, and the organic phase
was washed with H2O (twice) and saturated aqueous NaCl, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
a neutral silica gel column (10 × 15 cm, 15% AcOEt-hexane) to
give 11 (1.33 g, 68% in 3 steps) as a colorless glass: [R]21D +4.7
(c 0.9, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.63-7.58 (m, 4H,
phenyl), 7.42-7.17 (m, 15H, phenyl), 6.77 (m, 4H, phenyl), 5.62
(m, 1H, H-4), 5.10 (d, 1H, H-5a, J5a,4 ) 17.0 Hz), 5.02 (d, 1H,
H-5b, J5b,4 ) 10.3 Hz), 4.77 (d, 1H, TrocNH, JNH,2 ) 8.2 Hz),
4.73 (d, 1H, CH2CCl3, J ) 13.5 Hz), 4.61 (d, 1H, CH2CCl3, J )
13.5 Hz), 4.48 (m, 1H, H-3), 4.01 (m, 1H, H-2), 3.77 (s, 6H, OMe
× 2), 3.20 (m, 1H, H-1a), 3.08 (m, 1H, H-1b), 0.99 (s, 9H, tert-
butyl); 13C NMR (CDCl3, 125 MHz) δ 158.6, 158.4, 154.5, 154.3,
147.3, 144.7, 139.4, 136.6, 136.1, 136.0, 135.9, 135.9, 135.8, 135.8,
135.7, 133.4, 132.8, 130.2, 130.0, 129.9, 129.9, 129.8, 129.7, 129.1,
128.0, 127.9, 127.8, 127.8, 127.7, 127.7, 127.6, 127.5, 127.5, 127.1,
126.7, 118.0, 117.7, 113.1, 113.0, 95.6, 86.1, 86.4, 76.1, 74.5, 79.4,
74.1, 62.1, 56.7, 55.9, 55.2, 55.2, 27.0, 27.0, 26.9, 19.3, 19.3, 19.2;
FABMS-HR (NBA) calcd for C45H49Cl3NO6Si 832.2395, found
832.2390.
(2R,3S)-3-O-tert-Butyldiphenylsilyl-2-(N-methyl-2,2,2-trichlo-
roethoxycarbonylamino)-4-pentene-1,3-diol (12). A solution of
11 (185 mg, 0.22 mmol) in DMF (3 mL) was treated with MeI
(222 µL, 0.44 mmol) and NaH (14 mg, 60% purity, 0.33 mmol) at
0 °C for 8 h. The reaction mixture was partitioned between AcOEt
and H2O, and the organic phase was washed with H2O (twice) and
saturated aqueous NaCl, dried (Na2SO4), and concentrated in vacuo.
The residue was dissolved in CH2Cl2 (3 mL) and treated with 90%
aqueous AcOH (10 mL) at room temperature for 1 h. The reaction
mixture was carefully concentrated in vacuo (being kept under
10 °C). The residue was purified by a flash silica gel column (3 ×
20 cm, 33% AcOEt-hexane) to give 12 (87.9 mg, 74% in 2 steps)
as a colorless glass: 1H NMR (CDCl3, 500 MHz, 10:1 mixture of
the rotamers, assignment for the major isomer) δ 7.69-7.63 (m,
4H, phenyl), 7.44-7.36 (m, 6H, phenyl), 5.75 (ddd, 1H, H-4, J4,5a
) 17.2 Hz, J4,5a ) 10.1 Hz, J4,5b ) 8.3 Hz), 4.86 (d, 1H, H-5b,
J5b,4 ) 10.1 Hz), 4.76 (m, 1H, CH2CCl3), 4.74 (d, 1H, H-5a, J5a,5b
) 17.2 Hz), 4.62 (m, 1H, CH2CCl3), 4.34 (dd, 1H, H-3, J3,4 ) 8.3
Hz, J3,2 ) 8.2 Hz), 4.11 (m, 1H, H-2), 4.01 (m, 1H, H-1a), 3.81
(m, 1H, H-1b), 2.83 (s, 3H, NMe), 1.06 (s, 9H, tert-butyl); 13C
NMR (CDCl3, 125 MHz) δ 155.5, 154.6, 137.5, 137.4, 136.1, 136.1,
135.9, 135.9, 133.5, 133.4, 133.2, 133.1, 129.9, 129.9, 129.8, 129.7,
127.7, 127.4, 118.2, 117.9, 95.7, 95.4, 75.3, 75.2, 75.1, 74.6, 63.6,
60.9, 31.9, 27.0, 19.3; FABMS-HR (NBA) calcd for C25H33Cl3-
NO4Si 544.1245, found 544.1238.
permeability in bacterial cells.20 It is also extremely important
to simplify the hydrophilic core structures to reduce the size of
the molecules and to stabilize the chemically labile structure.
Although this aspect of the research will likely be the most
difficult to accomplish, a full chemical synthetic approach with
novel agents, based on nucleoside antibiotic research and rational
drug design, should result in the discovery of novel antibacterial
drugs.
Conclusion. In summary, we have described the synthesis
of caprazamycin analogues and their structure-activity relation-
ship. The key elements of our approach include the improved
synthesis of the key 5′-â-O-aminoribosyl-glycyluridine deriva-
tive, installation of the palmitoyl side chain to the cyclization
precursor, and the construction of the diazepanone by an
intramolecular reductive amination. Palmitoyl caprazol 7, which
possesses a simple fatty acyl side chain, exhibited antibacterial
activity against Mycobacterium smegmatis ATCC607 (MIC )
6.25 µg/mL) with a potency similar to that of the CPZs.
Analogues 7 and 28 also exhibited antibacterial activity against
drug-resistant bacteria including MRSA and VRE strains (MIC
) 3.13-12.5 µg/mL). This strategy would be suitable for
examining a general structure-activity relationship and for
synthesizing novel analogues because the 5′-â-O-aminoribosyl-
glycyluridine structure is predicted to be a pharmacophore of
this class of natural products.
Experimental Section
(2R,3S)-1-O-tert-Butyldiphenylsilyl-2-(2,2,2-trichloroethoxy-
carbonylamino)-4-pentene-1,3-diol (10). Compound 9 (100 mg,
0.22 mmol) was treated with 80% aqueous TFA (5 mL) at room
temperature for 2 h. The mixture was concentrated in vacuo. The
residue in CH2Cl2-H2O (1:1, 10 mL) was treated with TrocCl (91
mg, 0.44 mmol) at room temperature for 12 h. The organic phase
was washed with saturated aqueous NaCl, dried (Na2SO4), filtered,
and concentrated in vacuo. The residue was purified by a flash
silica gel column (3 × 10 cm, 20% AcOEt-hexane) to afford 10
(105 mg, 90% in 2 steps) as a colorless syrup: [R]21 -13.6 (c
D
1
2.20, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.65-7.61 (m, 4H,
(20) Green, D. W. Expert Opin. Ther. Targets 2002, 6, 1-19.
574 J. Org. Chem., Vol. 73, No. 2, 2008

Synthesis of Caprazamycin Analogues
tert-Butyl (2S,3S)-3-O-tert-Butyldiphenylsilyloxy-2-(N-methyl-
2,2,2-trichloroethoxycarbonylamino)-4-pentenate (13). A solution
of 12 (46.5 mg, 0.086 mmol) in 60% aqueous MeCN (1 mL) was
treated with PhI(OAc)2 (69 mg, 0.21 mmol) and TEMPO (7.0 mg,
0.045 mmol) at room temperature for 24 h. The reaction mixture
was concentrated in vacuo, and the residue was purified by a silica
gel column (1 × 3 cm, 25% MeOH/CHCl) to give the crude acid
as a colorless oil. The crude acid in CH2Cl2 (1 mL) was treated
with t-BuC(NH)CCl3 (186 mg, 0.86 mmol) and BF3‚OEt2 (3.2 µL,
0.026 mmol) at 0 °C for 1 h. The mixture was partitioned between
AcOEt and saturated aqueous NaHCO3. The organic phase was
washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was purified by a silica gel
column (3 × 10 cm, 16% AcOEt-hexane) to afford 13 (47 mg,
89% in 2 steps) as a colorless foam: 1H NMR (CDCl3, 500 MHz,
1:1.5 mixture of the rotamers) δ 7.71-7.67 (m, 4H, phenyl), 7.43-
7.34 (m, 6H, phenyl), 5.75 (m, 1H, H-4), 4.86-4.60 (m, 6H, H-2,
H-3, H-5a, H-5b, CH2CCl3), 2.91 (s, 1.8H, NMe), 2.86 (s, 1.2H,
NMe), 1.46 (s, 3.6H, tert-butyl), 1.44 (s, 5.4H, tert-butyl), 1.03 (s,
3.6H, tert-butyl), 1.02 (s, 5.4H, tert-butyl); 13C NMR (CDCl3, 125
MHz) δ 169.8, 169.8, 154.8, 154.9, 136.1, 135.8, 118.2, 117.9,
95.5, 95.2, 83.3, 83.2, 75.2, 71.6, 71.4, 65.1, 64.4, 34.2, 28.0, 28.0;
FABMS-HR (NBA) calcd for C29H39Cl3NO5Si 614.1663, found
614.1664.
Methyl 6-Benzyloxycarbonylamino-6-deoxy-2,3-O-isopropy-
lidene-1-(uracil-1-yl)-â-D-glycero-L-talo-heptofuranuronate (17).
tert-Butyl hypochlorite (2.9 mL, 25.4 mmol) was added to a solution
of benzyl carbamate (2.6 g, 17.3 mmol) in aqueous NaOH (0.6 M,
28.5 mL) and n-PrOH (57 mL) at 0 °C, and the mixture was stirred
for 10 min, then allowed to reach room temperature. [DHQD]2AQN
(738 mg, 0.86 mmol), 16 (1.94 g, 5.74 mmol), and K2OsO2(OH)4
(317 mg, 0.86 mmol) were sequentially added to the mixture. The
resulting whole mixture was stirred at room temperature for 2 h.
After addition of saturated aqueous Na2S2O3, the reaction mixture
was extracted with AcOEt. The combined organic phases were
washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was purified by a silica gel
column (15 × 20 cm, 40-45% AcOEt-hexane) to afford 17 (2.78
g, 96%, >98% de) as a white foam: [R]23D +20.7 (c 1.04, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 8.45 (br s, 1H, NH-3), 7.35-7.31
(m, 5H, phenyl), 7.18 (d, 1H, H-6, J6,5 ) 7.8 Hz), 5.70 (dd, 1H,
H-5, J5,6 ) 7.8 Hz, J5,OH ) 1.9 Hz), 5.62 (d, 1H, NH-6′, JNH,6′
)
8.2 Hz), 5.45 (s, 1H, H-1′), 5.13 (d, 1H, benzyl, J ) 11.9 Hz),
5.08 (d, 1H, benzyl, J ) 11.9 Hz), 5.01 (dd, 1H, H-2′, J2′,3′ ) 6.5
Hz, J2′,3′ ) 3.1 Hz), 4.94 (dd, 1H, H-3′, J3′,2′ ) 6.5 Hz, J3′,4′ ) 3.3
Hz), 4.54 (m, 1H, H-6′), 4.27 (m, 2H, H-4′, H-5′), 3.76 (m, 4H,
OMe, OH), 1.54 (s, 3H, acetonide), 1.26 (s, 3H, acetonide); 13C
NMR (CDCl3, 125 MHz) δ 170.9, 163.1, 156.23, 150.4, 143.2,
136.2, 128.5, 128.2, 114.8, 102.8, 96.2, 86.1, 82.7, 81.4, 71.4, 67.1,
56.6, 52.8, 27.2, 25.3; FABMS-HR (NBA) calcd for C23H28N3O10
506.1774, found 506.1778.
tert-Butyl (2S,3S)-3-O-tert-Butyldiphenylsilyloxy-2-methylamino-
4-pentenate (14). A mixture of 13 (184 mg, 0.3 mmol), NH4Cl
(477 mg, 9 mmol), and Zn powder (230 mg, 85% purity, 3 mmol)
in MeOH (5 mL) was stirred at room temperature for 12 h. Insoluble
materials were filtered off through a Celite pad, and the filtrate
was concentrated in vacuo. The residue was purified by a neutral
Methyl 5-O-[5-Azido-5-deoxy-2,3-O-(3-pentylidene)-â-D-ri-
bofuranosyl]-6-benzyloxycarbonylamino-6-deoxy-2,3-O-isopro-
pylidene-1-(uracil-1-yl)-â-D-glycero-L-talo-heptofuranuronate (19).
A mixture of 17 (50.5 mg, 0.1 mmol), 18 (37 mg, 0.15 mmol), and
MS4A (150 mg) in CH2Cl2 (1 mL) was stirred at -30 °C for 15
min. BF3‚OEt2 (20 µL, 0.15 mmol) was added five times at each
hour, and the reaction mixture was stirred for a total of 12 h.
Saturated aqueous NaHCO3 was added, and the mixture was
extracted with AcOEt. The organic phase was washed with saturated
aqueous NaCl, dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was purified by a silica gel column (1.5 × 15 cm,
silica gel column (3 × 5 cm, 50% AcOEt-hexane) to give 14 (120
1
mg, 91%) as a colorless syrup: [R]22 +3.9 (c 1.03, CHCl3); H
D
NMR (CDCl3, 500 MHz) δ 7.72 (dd, 2H, phenyl, J ) 1.5, 7.9
Hz), 7.67 (dd, 2H, phenyl, J ) 1.5, 7.9 Hz), 7.43-7.34 (m, 6H,
phenyl), 5.81 (ddd, 1H, H-4, J4,5a ) 17.2 Hz, J4,5b ) 10.3 Hz, J4,3
) 6.9 Hz), 5.00 (dd, 1H, H-5b, J5b,4 ) 10.3 Hz, J5b,5a ) 1.0 Hz),
4.96 (dd, 1H, H-5a, J5a,4 ) 10.3 Hz, J5a,5b ) 1.0 Hz), 4.45 (m, 1H,
H-3), 3.06 (d, 1H, H-2, J2,3 ) 3.6 Hz), 2.34 (s, 3H, NMe), 1.63 (br
s, 1H, NH), 1.40 (s, 9H, tert-butyl), 1.07 (s, 9H, tert-butyl); 13C
NMR (CDCl3, 125 MHz) δ 170.9, 136.6, 136.0, 135.9, 133.7, 133.5,
129.7, 129.6, 127.6, 127.4, 127.3, 126.9, 126.5, 126.1, 116.8, 81.1,
76.3, 69.3, 35.1, 28.2, 28.1, 27.0, 19.4; FABMS-HR (NBA) calcd
for C26H38NO3Si 440.2621, found 440.2629.
33-50% AcOEt-hexane) to afford 19 (52 mg, 71%, >97% de)
1
as a white foam: [R]25 +6.3 (c 0.73, CHCl3); H NMR (CDCl3,
D
500 MHz) δ 9.40 (br s, 1H, NH-3), 7.40-7.30 (m, 6H, phenyl,
H-6), 5.86 (d, 1H, NH-6′, JNH,6′ ) 9.8 Hz), 5.70 (d, 1H, H-5, J5,6
) 8.1 Hz), 5.67 (s, 1H, H-1′), 5.22 (d, 1H, benzyl, J ) 12.3 Hz),
5.15 (s, 1H, H-1′′), 5.05 (d, 1H, benzyl, J ) 12.3 Hz), 4.81 (m,
2H, H-2′, H-3′), 4.67 (d, 1H, H-6′, J6′,NH ) 9.8 Hz), 4.58 (m, 2H,
H-2′, H-3′), 4.47 (d, 1H, H-5′, J5′,4′ ) 7.3 Hz), 4.24 (dd, 1H, H-4′′,
J4′′,5′′a ) 5.8 Hz, J4′′,5′′b ) 6.3 Hz), 3.77 (s, 3H, OMe), 3.39 (dd,
1H, H-5′′a, J5′′a,5′′b ) 12.8 Hz, J5′′a,4′′ ) 4.8 Hz), 3.36 (dd, 1H, H-5′′b,
J5′′b,5′′a ) 12.8 Hz, J5′′b,4′′ ) 6.3 Hz), 1.62 (m, 2H, CH2CH3), 1.53
(m, 2H, CH2CH3), 1.50 (s, 3H, acetonide), 1.30 (s, 3H, acetonide),
0.84 (m, 6H, 2 × CH2CH3); 13C NMR (CDCl3, 125 MHz) δ 170.5,
163.2, 156.2, 150.0, 142.1, 136.2, 128.4, 128.2, 128.1, 117.3, 114.9,
111.2, 102.5, 93.4, 86.2, 86.0, 85.3, 83.7, 81.8, 80.5, 78.5, 67.2,
54.4, 53.1, 52.8, 29.3, 28.9, 27.0, 25.3, 8.3, 7.3; FABMS-HR (NBA)
calcd for C33H43N6O13 731.2888, found 731.2892.
Methyl (E)-5,6-Dideoxy-2,3-O-isopropylidene-1-(uracil-1-yl)-
â-D-ribo-5-eneheptofranuronate (16). A solution of 15 (4.0 g, 14.2
mmol) and IBX (9.9 g, 35.5 mmol) in MeCN (140 mL) was heated
at 80 °C for 1 h. The reaction mixture was cooled in an ice bath,
and the resulting white precipitates were filtered off through a Celite
pad. The filtrate was concentrated in vacuo. The residue in CH2-
Cl2 (140 mL) was cooled to -20 °C, to which a solution of
Ph3PdCHCO2Me (5.7 g, 17.0 mmol) in CH2Cl2 (20 mL) was added
dropwise. The reaction mixture was stirred at -20 °C for 1 h. The
mixture was diluted with AcOEt, then washed with H2O and
saturated aqueous NaCl. The organic phase was dried (Na2SO4),
filtered, and concentrated in vacuo. The residue was purified by a
silica gel column (10 × 20 cm, 25-45% AcOEt-hexane) to afford
Methyl 6-Benzyloxycarbonylamino-5-O-[5-tert-butoxycarbo-
nylamino-5-deoxy-2,3-O-(3-pentylidene)-â-D-ribofuranosyl]-6-
deoxy-2,3-O-isopropylidene-1-(uracil-1-yl)-â-D-glycero-L-talo-
heptofuranuronate (20). A mixture of 19 (793 mg, 1.09 mmol),
Ph3P (854 mg, 3.26 mmol), and H2O (900 µL) in THF-benzene
(1:1, 10 mL) was stirred at 45 °C for 12 h. After the reaction mixture
was cooled to room temperature, (Boc)2O (918 µL, 3.96 mmol)
was added, and the resulting mixture was stirred for an additional
5 h. The reaction mixture was partitioned between AcOEt and H2O,
and the organic phase was washed with saturated aqueous NaCl,
dried (Na2SO4), and concentrated in vacuo. The residue was purified
by a silica gel column (3.0 × 15 cm, 50% AcOEt-hexane) to give
20 (782 mg, 90% in 2 steps) as a white foam: [R]23D +25.2 (c 0.7,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 8.73 (br s, 1H, NH-
16 (4.3 g, 91% in 2 steps) as a colorless syrup: [R]23 +45.4 (c
D
1
0.7, CHCl3); H NMR (CDCl3, 500 MHz) δ 8.60 (br s, 1H, NH-
3), 7.19 (d, 1H, H-6, J6,5 ) 8.0 Hz), 7.01 (dd, 1H, H-5′, J5′,6′
)
15.8 Hz, J5′,4′ ) 5.9 Hz), 6.04 (dd, 1H, H-6′, J6′,5′ ) 15.8 Hz, J6′,4′
) 1.7 Hz), 5.75 (dd, 1H, H-6, J6,5 ) 8.0 Hz, J6,OH ) 2.2 Hz), 5.62
(d, 1H, H-1′, J1′,2′ ) 1.6 Hz), 5.08 (dd, 1H, H-2′, J2′,1′ ) 1.6 Hz,
J2′,3′ ) 6.4 Hz), 4.84 (dd, 1H, H-3′, J3′,2′ ) J3′,4′ ) 6.4 Hz), 4.66
(m, 1H, H-4′), 3.75 (s, 3H, OMe), 1.59 (s, 3H, acetonide), 1.36 (s,
3H, acetonide); 13C NMR (CDCl3, 125 MHz) δ 166.1, 162.6, 145.6,
143.6, 142.5, 122.3, 114.9, 102.9, 95.2, 86.8, 84.5, 84.0, 51.8, 27.1,
25.3; FABMS-HR (NBA) calcd for C15H19N2O7 339.1192, found
339.1199.
J. Org. Chem, Vol. 73, No. 2, 2008 575

Hirano et al.
3), 7.36-7.31 (m, 5H, phenyl), 7.27 (d, 1H, H-6, J6,5 ) 8.0 Hz),
5.70 (d, 1H, H-5, J5,6 ) 8.0 Hz), 5.55 (s, 1H, H-1′), 5.51 (d, 1H,
NH-6′, JNH,6′ ) 8.5 Hz), 5.39 (br s, 1H, NH-5′′), 5.19 (d, 1H, benzyl,
J ) 12.2 Hz), 5.14 (s, 1H, H-1′′), 5.07 (d, 1H, benzyl, J ) 12.2
Hz), 5.00 (d, 1H, H-2′, J2′,3′ ) 4.7 Hz), 4.84 (m, 1H, H-3′), 4.67
(d, 1H, H-6′, J6′,NH ) 8.5 Hz), 4.54 (m, 2H, H-2′′, H-3′′), 4.43 (d,
1H, H-5′, J5′,4′ ) 7.5 Hz), 4.23 (m, 2H, H-4′, H-4′′), 3.79 (s, 3H,
OMe), 3.25 (m, 1H, H-5′′a), 3.03 (m, 1H, H-5′′b), 1.72 (s, 3H,
acetonide), 1.57 (m, 2H, CH2CH3), 1.55 (m, 2H, CH2CH3), 1.48
(s, 9H, tert-butyl), 1.32 (s, 3H, acetonide), 0.80 (m, 6H, 2 ×
CH2CH3); 13C NMR (CDCl3, 125 MHz) δ 171.1, 162.8, 156.2,
156.0, 150.0, 142.9, 136.1, 128.5, 128.2, 116.6, 114.8, 112.0, 102.7,
95.4, 87.1, 86.2, 84.0, 82.1, 81.2, 79.6, 79.0, 67.3, 54.8, 53.0, 43.3,
29.4, 28.8, 28.4, 27.0, 25.3, 8.3, 7.3; FABMS-HR (NBA) calcd
for C38H53N4O15 805.3527, found 805.3517.
6-Benzyloxycarbonylamino-5-O-[5-tert-butoxycarbonylamino-
5-deoxy-2,3-O-(3-pentylidene)-â-D-ribofuranosyl]-6-deoxy-2,3-
O-isopropylidene-1-(uracil-1-yl)-â-D-glycero-L-talo-heptofura-
nuronoic acid (21). A solution of 20 (32 mg, 0.04 mmol) in THF-
H2O (4:1, 1 mL) was treated with Ba(OH)2‚8H2O (13 mg, 0.04
mmol) at -30 °C for 12 h. The solution was partitioned between
AcOEt and 0.3 N aqueous HCl, and the organic phase was washed
with saturated aqueous NaCl, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by a silica gel column (1.5 × 5
cm, 17% MeOH-CHCl3) to give 21 (23 mg, 73%) as a white
foam: [R]21D +21.6 (c 1.00, CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 7.64 (br d, 1H, H-6, J6,5 ) 8.0 Hz), 7.38-7.27 (m, 5H, phenyl),
5.74 (br s, 1H, H-1′), 5.65 (br d, 1H, H-5, J5,6 ) 8.0 Hz), 5.22 (s,
1H, H-1′′), 5.16 (d, 1H, benzyl, J ) 12.5 Hz), 5.11 (m, 1H, H-2′),
5.02 (d, 1H, benzyl, J ) 12.5 Hz), 4.98 (m, 1H, H-3′), 4.90 (m,
1H, H-2′′), 4.65 (m, 1H, H-6′), 4.56 (d, 1H, H-3′′, J3′′,2′′ ) 5.8 Hz),
4.50 (m, 1H, H-5′), 4.18-4.11 (m, 2H, H-4′, H-4′′), 3.13 (m, 2H,
H-5′′a, H-5′′b), 1.60 (m, 4H, 2 × CH2CH3), 1.49 (s, 3H, acetonide),
1.48 (s, 9H, tert-butyl), 1.31 (s, 3H, acetonide), 0.79 (m, 6H, 2 ×
CH2CH3); 13C NMR (CDCl3, 125 MHz) δ 177.5, 166.2, 158.5,
152.0, 138.3, 130.3, 129.7, 129.2, 128.7, 117.4, 115.6, 88.4, 87.9,
83.8, 83.4, 80.5, 57.4, 44.5, 30.5, 29.0, 28.6, 28.2, 27.8, 27.3, 25.8,
8.6, 7.9, 7.6; FABMS-HR (NBA) calcd for C37H49N4O15 789.3194,
found 789.3194.
N-[(1S,2S)-2-tert-Butyldiphenylsiloxy-1-tert-butoxycarbonyl-
3-butenyl]-N-methyl-6-benzyloxycarbonylamino-5-O-[5-tert-bu-
toxycarbonylamino-5-deoxy-2,3-O-(3-pentylidene)-â-D-ribofura-
nosyl]-6-deoxy-2,3-O-isopropylidene-1-(uracil-1-yl)-â-D-glycero-
L-talo-heptofuranuronamide (22). A mixture 21 (55 mg, 0.13
mmol) and 14 (129 mg, 0.16 mmol) in THF (2 mL) was treated
with DEPBT (194 mg, 0.65 mmol) at room temperature for 18 h.
The reaction mixture was partitioned between AcOEt and 0.5 N
aqueous HCl, and the organic phase was washed with saturated
aqueous NaHCO3 and saturated aqueous NaCl, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by a silica gel
column (3 × 22 cm, 40% AcOEt-hexane) to give 22 (108 mg,
66%) as a white foam: 1H NMR (CDCl3, 500 MHz, 7:1 mixture
of the rotamers) δ 8.67 (br s, 1H, NH-3), 7.69-7.65 (m, 4H,
phenyl), 7.48 (d, 1H, H-6, J6,5 ) 8.0 Hz), 7.41-7.31 (m, 11H,
phenyl), 5.43 (br s, 1H, NHBoc), 5.80 (s, 1H, H-1′), 5.77-5.74
(m, 3H, H-11′, H-5, NHCbz), 5.19 (d, 1H, H-2′, J2′,3′ ) 6.6 Hz),
5.14 (d, 1H, benzyl, J ) 12.3 Hz), 5.06 (s, 1H, H-1′′), 4.98 (d, 1H,
benzyl, J ) 12.3 Hz), 4.90 (m, 1H, H-3′), 4.78 (m, 3H, H-12′a,
H-6′, H-10′), 4.67 (d, 1H, H-12′b, J12′b,11′ ) 17.2 Hz), 4.59 (d, 1H,
H-2′′, J2′′,3′′ ) 7.7 Hz), 4.56 (d, 1H, H-3′′, J3′′,2′′ ) 7.7 Hz), 4.23
(m, 1H, H-4′), 4.19 (dd, 1H, H-4′′, J4′′,5′′a ) 5.4 Hz, J4′′,5′′b ) 4.8
Hz), 4.05 (m, 1H, H-9′), 3.25 (m, 1H, H-5′a), 3.04 (m, 1H, H-5′′b),
3.03 (s, 3H, NMe), 1.61 (m, 2H, CH2CH3), 1.54 (s, 3H, acetonide),
1.48 (m, 2H, CH2CH3), 1.44 (s, 9H, tert-butyl), 1.42 (s, 9H, tert-
butyl), 1.27 (s, 3H, acetonide), 1.00 (s, 9H, tert-butyl), 0.81 (t, 6H,
2 × CH2CH3, J ) 7.4 Hz); 13C NMR (CDCl3, 125 MHz) δ 170.5,
167.6, 162.6, 156.4, 156.0, 152.0, 149.9, 146.2, 142.8, 141.7, 136.6,
136.2, 136.1, 136.1, 133.7, 133.0, 129.7, 129.5, 128.5, 128.3, 128.3,
128.2, 128.1, 127.5, 127.3, 118.2, 116.9, 116.4, 114.9, 113.6, 112.5,
112.3, 103.4, 103.0, 98.9, 92.9, 87.5, 87.5, 86.6, 86.0, 85.4, 84.3,
83.9, 83.0, 82.1, 81.9, 80.5, 80.3, 79.56, 79.1, 78.7, 74.5, 67.1, 61.7,
53.8, 51.0, 43.2, 39.6, 36.2, 32.9, 29.7, 29.5, 28.8, 28.4, 28.4, 28.0,
27.9, 27.9, 27.1, 27.0, 27.0, 26.7, 25.3, 25.1, 22.7, 19.2, 14.1, 8.4,
7.8, 7.3; FABMS-HR (NBA) calcd for C63H86N5O17Si 1212.5788,
found 1212.5790.
N-[(1S,2S)-1-tert-Butoxycarbonyl-2-hydroxy-3-butenyl]-N-
methyl-6-benzyloxycarbonylamino-5-O-[5-tert-butoxycarbony-
lamino-5-deoxy-2,3-O-(3-pentylidene)-â-D-ribofuranosyl]-6-deoxy-
2,3-O-isopropylidene-1-(uracil-1-yl)-â-D-glycero-L-talo-
heptofuranuronamide (23). A solution of 22 (435 mg, 0.34 mmol)
in THF (2 mL) was treated with AcOH (98 µL) and TBAF solution
(1 M solution in THF, 1.7 mL) at room temperature for 1 week.
The mixture was partitioned between AcOEt and saturated aqueous
NaHCO3, and the organic phase was washed with saturated aqueous
NaCl, dried (Na2SO4), and concentrated in vacuo. The residue was
purified by a neutral flash silica gel column (3.0 × 10 cm, 60%
AcOEt-hexane) to give 23 (279 mg, 78%) as a colorless foam:
1H NMR (CDCl3, 500 MHz, 8:1 mixture of the rotamers) δ 9.32
(br s, 1H, NH-3), 7.45 (d, 1H, H-6, J6,5 ) 8.0 Hz), 5.89-5.74 (m,
5H, H-1′, H-5′, H-11′, NHBoc, NHCbz), 5.38 (d, 1H, H-12′a, J12′a,11′
) 17.2 Hz), 5.18 (d, 1H, H-12′b, J12′b,11′ ) 12.6 Hz), 5.17 (d, 1H,
benzyl, J ) 13.0 Hz), 4.99 (s, 1H, H-1′′), 5.04 (d, 1H, benzyl, J )
13.0 Hz), 4.89 (m, 1H, H-2′), 4.86 (m, 1H, H-3′), 4.81 (m, 2H,
H-2′′, H-3′′), 4.63 (m, 1H, H-10′), 4.56 (m, 1H, H-6′), 4.51 (m,
2H, H-5′, H-9′), 4.22 (m, 1H, H-4′′), 4.11 (m, 1H, H-4′), 3.78 (d,
1H, OH, JOH,10 ) 3.4 Hz), 3.26 (m, 1H, H-5′′a), 3.15 (s, 3H, NMe),
3.03 (m, 1H, H-5′′b), 1.59 (m, 2H, CH2CH3), 1.52 (s, 3H,
acetonide), 1.50 (m, 2H, CH2CH3), 1.45 (s, 9H, tert-butyl), 1.43
(s, 9H, tert-butyl), 1.39 (s, 3H, acetonide), 0.82 (m, 6H, 2 ×
CH2CH3); 13C NMR (CDCl3, 125 MHz) δ 170.6, 169.5, 163.1,
156.2, 156.1, 150.1, 141.8, 136.1, 128.5, 128.4, 128.3, 118.0, 116.8,
114.9, 112.3, 103.0, 93.0, 86.5, 85.9, 85.6, 83.9, 83.2, 81.9, 80.5,
79.4, 79.2, 71.4, 67.1, 64.0, 50.8, 43.1, 35.6, 29.5, 28.7, 28.4, 27.8,
27.7, 27.7, 25.3, 8.4, 7.2; FABMS-HR (NBA) calcd for C47H68N5O17
974.4610, found 974.4602.
N-[(1S,2S)-1-tert-Butoxycarbonyl-3-oxo-2-palmitoyloxypropyl]-
N-methyl-6-benzyloxycarbonylamino-5-O-[5-tert-butoxycarbo-
nylamino-5-deoxy-2,3-O-(3-pentylidene)-â-D-ribofuranosyl]-6-
deoxy-2,3-O-isopropylidene-1-(uracil-1-yl)-â-D-glycero-L-talo-
heptofuranuronamide (25). A solution of 23 (50 mg, 0.051 mmol)
in CH2Cl2 (1 mL) was treated with DMAP (2 mg, 0.015 mmol),
palmitic acid (39 mg, 0.15 mmol), and EDCI (29 mg, 0.15 mmol)
at room temperature for 24 h. After the reaction was quenched by
addition of MeOH, the mixture was partitioned between AcOEt
and saturated aqueous NaHCO3, and the organic phase was washed
with 0.3 N aqueous HCl and saturated aqueous NaCl, dried (Na2-
SO4), and concentrated in vacuo to give crude 24. The residue in
80% aqueous dioxane was treated with NMO (33 mg, 0.15 mmol)
and K2OsO2(OH)4 (6 mg, 0.15 mmol) at room temperature for 7 h.
NaIO4 (88 mg, 0.41 mmol) was added to the mixture, and the
resulting mixture was stirred for an additional 18 h. The mixture
was diluted with AcOEt, and the organic phase was washed with
saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (Na2-
SO4), and concentrated in vacuo. The residue was purified by a
silica gel column (2 × 5 cm, 50% AcOEt-hexane) to give 25 (50
mg, 83% in 3 steps) as a colorless foam. Data for major rotamer:
1H NMR (CDCl3, 500 MHz, 7:1 mixture of the rotamers) δ 9.50
(s, 1H, H-11′), 8.36 (br s, 1H, NH-3), 7.46 (d, 1H, H-6, J6,5 ) 8.0
Hz), 7.35-7.32 (m, 5H, phenyl), 5.82-5.61 (m, 3H, NHBoc,
NHCbz, H-10′), 5.82 (s, 1H, H-1′), 5.78 (d, 1H, H-5, J5,6 ) 8.0
Hz), 5.42 (m, 1H, H-2′), 5.19 (d, 1H, benzyl, J ) 12.1 Hz), 5.08
(s, 1H, H-1′′), 5.02 (d, 1H, benzyl, J ) 12.1 Hz), 4.96 (m, 1H,
H-3′), 4.83 (m, 1H, H-6′), 4.79 (m, 1H, H-5′), 4.57 (d, 1H, H-2′′,
J2′′,3′′ ) 5.2 Hz), 4.50 (d, 1H, H-3′′, J3′′,2′′ ) 5.2 Hz), 4.22-4.10
(m, 3H, H-4′, H-4′′, H-9′), 3.23 (m, 1H, H-5′′a), 3.21 (s, 3H, NMe),
2.95 (m, 1H, H-5′′b), 2.43 (m, 2H, COCH2), 1.68-1.48 (m, 9H, 2
× CH2CH3, acetonide, COCH2CH2) 1.45 (s, 9H, tert-butyl), 1.43
(s, 9H, tert-butyl), 1.34 (s, 3H, acetonide), 1.26 (m, 24H, palmitoyl),
576 J. Org. Chem., Vol. 73, No. 2, 2008

Synthesis of Caprazamycin Analogues
0.88 (t, 3H, palmitoyl terminal-Me, J ) 6.4 Hz), 0.82 (m, 6H, 2 ×
CH2CH3); FABMS-LR m/z 1214 (MH+); FABMS-HR (NBA) calcd
for C62H96N5O19 1214.6694, found 1214.6694.
71.0, 64.9, 63.0, 43.2, 38.7, 34.5, 31.9, 29.7, 29.6, 29.7, 29.4, 29.3,
29.2, 29.2, 28.9, 28.5, 27.7, 27.3, 25.3, 24.9, 22.7, 14.1, 8.4, 7.4;
FABMS-HR (NBA) calcd for C55H92N5O16 1078.6539, found
1078.6536.
Diazepanone (26). A mixture of 25 (13.4 mg, 0.011 mmol) and
Pd black (15 mg) in i-PrOH (2 mL) was vigorously stirred under
H2 atmosphere for 2 h. The insoluble materials were filtered off
through a Celite pad, and the filtrate was concentrated in vacuo.
The residue in CH2Cl2 (2 mL) was treated with AcOH (10 µL)
and NaBH(OAc)3 (10 mg, 0.044 mmol) at room temperature for
24 h. The mixture was partitioned between AcOEt and saturated
aqueous NaHCO3, and the organic phase was washed with saturated
aqueous NaCl, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by a silica gel column (1 × 5 cm, 33-50%
AcOEt-hexane) to give 26 (11 mg, 96%) as a colorless foam:
Des-N-methyl Palmitoyl Caprazol (28). Compound 26 (10 mg,
9.4 µmol) was treated with 80% aqueous TFA (1 mL) at room
temperature for 1 h. The mixture was concentrated in vacuo, and
the residue was lyophilized to afford 28 (a TFA salt, 8.6 mg, quant.)
as a white solid: mp 195 °C dec; [R]23D +18.1 (c 0.4, DMSO); 1H
NMR (CD3OD, 500 MHz) δ 7.65 (d, 1H, H-6, J6,5 ) 8.1 Hz), 5.70
(d, 1H, H-5, J5,6 ) 8.1 Hz), 5.67 (d, 1H, H-1′, J1′,2′ ) 2.1 Hz), 5.61
(m, 1H, H-3′′′), 5.45 (s, 1H, H-1′′), 4.80 (d, 1H, H-2′′′, J2′′′,3′′′
)
5.1 Hz), 4.22 (dd, 1H, H-2′, J2′,1′ ) 2.1 Hz, J2′,3′ ) 6.7 Hz), 4.21
(m, 1H, H-3′), 4.11-4.02 (m, 5H, H-4′, H-4′′, H-6′, H-2′′, H-3′′),
3.51 (m, 2H, H-4′′′a, H-4′′′b), 3.27 (m, 2H, H-5′′a, H-5′′b), 3.09
(s, 3H, CONMe), 2.41 (t, 2H, COCH2, J ) 7.5 Hz), 1.64 (m, 2H,
COCH2CH2), 1.28 (m, 24H, palmitoyl), 0.89 (m, 3H, palmitoyl
terminal-Me); 13C NMR (CD3OD, 125 MHz) δ 173.8, 170.3, 165.9,
151.9, 143.2, 108.8, 102.8, 94.2, 84.9, 80.3, 76.3, 75.9, 74.4, 73.5,
73.2, 71.3, 68.7, 65.4, 62.2, 60.4, 50.2, 43.0, 39.5, 35.0, 34.8, 33.1,
30.8, 30.7, 30.6, 30.5, 30.5, 30.2, 26.1, 25.8, 23.8, 14.5; FABMS-
HR (NBA) calcd for C37H60N5O14 798.4142, found 798.4142.
23
1
[R]D +9.4 (c 0.89, CHCl3); H NMR (CDCl3, 500 MHz) δ 8.18
(s, 1H, NH-3), 7.33 (d, 1H, H-6, J6,5 ) 8.1 Hz), 6.91 (br s, 1H,
NHBoc), 5.70 (d, 1H, H-5, J5,6 ) 8.1 Hz), 5.68 (s, 1H, H-1′), 5.41
(s, 1H, H-1′′), 5.22 (m, 1H, H-3′′′), 4.89 (dd, 1H, H-2′, J2′,3′ ) 6.5
Hz, J2′,1′ ) 1.6 Hz), 4.63 (m, 2H, H-3′, H-2′′), 4.53 (d, 1H, H-5′,
J5′,6′ ) 9.6 Hz), 4.49 (d, 1H, H-3′′, J3′′,2′′ ) 5.9 Hz), 4.42 (d, 1H,
H-2′′′, J2′′′,3′′′ ) 5.2 Hz), 4.38 (m, 1H, H-4′), 4.26 (dd, 1H, H-4′′,
J4′′,5′′a ) 4.2 Hz, J4′′,5′′b ) 7.5 Hz), 3.35 (m, 1H, H-5′′a), 3.30 (m,
1H, H-6′), 3.30 (d, 1H, H-4′′′a, J4′′′a,4′′′b ) 12.7 Hz), 3.02 (s, 3H,
NMe), 2.98 (d, 1H, H-4′′′b, J4′′′b,4′′′a ) 12.7 Hz), 2.97 (m, 1H,
H-5′′b), 2.33 (m, 2H, COCH2), 1.61 (m, 6H, 2 × CH2CH3,
COCH2CH2), 1.52 (s, 3H, acetonide), 1.49 (s, 9H, tert-butyl), 1.42
(s, 9H, tert-butyl), 1.29 (s, 3H, acetonide), 1.25 (m, 24H, palmitoyl),
0.88 (m, 3H, palmitoyl terminal-Me), 0.82 (m, 6H, 2 × CH2CH3);
13C NMR (CDCl3, 125 MHz) δ 174.5, 173.1, 166.9, 162.5, 156.1,
149.6, 141.9, 116.5, 114.8, 110.9, 102.5, 93.1, 87.2, 86.8, 86.5,
84.5, 83.8, 82.2, 81.1, 78.9, 69.4, 64.9, 60.4, 49.5, 43.5, 39.5, 34.2,
31.9, 29.7, 29.6, 29.6, 29.5, 29.3, 29.3, 29.1, 28.5, 28.0, 27.3, 25.5,
24.9, 22.7, 14.1, 8.3, 7.4; FABMS-HR (NBA) calcd for C54H90N5O16
1064.6383, found 1064.6375.
Palmitoyl Caprazol (7). Compound 27 (7.8 mg, 7.3 µmol) was
treated with 80% aqueous TFA (1 mL) at room temperature for
1 h. The mixture was concentrated in vacuo, and the residue was
lyophilized to afford 7 (a TFA salt form, 6.7 mg, quant.) as a white
solid: mp 210 °C dec; [R]23D +17.0 (c 0.5, DMSO); 1H NMR (CD3-
OD, 500 MHz) δ 7.74 (d, 1H, H-6, J6,5 ) 8.0 Hz), 5.70 (d, 1H,
H-5, J5,6 ) 8.0 Hz), 5.63 (s, 1H, H-1′), 5.43 (m, 1H, H-3′′′), 5.19
(s, 1H, H-1′′), 4.65 (d, 1H, H-2′′′, J2′′′,3′′′ ) 4.6 Hz), 4.37 (d, 1H,
H-5′, J5′,6′ ) 8.8 Hz), 4.24 (d, 1H, H-3′′, J3′′,2′′ ) 8.0 Hz), 4.15 (m,
2H, H-3′, H-4′), 4.11-4.07 (m, 3H, H-2′, H-2′′, H-4′′), 3.78 (d,
1H, H-6′, J6′,5′ ) 8.8 Hz), 3.44 (d, 1H, H-4′′′a, J4′′′a,4′′′b ) 16.3 Hz),
3.26 (m, 1H, H-5′′a), 3.19 (m, 1H, H-5′′b), 3.14 (d, 1H, H-4′′′b,
J4′′′b,4′′′a ) 16.3 Hz), 3.13 (s, 3H, CONMe), 3.48 (s, 3H, NMe),
2.38 (m, 2H, COCH2), 1.60 (m, 2H, COCH2CH2), 1.30 (m, 24H,
palmitoyl), 0.89 (m, 3H, palmitoyl terminal-Me); 13C NMR
(DMSO-d6, 150 MHz) δ 171.9, 170.3, 163.4, 150.3, 140.1, 110.1,
101.0, 100.2, 89.3, 82.7, 78.2, 76.0, 74.4, 74.2, 70.0, 69.7, 68.8,
67.4, 38.1, 35.9, 33.8, 31.2, 29.8, 29.0, 28.9, 28.8, 28.8, 28.6, 28.5,
28.4, 24.3, 23.2, 22.3, 22.0, 13.9; FABMS-HR (NBA) calcd for
C38H62N5O14 812.4299, found 812.4301.
Diazepanone (27). A solution of 26 (10 mg, 9.4 µmol) in AcOEt
(1 mL) was treated with paraformaldehyde (1.5 mg, 47 µmol),
AcOH (20 µL), and NaBH(OAc)3 (8 mg, 38 µmol) at room
temperature for 72 h. The mixture was partitioned between AcOEt
and saturated aqueous NaHCO3, and the organic phase was washed
with saturated aqueous NaCl, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by a silica gel column (1 × 5 cm,
50% AcOEt-hexane) to give 27 (7.8 mg, 77%) as a colorless
1
foam: [R]22 -20.2 (c 0.7, CHCl3); H NMR (CDCl3, 500 MHz)
D
δ 8.11 (s, 1H, NH-3), 7.72 (d, 1H, H-6, J6,5 ) 8.0 Hz), 6.36 (br s,
1H, NHBoc), 5.98 (s, 1H, H-1′), 5.67 (d, 1H, H-5, J5,6 ) 8.0 Hz),
5.35 (m, 1H, H-3′′′), 5.25 (s, 1H, H-1′′), 4.84 (d, 1H, H-3′, J3′,2′
Acknowledgment. This work was supported by grants-in-
aid for scientific research from the Ministry of Education. We
thank Dr. Masayuki Igarashi (Bioresources Unit, Bioactive
Molecular Research Group, Microbial Chemistry Research
Center) for evaluating the antibacterial activities of the synthe-
sized analogues. We thank Ms. S. Oka (Center for Instrumental
Analysis, Hokkaido University) for measurement of the mass
spectra.
)
4.5 Hz), 4.67 (d, 1H, H-2′′, J2′′,3′′ ) 4.5 Hz), 4.59 (d, 1H, H-2′′,
J2′′,3′′ ) 6.0 Hz), 3.53 (d, 1H, H-6′, J6′,5′ ) 9.0 Hz), 3.43 (m, 1H,
H-5′′a), 3.36 (d, 1H, H-4′′′a, J4′′′a,4′′′b ) 15.0 Hz), 3.19 (d, 1H,
H-4′′′b, J4′′′b,4′′′a ) 15.0 Hz), 3.15 (m, 1H, H-5′′b), 3.09 (s, 3H,
CONMe), 2.43 (s, 3H, NMe), 2.32 (t, 2H, COCH2, J ) 7.5 Hz),
1.65 (dd, 2H, CH2CH3, J ) 7.4, 14.8 Hz), 1.61 (s, 3H, acetonide),
1.53 (dd, 2H, CH2CH3, J ) 7.4, 14.8 Hz), 1.45 (s, 9H, tert-butyl),
1.42 (m, 2H, COCH2CH2), 1.40 (s, 9H, tert-butyl), 1.36 (s, 3H,
acetonide), 1.28 (m, 24H, palmitoyl), 0.89-0.82 (m, 9H, 2 ×
CH2CH3, palmitoyl terminal-Me); 13C NMR (CDCl3, 125 MHz) δ
172.7, 171.4, 166.6, 162.3, 156.2, 149.6, 140.5, 116.7, 115.1, 111.4,
102.5, 99.1, 89.7, 86.9, 86.8, 85.1, 83.9, 83.6, 82.5, 80.3, 79.3, 75.8,
Supporting Information Available: 1H NMR and 13C NMR
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO702264E
J. Org. Chem, Vol. 73, No. 2, 2008 577