Annulation of thioimidates and vinyl carbodiimides to prepare 2-aminopyrimidines, competent nucleophiles for intramolecular alkyne hydroamination. Synthesis of (-)-crambidine

Article abstract of DOI:10.1021/ja910831k

(Chemical Presented) A convergent synthesis of (-)-crambidine is reported. The sequence capitalizes on two novel key transformations, including a [4+2] annulation of thioimidates with vinyl carbodiimides and an alkyne hydroamination employing 2-aminopyrimidine nucleophiles. Copyright

Full text of DOI:10.1021/ja910831k

Published on Web 01/22/2010
Annulation of Thioimidates and Vinyl Carbodiimides to Prepare
2-Aminopyrimidines, Competent Nucleophiles for Intramolecular Alkyne
Hydroamination. Synthesis of (-)-Crambidine
Nicholas R. Perl,† Nathan D. Ide,‡ Sudeep Prajapati,† Hahdi H. Perfect,†,‡ Sergio G. Duro´n,‡ and
David Y. Gin*,†
Memorial Sloan-Kettering Cancer Center, 1275 York AVenue, New York, New York 10065, and the Department of
Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received December 23, 2009; E-mail: gind@mskcc.org
Certain members of the crambescidin natural products,1-5
Scheme 1
derived from the marine sponge Crambe crambe, have exhibited
remarkable biological properties, including anticancer, anti-HIV,
antifungal, and Ca2+ ion channel blocking activities. Many com-
pounds within this class are characterized by a polycyclic guanidine
core linked to a hydroxyspermidine moiety by a linear ω-hydroxy
fatty acid. Crambidine (1, Figure 1) is atypical within this family
of alkaloids in that it possesses a fused pyrimidine heterocyclic
core, while most of its other congeners exist in more highly reduced
forms. Several elegant strategies have been reported for the synthesis
of crambescidin alkaloids.6-9 However, only a single reported
synthesis of crambidine (1) has appeared,10 involving dihydropy-
rimidine construction via Biginelli condensation, followed by
oxidation. We report herein a synthesis of (-)-crambidine that
Scheme 2a
capitalizes on two key processes, including a [4+2] annulation of
thioimidates with vinyl carbodiimides and a hydroamination of
alkynes with 2-aminopyrimidine nucleophiles.
a Reagents and conditions: (a) n-BuLi, THF, -78 °C; AllylOCOCl, 90%;
(b) (Me2N)2CdNH2N3, CHCl3, 23 °C, 69% (2:1, E/Z); (c) PPh3, CH2Cl2,
23 °C; add TBSOCH2NdCdO, PhH, 80 °C, 49% from (E)-13, 43% from
(Z)-13.
Figure 1
to afford the propargylic ester 12. This intermediate was subjected to
conjugate addition with azide to afford a separable E/Z mixture (2:1)
of the corresponding ꢀ-azidoacrylate 13. Reduction of the azide in
(E)-13 with PPh3, followed by condensation with TBSOCH2NdCdO,
provided the vinyl carbodiimide 14. Importantly, advancement of (Z)-
13 under analogous conditions also led to the formation of the (E)-
isomer of 14 in a similar yield, wherein stereochemical convergence
occurs at the iminophosphorane stage.
Synthesis of an initial crambidine-relevant thioimidate employed
methyl thioimidate 1513 (Scheme 3). This served as a suitable
acylation agent for the alkyl lithium species derived from the
homoallylic iodide 16, prepared in the manner described by
Overman.14 The resulting keto-thioimidate 17 was then heated with
vinyl carbodiimide 14 to effect [4+2] annulation. Unfortunately,
the bicyclic pyrimidine 18 was not observed; instead, the sole
isolable product was pyrimidine 19, presumably a result of C9-C10
ꢀ-elimination of the heterocycle in 18.7
Vinylcarbodiimides derived from pyrimidine-diones have been
shown to converge with O-methyl imidates to furnish 2-aminopy-
rimidines.11 However, when this annulation process was applied
to vinylcarbodiimides and O-imidates more appropriate to the
synthesis of 1, the reaction was inefficient. For example, heating a
mixture of O-methyl imidate 2 (Scheme 1A) with benzylvinylcar-
bodiimide 4 at elevated temperature in C6D6 for 24 h provided only
24% conversion to the 2-aminopyrimidine 5. By contrast, when
the corresponding thiomethyl imidate 3 was exposed to carbodi-
imide 4 under otherwise identical conditions, conversion to the
pyrimidine 5 was accomplished with marked improvement (59%).
Addition of the thiol scavenger AgOTf further enhanced the
efficiency of the thioimidate annulation, allowing for the preparation
of a variety of bicyclic 2-aminopyrimidines (Scheme 1B, 8-10).
Extension of this [4+2] annulation reaction to access a complex
substrate more suited to the synthesis of 1 commenced with the
synthesis of a fully elaborated vinyl carbodiimide 14 (Scheme 2). Silyl
ether 11, obtained in enantiopure form according to the procedure of
Campagne and co-workers,12 was acylated with allyl chloroformate
Given that the fragmentation (18f19) and concomitant destruction
of the C10 stereoconfiguration could not be avoided, attention turned
to thioimidate 26 (Scheme 4) as an alternate annulation substrate in
which the internal alkyne would serve as a less acidic ketone surrogate.
Thus, Z-selective Wittig olefination of (S)-2-(tert-butylsilyloxy)bu-
† Memorial Sloan-Kettering Cancer Center.
‡ University of Illinois at Urbana-Champaign.
9
1802 J. AM. CHEM. SOC. 2010, 132, 1802–1803
10.1021/ja910831k  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3a
lowing iodination of the terminal alkyne, the alkynyl iodide 23 was
subjected to a sequence involving the following: (1) Cu-mediated
coupling with pyrrolidinone 24 to afford internal alkyne 25; (2) a two-
step conversion of the lactam 25 to the thioimidate 26 via carbonyl
thionation and S-alkylation; (3) [4+2] annulation with vinylcarbodi-
imide 14 to furnish bicyclic pyrimidine 27; and (4) chemoselective
N-deprotection to provide the free 2-aminopyrimidine 28, a substrate
poised for intramolecular alkyne hydroamination.
Transition metal catalyzed hydroamination of alkynes15,16 is a
powerful reaction in synthesis;17-19 however, the paucity of
guanidine or 2-aminopyrimidine nucleophiles engaging in this
reaction is notable. After extensive experimentation, this transfor-
mation was validated by treatment of alkyne 28 (Scheme 4) with
10 mol % AuCl320 at 40 °C, leading to efficient production of the
tricyclic pyrimidine 29 as a single isomer (78%).
Subsequent spiroaminal formation at C8 in enamine 29 was
conducted under carefully controlled acidic conditions, being mindful
of the possibility of undesired C10-N bond rupture via potential
C8-iminium reactivity. This liability was precluded by treatment with
TsOH, effecting TBS removal and spirocyclization to provide the
tetracyclic pyrimidinium 30 (77%).21 The final stages of the synthesis
involved conversion of the allyl ester 30 to its Cs-carboxylate. This
nucleophile, obtained from carboxylic acid 31, was amenable to
selective alkylation with iodide 32.13 The resulting ester 33 was then
subjected to tert-butylcarbamate removal to afford (-)-crambidine (1).
A convergent synthesis of crambidine has been described,
showcasing a [4+2] thioimidate-vinyl carbodiimide annulation and
an intramolecular alkyne-guanidine hydroamination. This strategy
should not only prove useful for preparing other members of the
crambescidins, but also provide an attractive means with which to
access complex N-heterocycles in general.
a Reagents and conditions: (a) 16, t-BuLi, Et2O, hexanes, -78 °C; add
15, -78 f 23 °C, 67%; (b) 14 (2 equiv), (CH2Cl)2, 60 °C, 70%.
Scheme 4a
Acknowledgment. This research was supported by the NIH
(GM57859) and Merck, Inc. We thank Prof. Larry Overman for
providing a copy of a 13C NMR spectrum of synthetic 1.
Supporting Information Available: Experimental details. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Heys, L.; Moore, C. G.; Murphy, P. J. Chem. Soc. ReV. 2000, 29, 57–67.
(2) Jares-Erijman, E. A.; Sakai, R.; Rinehart, K. L. J. Org. Chem. 1991, 56, 5712–
5715.
(3) Ohtani, I.; Kusumi, T.; Kakisawa, H.; Kashman, Y.; Hirsh, S. J. Am. Chem.
Soc. 1992, 114, 8472–8479.
(4) Berlinck, R. G. S.; Braekman, J. C.; Daloze, D.; Bruno, I.; Riccio, R.; Ferri,
S.; Spampinato, S.; Speroni, E. J. Nat. Prod. 1993, 56, 1007–1015.
(5) Jares-Erijman, E. A.; Ingrum, A. L.; Carney, J. R.; Rinehart, K. L.; Sakai, R.
J. Org. Chem. 1993, 58, 4805–4808.
(6) Snider, B. B.; Shi, Z. P. J. Am. Chem. Soc. 1994, 116, 549–557.
(7) Coffey, D. S.; McDonald, A. I.; Overman, L. E.; Rabinowitz, M. H.; Renhowe,
P. A. J. Am. Chem. Soc. 2000, 122, 4893–4903.
(8) Nagasawa, K.; Georgieva, A.; Koshino, H.; Nakata, T.; Kita, T.; Hashimoto,
Y. Org. Lett. 2002, 4, 177–180.
(9) Moore, C. G.; Murphy, P. J.; Williams, H. L.; McGown, A. T.; Smith, N. K.
Tetrahedron Lett. 2003, 44, 251–254.
(10) Overman, L. E.; Rhee, Y. H. J. Am. Chem. Soc. 2005, 127, 15652–15658.
(11) Wamhoff, H.; Schmidt, A. Heterocycles 1993, 35, 1055–1066.
(12) Pétry, N.; Parenty, A.; Campagne, J.-M. Tetrahedron: Asymmetry 2004, 15,
1199–1201.
(13) See Supporting Information.
a Reagents and conditions: (a) 21, n-BuLi, THF, -78 f 0 °C; add 20,
-78 f 23 °C, 85%; (b) NIS, AgNO3, Me2CO, 23 °C, 91%; (c) 24, Zn,
DMF, 0 °C; CuCN, LiCl, THF, DMF, -40 f 23 °C; add 23, -40 f 23
°C, 54%; (d) Lawesson’s Rgt, THF, 0 °C, 94%; (e) MeI, K2CO3, THF, 23
°C, 95%; (f) 14 (2 equiv), (CH2Cl)2, 23 °C, 65%; (g) NH4F, MeOH, 23 °C,
79%; (h) AuCl3, MeCN, 40 °C, 78%; (i) p-TsOH·H2O, MeCN, 23 °C,
77%; (j) Pd(PPh3)4, pyrrolidine, MeCN, 23 °C, 81%; (k) Cs2CO3, DMF,
23 °C, 88%; (l) HCl, Et2O, 0 °C, 77%.
(14) Coffey, D. S.; McDonald, A. I.; Overman, L. E.; Stappenbeck, F. J. Am. Chem.
Soc. 1999, 121, 6944–6945.
(15) Pohlki, F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104–114.
(16) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. ReV.
2008, 108, 3795–3892.
(17) McGrane, P. L.; Livinghouse, T. J. Am. Chem. Soc. 1993, 115, 11485–11489.
(18) Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995–3998.
(19) Kadzimirsz, D.; Hildebrandt, D.; Merz, K.; Dyker, G. Chem. Commun. 2006,
661–662.
(20) Fukuda, Y.; Utimoto, K. Synthesis 1991, 975–978.
(21) This and subsequent aminopyrimidine intermediates were purified by RP-HPLC
(water/MeCN/TFA).
tyraldehyde (20) with the phosphonium ylide derived from 4-(tri-
phenylphosphonium)but-1-yne bromide (21) afforded enyne 22. Fol-
JA910831K
9
J. AM. CHEM. SOC. VOL. 132, NO. 6, 2010 1803