An innovative strategy for the synthesis of a new series of potent aminopeptidase (APN or CD13) inhibitors derived from the oxepin-4-one family

Article abstract of DOI:10.1016/j.tetlet.2011.03.043

Derivatives from the aminobenzosuberone family have been recently synthesized and recognized as highly selective inhibitors of aminopeptidase N (APN)/CD13 (EC 3.4.11.2), an important target for cell migration processes involved in particular in tumor inva

Full text of DOI:10.1016/j.tetlet.2011.03.043

Tetrahedron Letters 52 (2011) 2586–2589
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An innovative strategy for the synthesis of a new series of potent
aminopeptidase (APN or CD13) inhibitors derived from the oxepin-4-one family
⇑
⇑
Lionel Roux, Cédric Charrier, Emmanuel Salomon, Meral Ilhan, Philippe Bisseret , Céline Tarnus
FRE 3253, Laboratoire de Chimie Organique et Bioorganique associé au CNRS, ENSCMu, 3 rue A. Werner, 68093 Mulhouse Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Derivatives from the aminobenzosuberone family have been recently synthesized and recognized as
highly selective inhibitors of aminopeptidase N (APN)/CD13 (EC 3.4.11.2), an important target for cell
migration processes involved in particular in tumor invasion. We present here a much more straightfor-
ward synthesis of analogues belonging to a novel isosteric oxo series which also possesses excellent
inhibitory potential against APN. Their synthesis, as reported here, relied on an interesting iodine(III)-
mediated rearrangement originally described by Koser and Justik as the key step. This represents the sec-
ond application of this rearrangement in medicinal chemistry.
Received 12 January 2011
Revised 7 March 2011
Accepted 8 March 2011
Available online 16 March 2011
Keywords:
Aminopeptidase
APN or CD13 inhibitors
Oxepin-4-one
Ó 2011 Published by Elsevier Ltd.
Hypervalent iodine chemistry
Among proteolytic enzymes, the ubiquitous aminopeptidase N
(APN)/CD13 (EC 3.4.11.2)1 has been shown to play an important role
in tumor angiogenesis and metastasis.2 Although many inhibitors of
this ectopeptidase are available, most of them are poorly selective.3
The development of highly specific and potent inhibitors remains
a challenge since most aminopeptidases are zinc-dependent en-
zymes that share a broad substrate specificity. Structural require-
ments for APN inhibition were previously determined4,5 and led
to the discovery of ( )-7-amino-6-benzosuberone scaffold 1 as a
lead structure, which demonstrated a remarkable inhibitory po-
Koser on simple 1-tetralone.7 Although our synthesis relied, for
the first time in medicinal chemistry, on this efficient rearrange-
ment, it remained somewhat tedious because of its number of steps.
We present here a much more straightforward synthesis of the 9-
oxo isostere 4 of aminobenzosuberone 1, as well as the preparation
of a key protected precursor 10 ideally substituted for the synthesis
of oxepin-4-one derivatives 5. Our strategy is described in Figure 1.
In both cases simple iodo-phenol-derivatives as well as 2-benzyl-
oxycarbonylamino-but-3-en-1-ol 6 are used as starting reagents.
In the first place, we needed an efficient preparation of 2-ben-
zyloxycarbonylamino-but-3-en-1-ol 6. This compound was readily
tency and selectivity toward APN, with a Ki value of 1 lM.
Br
R2
R1
O
O
O
O
6
4
5
O
3
NHCbz
NH2
NH2
NH2
NH2
7
2
O
R
O
8
1
9
NHBoc
3
2
4
5
1
This scaffold therefore appeared as an excellent candidate for
obtained in an overall yield of 41% from DL-serine methyl ester
hydrochloride as indicated in Scheme 1, taking advantage of a
new short and quick synthesis.8,9 After protection as a N-benzyl-
oxycarbonyl derivative and as a O-tert-butyldimethylsilyl deriva-
tive,10 intermediate 13 was reduced with Dibal-H. Alcohol 14
was then converted into aldehyde 15 after an oxidation with
Dess-Martin periodinane, which in turn was transformed into al-
kene 16 via a Wittig reaction in good yield.11,12 Removal of the
O-tert-butyldimethylsilyl protection was accomplished with TBAF
and yielded the desired racemic compound 6.13
further chemical elaboration and derivatization and we already
pointed out the outstanding inhibitory activity and selectivity to-
ward APN of ( )-1,4-difunctionalized derivatives 2. This series of
aminobenzosuberones was easily obtained from the protected
derivative 3.5 This latter compound could be synthesized in about
15 steps from L
-tryptophane6 highlighting, as a key step, an iodi-
ne(III)-mediated ring expansion originally described by Justik and
⇑
Corresponding authors.
E-mail address: philippe.bisseret@uha.fr (P. Bisseret).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.03.043

L. Roux et al. / Tetrahedron Letters 52 (2011) 2586–2589
2587
Heck
O
I
Koser
NHCbz
4
NHCbz
OH
O
O
7
Mitsunobu
8
O
HO
NHCbz
Heck
6
F3C
NH
NO2
OH
OMe
O
NHCbz
Koser
NO2
NH2
NHCbz
I
R
O
O
O
Mitsunobu
5
10
9
OH
Figure 1. Retrosynthetic pathway.
CbzCl, Na2CO3,
THF, r.t., 12 h
TBDMSCl, Imidazole,
CH2Cl2, 50°C, 12 h
Dibal-H, THF,
-78°C, 2 h
O
O
O
TBDMSO
OH
NHCbz
HO
O
HO
O
TBDMSO
96%
O
100%
100%
NH2, HCl
NHCbz
NHCbz
14
12
13
11
1) KHDMS, BrCH3P(C6H5)3,
THF, 3 h, 0°C
DMP, CH 2Cl2,
r.t., 2 h
TBAF, THF,
0°C, 3 h
2) 15, THF, -78°C to r.t., 2h
TBDMSO
TBDMSO
O
6
82%
63%
NHCbz
82%
NHCbz
16
Scheme 1. Synthesis of 2-benzyloxycarbonylamino-but-3-en-1-ol 6.
15
As shown in Scheme 2, the preparation of 3-benzyloxycarbonyl-
amino-4-methylene-chromane 714 was accomplished in good
overall yield using a Mitsunobu reaction15 between alcohol 6 and
2-iodophenol 17, followed by an intramolecular Heck reaction.16,17
The resulting methylenic derivative 7 was then treated with
[hydroxy(tosyloxy)iodo]benzene HTIB in methanol at room tem-
perature according to Koser and Justik.7 Under these conditions,
we were pleased to isolate after 20 min the desired benzo[b]oxe-
pin-4-one 8 in good yield. The removal of the N-tert-butylcarba-
mate protection was accomplished under acidic conditions (HBr
33% in acetic acid) leading the desired inhibitor 4, as a racemic
mixture.
The inhibitory activity of 4 on APN was evaluated and compared
to the one of the parent isostere 1. As presented in Table 1, both
compounds exhibited similar Ki.
Encouraged by these promising results, we then investigated
the preparation of 9-amino isostere 23, starting from 2-iodo-N-
Table 1
Inhibition of aminopeptidase N
Compounds
Ki (
l
M)
c log P
APN EC 3.4.11.2
O
l
1.08
0.39
NH2, HCl
O
1
4
l
NH2, HBr
O
(methylsulfonyl)-aniline 19. As outlined in Scheme 2, although
both the Mitsunobu coupling and Heck cyclization went unevent-
fully, we could not perform the key ring expansion: by making use
X = O: Pd(OAc)2, PPh3,
Ag2CO3, MeCN, 12 h, 80°C
DEAD, PPh3,
toluene
I
I
NHCbz
+
6
X
0°C to r.t., 12 h
X
X = NMs: Pd2(dba)3, dppf,
Et3N, MeCN, 12 h, 80°C
X
NHCbz
X = O, 7, 62%
X = NMs, 21, 100%
X = O, 18, 65%
X = NMs, 20, 54%
X = OH, 17
X = NHMs, 19
O
PhI(OH)OTs,
MeOH 95%
HBr 33%/ AcOH
4 (HBr salt)
NHCbz
12 h, r.t., 62%
20 min, r.t.
X
X = O, 8, 64%
X = NMs, 22, 0%
O
X
23
NH2
N
H
Scheme 2. Synthesis of 9-oxo derivative 4 and tentative preparation of its 9-aza isostere 23.

2588
L. Roux et al. / Tetrahedron Letters 52 (2011) 2586–2589
Pd(OAc)2, PPh3,
X
NO2
NO2
Ag2CO3, CH3CN,
6, DEAD, PPh3
NHCbz
R
I
12 h, 80°C, Ar
68%
toluene, 12 h, r.t.
100%
O
OH
O
NHCbz
26
X = NO2, 9
R = NH2, 24
R = I, 25
Fe, AcOH / H2O / EtOH,
6 h, 50°C, Ar
NaNO2, KI, H2SO4
DME, 2 h, 50°
58%
X = NH2, 27
(CF3CO)2O,
CH2Cl2, 2 h, r.t.
95%
X = NHCOCF3, 28
O
O
F3C
NH
O
F3C
NH
O
HTIB, MeOH,
4 h, r.t.
OH
NHCbz
O
OH
NHCbz
52%
O
10a(+/-)
10b(+/-)
Scheme 3. Synthesis of 6-benzyloxycarbonylamino-4-hydroxy-4-methoxy-6-(2,2,2-trifluoroacetamido)-2,3,4,5-tetrahydrobenzo[b]oxepine 10.
5. Dérivés d’aminobenzocycloheptène, leurs procédés de préparation et leur
of the conditions previously described, we only got a complex
mixture.
utilisation en thérapeutique. Albrecht, S.; Maiereanu, A.; Faux, N.; Tarnus-
Rondeau, C.; Defoin, A.; Pale, P. WO2008059141 (A1).
Instead of pursuing experiments starting from other protected
anilines, we focussed our attention on the oxepinone series in view
of preparing analogues substituted on the aromatic ring. Commer-
cial 3-nitro-2-amino-phenol 24 was first submitted to a Sandmey-
er reaction leading to derivative 25.18 Like previously, the
preparation of 3-benzyloxycarbonylamino-4-methylene-5-nitro-
chromane 9 required two steps: a Mitsunobu reaction between
alcohol 6 and compound 25, followed by an intramolecular Heck
reaction (Scheme 3). The resulting methylenic derivative 9 was
then submitted to Koser and Justik’s conditions without success.
Realizing that the nitro function could be responsible for this fail-
ure, we decided to repeat the experiment starting from N-trifluoro-
acetyl derivative 28, easily obtained in two steps from 9.19,20 We
were pleased to observe that, in this case, the iodine (III)–mediated
ring expansion worked with a correct yield. Indeed, after chroma-
tography, we could isolate, in place of the expected keto derivative,
the pair of hemi-ketals 10a and 10b (Scheme 3).21
In conclusion, we synthesized 3-amino-2-hydro-5H-benzo[b]
oxepin-4-one 4 as a new lead structure for the preparation of APN
inhibitors. Indeed, compared to its 9-methylenic isostere 1, this
compound exhibited a similar inhibitory activity but could be pre-
pared in a much more efficient way from simple starting materials,
by making use of an iodine (III)-mediated ring expansion as a key-
step.7 Although we could not apply this reaction for the preparation
of the 9-aza isostere 23, the relevance of our synthetic strategy was
highlighted by its extension to the preparation of a key functional-
ized precursor 10 to substituted oxepin-4-one derivatives of type 5.
6. Roux, L.; Charrier, C.; Defoin, A.; Bisseret, P.; Tarnus, C. Tetrahedron 2010, 66,
8722–8728.
7. (a) Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004, 45, 6159–6163; (b) Justik,
M. W.; Koser, G. F. Molecules 2005, 10, 217–225.
8. Aponick, A.; Dietz, A. L.; Pearson, W. H. Eur. J. Org. Chem. 2008, 4264–4276.
9. Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am. Chem. Soc. 2000, 122,
5968–5976.
10. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190–6191.
11. Wen, S.-J.; Yao, Z.-J. Org. Lett. 2004, 6, 2721–2724.
12. Ragains, J. R.; Winkler, J. D. Org. Lett. 2006, 8, 4437–4440.
13. Paterson, I.; Mhlthau, F. A.; Cordier, C. J.; Housden, M. P.; Burton, P. M.;
Loiseleur, O. Org. Lett. 2009, 11, 353–356.
14. Selected analytical data: 3-Benzyloxycarbonylamino-4-(2-iodo-phenoxy)-but-
1-ene 18:
1H NMR (CDCl3, 400 MHz, 295 K): d 7.75 (dd, J = 1.5, 7.8 Hz, 1H, H3ar), 7.34 (m,
6H, 5HCbz and H5ar), 6.78 (d, J = 8.1 Hz, 1H H6ar), 6.73 (t, J = 7.8 Hz, 1H, H4ar),
6.04 (ddd, J = 5.8, 10.6, 17.4 Hz, 1H, H2), 5.38 (br d, J = 17.4 Hz, 1H, H1trans + NH),
5.28 (br d, J = 10.6 Hz, 1H, H1cis), 5.15 (br s, 2H, H CH2 Cbz), 4.63 (m, 1H, H3), 4.11
(br s, 2H, H4). 13C NMR (CDCl3, 100.6 MHz, 295 K): d 156.8 (Cq carbamate), 155.8
(Cq), 139.4 (C3ar), 136.4 (Cq Cbz), 135.2 (C2), 129.5 (C5ar), 128.5, 128.2 and 128.1
(5CCbz), 123.1 (C4ar), 117.0 (C1), 112.3 (C6ar), 86.8 (Cq), 71.1 (C4), 66.9 (CH2 Cbz),
52.8 (C3). IR (cmÀ1, KBr): 3295, 2924, 1680, 1541, 1458, 1247, 1052, 747, 699.
HRMS calcd for [C18H18INO3, Na+] = 446.0224; found: 446.0224.
3-Benzyloxycarbonylamino-4-methylen-chromane 7:
1H NMR (CDCl3, 400 MHz, 295 K): d 7.56 (d, J = 8.0 Hz, 1H, H5), 7.34 (m, 5H,
H
Cbz), 7.20 (t, J = 8.3 Hz, 1H, H7), 6.95 (t, J = 8.3 Hz, 1H, H6), 6.87 (br d, J = 8.1 Hz,
1H, H8), 5.55 (br s, 1H, 1Hmethylene), 5.25 (br s, 1H, 1Hmethylene), 5.11 (m, 3H, H
CH2 Cbz + NH), 4.61(m, 1H, H3), 4.26 (dd, J = 3.8, 10.9 Hz, 1H, H2b), 4.18 (dd,
J = 2.5, 10.9 Hz, 1H, H2a). 13C NMR (CDCl3, 100.6 MHz, 295 K): d 155.7 (Cq
carbamate), 153.6 (Cq), 137.3 (Cq), 136.2 (Cq Cbz), 129.9 (C7), 128.5, 128.2 and
128.2 (5CCbz), 125.2 (C5), 121.6 (C6), 119.6 (Cq); 117.5 (C8), 109.2 (Cmethylene),
69.2 (C2), 67.0 (CH2 Cbz), 50.0 (C3). IR (cmÀ1, KBr): 3417, 3342, 2928, 1698,
1541, 1222, 1068, 752, 697. HRMS calcd for [C18H17NO3, Na]+: 318.1100;
found: 318.1094.
3-Benzyloxycarbonylamino-2-hydro-5H-benzo[b]oxepin-4-one 8:
1H NMR (CDCl3, 400 MHz, 295 K): d 7.35 (m, 5H, HCbz), 7.23 (d, J = 7.6 Hz, 1H,
H6), 7.17 (br d, J = 7.3 Hz, 1H, H9), 7.10–7.06 (2t, J = 7.6 Hz, 2H, H7 and H8), 5.65
(br d, J = 5.1 Hz, 1H, NH), 5.11 (br s, 2H, H CH2 Cbz), 4.92 (dt, J = 6.6, 9.6 Hz, 1H,
H3), 4.76 (dd, J = 6.6, 11.4 Hz, 1H, H2a), 4.14 (d, J = 14.0 Hz, 1H, H5b), 3.74 (dd,
Acknowledgments
J = 9.6, 11.4 Hz, 1H,
H
2a), 3.60 (d, J = 14.0 Hz, 1H, H5a). 13C NMR (CDCl3,
The financial supports of the Centre National de la Recherche
Scientifique (FRE-3253) and the Ecole Nationale Supérieure de Chi-
mie de Mulhouse are gratefully acknowledged. We also wish to
thank the Region Alsace for a Ph.D. Grant to L.R.
100.6 MHz, 295 K): d 202.2 (C4), 158.2 (Cq),155.6 (Cq carbamate), 136.0 (Cq Cbz),
130.4 (C9), 129.2 (C6), 128.6, 128.3 and 128.2 (5C Cbz), 124.9 and 121.4 (C7 and
C8), 124.5 (Cq), 73.4 (C2),67.2 (CH2 Cbz),60.4 (C3), 45.8 (C5). IR (cmÀ1, KBr) :
3421, 2926, 2361, 1688, 1527, 1457, 1262, 1081, 754, 695, 474. HRMS calcd for
[C18H17NO4, Na]+: 334.1050; found: 334.1047.
3-Amino-2,2-dihydro-5H-benzo[b]oxepin-4-one, hydrobromide 4:
1H NMR (CD3OD, 400 MHz, 295 K): d 7.21 (d, J = 7.1 Hz, 1H, H6), 7.21 (t,
J = 7.6 Hz, 1H, H8), 7.07 (t, J = 7.6 Hz, 1H, H7), 7.00 (br d, J = 7.3 Hz, 1H, H9), 4.56
(d, J = 14.1 Hz, 1H, H5b), 4.23 (dd, J = 4.0, 13.6 Hz, 1H, H2a), 4.09 (dd, J = 2.0,
13.6 Hz, 1H, H2b), 3.64 (d, J = 14.1 Hz, 1H, H5a), 3.44 (m, 1H, H3). 13C NMR
(CD3OD, 100.6 MHz, 295 K): d 200.05 (C4), 160.8 (Cq), 133.1 (C6), 129.7 (C8),
125.9 (C7), 122.0 (C9), 96.0 (Cq), 69.7 (C2), 59.9 (C3), 46.1 (C5). IR (cmÀ1, KBr):
3446, 2927, 2361, 1732, 1653, 1559, 1541, 1506, 1488, 1457, 1258, 1075, 763.
HRMS calcd for [C10H12NO2, H]+: 178.0863; found: 178.071.
References and notes
1. (a) Mina-Osorio, P. Trends Mol. Med. 2008, 14, 361–371; (b) Zhang, X.; Xu, W.
Curr. Med. Chem. 2008, 15, 2850–2865.
2. Bergers, G.; Benjamin, L. E. Nat. Rev. Cancer 2003, 3, 401–410.
3. Bauvois, B.; Dauzonne, D. Med. Res. Rev. 2006, 26, 88–130.
4. Pasqualini, R.; Koivunen, E.; Kain, R.; Lahdenranta, J.; Sakamoto, M.; Stryhn, A.;
Ashmun, R. A.; Shapiro, L. H.; Arap, W.; Ruoslahti, E. Cancer Res. 2000, 60, 722–
727.
3-Benzyloxycarbonylamino-4-(2-iodo-3-nitro-phenoxy)-but-1-ene 26:

L. Roux et al. / Tetrahedron Letters 52 (2011) 2586–2589
trifluoroacetamido)-2,3,4,5-tetrahydrobenzo[b]oxepine 10:
2589
1H NMR (CDCl3, 400 MHz, 295 K): d 7.36 (m, 7H, 5HCbz, H5ar, H4ar), 6.94 (d,
J = 8.1 Hz, 1H, H6ar), 6.04 (ddd, J = 5.8, 10.3, 17.4 Hz, 1H, H2), 5.38 (d, J = 17.4 Hz,
1H, H1trans), 5.34 (br s, 1H, NH), 5.30 (br d, J = 10.3 Hz, 1H, H1cis), 5.14 (br s, 2H,
H CH2 Cbz), 4.67 (m, 1H, H3), 4.18 (br s, 2H, H4). 13C NMR (CDCl3, 100.6 MHz,
295 K): d 158.3 (Cq carbamate), 155.8 and 136.1 (Cq), 134.5 (C2), 130.1 (Car), 128.5,
128.3 and 128.2 (5C Cbz), 118.7 (Cq), 117.6 and 117.5 (C1 and Car), 114.6 (C6ar),
80.7 (Cq), 71.9 (C4), 67.1 (CH2 Cbz), 52.5 (C3). IR (cmÀ1, KBr): 3309, 3246, 1697,
1533, 1350, 1281, 1251, 734. HRMS calcd for [C18H17IN2O5, Na]+: 491.0074;
found: 491.0068.
10a: 1H NMR (CDCl3, 400 MHz, 295 K): d 7.63 (d, J = 8.1 Hz, 1H, H7), 7.34 (m,
7H, NH, HCbz and H8), 6.73 (d, J = 8.3 Hz, 1 H, H9), 5.30 (br d, 1H, NH), 5.11 (s,
2H, H CH2 Cbz), 4.56 (d, J = 12.3 Hz, 1H, H5a), 4.28 (m, 2H, H3 and H2a), 4.11 (m,
2H, H5b and H2b), 3.13 (s, 3H, CH3). 13C NMR (CDCl3, 100.6 MHz, 295 K): d 155.7
(Cq carbamate), 153.6 (Cq amide, q, J = 38.1 Hz), 153.1, 143.3, 135.8 (3Cq), 133.6 (C8),
128.7, 128.5 and 128.3 (5C Cbz), 115.8 (Cq CF3, q, J = 288 Hz), 112.7 (C7), 111.6
(Cq), 109.5 (C9), 75.1 (Cq), 67.4 (CH2 Cbz), 65.3 (C2), 58.6 (C5), 51.3 (C2), 51.0
(COMe). 19F NMR (CDCl3, 376.5 MHz, 295 K): d À68.2 ppm.
3-Benzyloxycarbonylamino-4-methylen-5-nitro-chromane 9:
Compound 10b: 1H NMR (CDCl3, 400 MHz, 295 K): d 7.65 (d, 1H, H7, J = 7.8 Hz),
7.34 (m, 7H, NH, HCbz and H8), 6.73 (d, J = 8.3 Hz, 1H, H9), 5.09 (s, 2H, H CH2 Cbz),
4.71 (br d, 1H, NH), 4.67 (d, J = 12.0, 1.8 Hz, 1H, H2a), 4.56 (br d, J = 12.9 Hz, 1H,
1H NMR (CDCl3, 400 MHz, 295 K): d 7.35 (m, 5H, HCbz), 7.27 (dd, J = 8.6, 7.8 Hz,
1H, H7), 7.09 (br d, J = 7.8 Hz, 1H, H8), 7.02 (d, J = 8.6 Hz, 1H, H6), 5.43 (br s, 1H,
1Hmethylene), 5.30 (br s, 1H, 1Hmethylene), 5.13 (m, 3H, H CH2 Cbz + NH), 4.63(m,
H
5a), 4.33 (m, 1H, H3), 4.32 (d, J = 12.0, 1.8 Hz, 1H, H2b), 4.04 (br d, J = 12.9 Hz,
1H, H3), 4.26 (br d, J = 11.1 Hz, 1H, H2b), 4.25 (dd, J = 2.5, 11.1 Hz, 1H, H2a). 13
C
1H, H5a), 3.17 (s, 3H, CH3). RMN 13C (CDCl3): 155.7 (Cq carbamate), 153.6 (Cq amide
,
NMR (CDCl3, 100.6 MHz, 295 K): d 155.5 (Cq carbamate), 135.9 (Cq Cbz), 130.0 (Cq),
129.4 (C7), 128.6, 128.3 and 128.2 (5C Cbz), 128.1 (Cq), 120.8 (Cq), 120.3 (C6),
117.4 (Cq), 116.3 (C8), 116.1 (Cmethylene), 70.2 (C2),67.2 (CH2 Cbz), 50.3 (C3). IR
q, J = 38.1 Hz), 152.4, 143.8, 135.5 (3Cq), 133.5 (C8), 128.7, 128.6 and 128.4 (5C
Cbz), 115.8 (Cq CF3, q, J = 288 Hz), 112.6 (C7), 111.2 (Cq), 110.1 (C9), 76.1 (Cq),
67.7 (CH2 Cbz), 67.6 (C2), 55.7 (C5), 51.1 (C2), 47.2 (COMe). RMN 19F (CDCl3):
À68.2 ppm. HRMS calcd for [C22H23F3N2O5, Na]+: 477.1457; found: 477.1463.
15. Lin, K.-Y.; Matteucci, M. D. J. Am. Chem. Soc. 1998, 120, 8531–8532.
16. Ali, A.; Bryon, G.; Pattendon, G.; Graeme, A. R.; Kam, T.-S. J. Chem. Soc. Perkin
Trans. 1 1996, 1081–1087.
(cmÀ1
, KBr): 3421, 3305, 2931, 1699, 1531, 1249, 738. HRMS calcd for
[C18H16N2O5, Na]+: 363.0951; found: 363.0946.
3-Benzyloxycarbonylamino-4-methylen-5-trifluoroacetamide-chromane 28:
1H NMR (CDCl3, 400 MHz, 295 K): d 8.29 (s, 1H, NH), 7.69 (d, J = 8.1 Hz, 1H, H6),
7.34 (m, 5H, HCbz), 7.25 (dd, J = 8.1, 8.3 Hz, 1H, H7), 6.79 (br d, J = 7.8 Hz, 1H,
H8), 5.61 (br s, 1H, 1Hmethylene), 5.46 (br s, 1H, 1Hmethylene), 5.11 (m, 3H, H CH2
Cbz + NH); 4.60 (m, 1H, H3), 4.42 (br d, J = 11.3 Hz, 1H, H2b), 4.29 (dd, J = 2.3,
11.3 Hz, 1H, H2a). 13C NMR (CDCl3, 100.6 MHz, 295 K): d 155.5 (Cq carbamate),
154.0 (Cq amide), 136.2 (Cq), 135.9 (Cq Cbz), 132.8, 128.7, 119.5 and 114.08 (4Cq),
130.1 (C7), 128.6, 128.3 and 128.2 (5C Cbz), 115.7 (C6), 115.2 (C8), 114.3
(Cmethylene), 70.2 (C2), 67.2 (CH2 Cbz), 51.0 (C3). 19F NMR (CDCl3, 376.5 MHz,
295 K): d À68.2 ppm. IR (cmÀ1, KBr): 330, 3247, 1706, 1541, 1339, 1180, 740.
HRMS calcd for [C20H17F3N2O4, Na]+: 429.1033; found: 429.1033.
17. Davies, A. J.; Taylor, R. J. K.; Scopes, D. I.; Wadsworth, A. H. Bioorg. Med. Chem.
Lett. 1992, 2, 481–484.
18. Zhu, G.-D.; Staeger, M. A.; Boyd, S. A. Org. Lett. 2000, 21, 3345–3348.
19. Kuipers, W.; van Wijngaarden, I.; Kruse, C. G.; Ter Horst van Amstel, M.; Tulp,
M. Th. M.; IJzerman, A. P. J. Med. Chem. 1995, 38, 1942–1954.
20. Becalli, E. M.; Broggini, G.; Paladino, G.; Penoni, A.; Zoni, C. J. Org. Chem. 2004,
69, 5627–5630.
21. For another formation of a stable hemiketal after exposing a keto derivative to
methanol, see: Condie, G. C.; Bergman, J. Eur. J. Org. Chem. 2004, 6, 1286–1297.
6-Benzyloxycarbonylamino-4-hydroxy-4-methoxy-6-(2,2,2-