3228
D. Gravestock et al. / Tetrahedron Letters 53 (2012) 3225–3229
1,10-carbonyldiimidazole for coupling of the carboxylic acid 12 and
the Weinreb amine.
(c) Owens, T. D.; Semple, J. E. Org. Lett. 2001, 3, 3301–3304; (d) Faure, S.;
Hjelmgaard, T.; Roche, S. P.; Aitken, D. J. Org. Lett. 2009, 11, 1167–1170.
4. (a) Banfi, L.; Guanti, G.; Riva, R.; Basso, A.; Calcagno, E. Tetrahedron Lett. 2002,
43, 4067–4069; (b) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Mol. Divers. 2003, 6,
227–235; (c) Basso, A.; Banfi, L.; Guanti, G.; Riva, R.; Tosatti, P. Synlett 2011,
2009–2012.
5. (a) De Clercq, E. Int. J. Antimicrob. Agents 2009, 33, 307–320; (b) Wensing, A. M.
J.; van Maarseveen, N. M.; Nijhuis, M. Antiviral Res. 2010, 85, 59–74.
6. Abdel-Rahman, H. M.; Al-Karamany, G. S.; El-Koussi, N. A.; Youssef, A. F.; Kiso,
Y. Curr. Med. Chem. 2002, 9, 1905–1922.
The rationale behind the preparation of isocyanide 20 was that
it presents a unique opportunity for post-MCR modification, allow-
ing for divergence at a very late stage in the synthetic sequence.
The utility of Weinreb amides in the preparation of varied ketones
and aldehydes is well known,10 and at the end of the PADAM se-
quence, the Weinreb amide functionality could conveniently be
converted to give a diverse range of compounds. A pre-MCR mod-
ification of Weinreb amide 18 was also explored in an attempt to
prepare isocyanide 24. Weinreb amide 18 was initially reacted
with benzylmagnesium bromide to give the benzyl ketone 21, fol-
lowed by deprotection and formylation to give formamide 22.
Interestingly, under typical dehydration conditions, the formamide
22 gave exclusively compound 23, the enol form of the expected
product 24, as evidenced by spectroscopic data.11 This is presum-
ably due to conjugation of the enol double bond with the isocya-
nide. In addition to the isocyanides shown in Scheme 2,
adamantyl isocyanide 27, also a branched isocyanide and not com-
mercially available at the time, was prepared from adamantyl-
amine 25 (Scheme 3).
7. N-Boc-phenylalaninal was prepared from N-Boc-phenylalanine by LiAlH4
reduction of the Weinreb amide of N-Boc-phenylalanine.
_
8. Berłozecki, S.; Szyman´ ski, W.; Ostaszewski, R. Synth. Commun. 2008, 38, 2714–
2721.
9. (S)-3-(Benzyloxy)-2-formamido-N-methoxy-N-methylpropanamide (19). HCO2H
(18.8 ml) and Ac2O (4.63 ml, 49.0 mmol) were stirred together for 5 min
at room temperature and then added under N2 to (S)-tert-butyl (3-(benzyloxy)-
1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate 18 (5.53 g, 16.34
mmol). To this was added dropwise trifluoroacetic acid (3.77 ml, 49.0 mmol)
and the mixture was stirred for 1.5 h at room temperature. Brine (200 ml),
EtOAc (200 ml) and solid NaHCO3 (50 g) were added to the reaction mixture.
After effervescence had ceased, H2O (100 ml) was added and the organic layer
separated. The aqueous layer was extracted again with EtOAc (2 ꢁ 100 ml) and
combined organic layers dried over MgSO4. The solvent was removed in vacuo
to give (S)-3-(benzyloxy)-2-formamido-N-methoxy-N-methylpropanamide
(19) as a colourless gum (4.95 g) that was used in the next step without
further purification.
(S)-3-(Benzyloxy)-2-isocyano-N-methoxy-N-methylpropanamide (20). (S)-3-
These branched isocyanides (17a–c, 20, 23 and 27) were reacted
with N-Boc-phenylalaninal 1 and commercially available carbox-
ylic acids 2 according to Scheme 1. Disappointingly, isocyanide
17c appeared to decompose during the Passerini reaction and no
desired product was isolated. Reactions using compound 23 re-
turned only starting material. The other isocyanides were success-
fully reacted and the N-Boc-O-acyl compounds 4 were deprotected
using TFA and subsequent rearrangement of 5 to the desired prod-
ucts 6 was carried out in the presence of Et3N.12 Both the Passerini
4 and PADAM 6 products were screened in a fluorescence-based13
HIV-1 protease inhibition assay.14
Results from the screening show clearly that the products from
the Passerini reaction (column A, Table 1) were inactive against
HIV-1 protease, while the rearranged products (column B, Table 1)
were generally more active. This result is expected when consider-
ing that the rearranged products have the secondary hydroxy
groups considered essential for activity against HIV-1 protease.
The only exception to this is the Passerini product of entry 8, where
significant inhibitory activity was observed. The rearranged prod-
uct prepared from N-Boc-phenylalaninal, tert-butyl acetic acid
and adamantyl isocyanide showed the best inhibitory activity of
all the compounds tested (Table 1, entry 2). Interestingly, adaman-
tyl-based compounds are showing increasing utility in the treat-
ment of many different conditions, including as antiviral agents.15
In conclusion, a method has been demonstrated for the prepara-
tion of highly functionalised isocyanides that can be used in multi-
component reactions to gain rapid entry to complex molecules,
which may then be further functionalised. A number of different
MCRs utilise isocyanide building blocks and thus the type of
branched isocyanides reported here should find use in a range of
applications. Utilisation of these branched isocyanides in other
MCR applications is currently under investigation.
(Benzyloxy)-2-formamido-N-methoxy-N-methylpropanamide
19
(4.35 g,
16.34 mmol), PPh3 (6.43 g, 24.5 mmol), DIPEA (4.27 ml, 24.5 mmol) and CCl4
(2.37 ml, 24.5 mmol) were dissolved in CH2Cl2 (70 ml) and stirred under N2
overnight at room temperature. The reaction mixture was concentrated by
removal of two-thirds of the solvent in vacuo and the remaining mixture
purified by column chromatography (elution with EtOAc:hexane) to yield (S)-
3-(benzyloxy)-2-isocyano-N-methoxy-N-methylpropanamide (20) as a clear
viscous oil (3.53 g, 87% from 18). 1H NMR (400 MHz, CDCl3) d 7.40–7.24 (m,
5H), 4.85 (t, J = 6.3 Hz, 1H), 4.59 (s, 2H), 3.88–3.77 (m, 2H), 3.71 (s, 3H), 3.21 (s,
3H); 13C NMR (100 MHz, CDCl3) d 164.24, 159.76, 136.98, 128.36, 127.88,
127.67, 73.52, 69.14, 61.60, 53.38, 32.36.
10. (a) Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 3707–3738; (b) Sibi, M. P.
Org. Prep. Proced. Int. 1993, 25, 15–40.
11. Spectroscopic data for 4-(benzyloxy)-3-isocyano-1-phenylbut-2-en-2-ol (23).
1H NMR (400 MHz, CDCl3) d 7.73 (s, 1H), 7.37–7.15 (m, 10H), 4.58 (s, 2H), 4.47
(s, 2H), 4.02 (s, 2H); 13C NMR (100 MHz, CDCl3) d 149.62, 148.69, 137.93,
136.80, 132.15, 128.62, 128.51, 128.37, 127.82, 127.67, 126.81, 72.49, 63.51,
31.00; HRMS (ESI): m/z: 280.1339 [M+H]+; calcd for C18H18NO2: 280.1339.
12. The method for the Passerini reaction and subsequent deprotection and acyl
migration is exemplified by the reaction between N-Boc-phenylalaninal, tert-
butyl acetic acid and adamantyl isocyanide 27.
(3S)-1-(Adamantan-1-ylamino)-3-[(tert-butoxycarbonyl)amino]-1-oxo-4-phe-
nylbutan-2-yl 3,3-dimethylbutanoate.
isocyanide (27) (0.161 g,
Adamantyl
1.0 mmol), tBuCH2COOH (0.128 g, 1.1 mmol) and N-Boc-phenylalaninal
(0.250 g, 1.0 mmol) were stirred in dry CH2Cl2 (3 ml) at room temperature
for 3 days. The solvent was removed in vacuo and purification by column
chromatography (elution CHCl3/MeOH, 49:1 to 9:1) afforded the Passerini
product as a mixture of two diastereomers (0.223 g, 42%). 1H NMR (400 MHz,
CDCl3) d 7.48–6.93 (m, 5H), 5.86–5.52 (m, 1H), 5.33–4.60 (m, 2H), 4.24 (s, 1H),
3.05–2.52 (m, 2H), 2.24 (d, J = 19.6, 2H), 2.13–1.79 (m, 9H), 1.79–1.47 (m, 6H),
1.47–1.15 (m, 9H), 1.15–0.71 (m, 9H); 13C NMR (100 MHz, CDCl3) d 171.09,
170.09, 167.02, 166.67, 155.35, 154.81, 137.45, 129.22, 129.10, 128.41, 128.33,
126.50, 126.39, 79.20, 73.90, 73.46, 53.32, 52.95, 52.26, 52.21, 47.79, 47.49,
41.36, 37.80, 37.49, 36.18, 30.89, 29.60, 29.32, 28.20. HRMS (ESI): m/z:
527.3483 [M+H]+; calcd for C31H47N2O5: 527.3485.
(3S)-N-(Adamantan-1-yl)-3-(3,3-dimethylbutanamido)-2-hydroxy-4-phenylb-
utanamide. (3S)-1-(Adamantan-1-ylamino)-3-[(tert-butoxycarbonyl)amino]-
1-oxo-4-phenylbutan-2-yl 3,3-dimethylbutanoate (0.177 g, 0.335 mmol) was
dissolved in CH2Cl2 (0.8 ml) and TFA (0.26 ml, 3.35 mmol) was added. The
reaction mixture was stirred at room temperature for 2 h, after which the
solvent and most of the TFA were removed in vacuo. The residue was re-
dissolved in CH2Cl2 (0.8 ml) and Et3 N (0.30 ml) was added. This was stirred at
room temperature for 1 h after which H2O (5 ml) and additional CH2Cl2 (10 ml)
were added. The layers were separated and the aqueous layer was extracted
with CH2Cl2 (2 ꢁ 5 ml). The combined organic layer was dried over MgSO4 and
the solvent removed in vacuo. Column chromatography (elution CHCl3/MeOH,
49:1) afforded the PADAM product as a mixture of two diastereomers (0.091 g,
64%). Restricted rotation about an amide bond for diastereomer B gave rise to
two rotamers, apparent from the 1H and 13C NMR spectra. Only one amide
proton signal for each diastereomer was observed in the 1 H spectrum.
Diastereomer A: 1H NMR (400 MHz, CDCl3) d 7.33–7.13 (m, 5H), 6.91 (d, J = 8.3
Hz, 1H), 6.76 (s, 1H), 4.28–4.16 (m, 1H), 3.96 (d, J = 3.2 Hz, 1H), 3.15 (dd,
J = 13.9, 6.4 Hz, 1H), 2.92 (dd, J = 13.8, 9.3 Hz, 1H), 2.12–2.03 (m, 3H), 2.03–1.97
(m, 6H), 1.96 (d, J = 4.4 Hz, 2H), 1.71–1.64 (m, 6H), 0.90 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 173.67, 171.86, 138.18, 129.12, 128.34, 126.37, 73.31,
Acknowledgement
The authors wish to thank the Innovation Fund (now the Tech-
nology Innovation Agency, South Africa) for financial support.
References and notes
1. (a) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210; (b) Wang, S.-
X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47, 388–391.
2. (a) Dömling, A. Chem. Rev. 2006, 106, 17–89; (b) Maeda, S.; Komagawa, S.;
Uchiyama, M.; Morokuma, K. Angew. Chem., Int. Ed. 2011, 50, 644–649.
3. (a) Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985–986; (b) Owens, T.
D.; Araldi, G.-L.; Nutt, R. F.; Semple, J. E. Tetrahedron Lett. 2001, 42, 6271–6274;
55.45, 51.67, 49.99, 41.41, 36.23, 35.47, 30.66, 29.66, 29.32. Diastereomer B: 1
NMR (400 MHz, CDCl3) d 7.33–7.13 (m, 5H), 6.50 (br s, 1H), 6.25 and 6.15 (br d,
J = 6.9 Hz and br s, 1H), 4.97 and 4.14 (d, J = 5.0 Hz and d, J = 1.5 Hz, 1H),
H