1,3-Stereocontrol with bromoallenes. Synthesis of N-Boc-ADDA, the unique amino acid present in several inhibitors of serine/threonine phosphatases

Full text of DOI:10.1021/jo9605004

4870
J . Org. Chem. 1996, 61, 4870-4871
Communications
1,3-Ster eocon tr ol w ith Br om oa llen es.
Syn th esis of N-Boc-ADDA, th e Un iqu e
Am in o Acid P r esen t in Sever a l In h ibitor s
of Ser in e/Th r eon in e P h osp h a ta ses
Sch em e 1
F. D’Aniello and A. Mann*
Laboratoire de Pharmacochimie Mole´culaire, UPR 421,
Centre de Neurochimie, 5, rue B. Pascal,
F-67084-Strasbourg Cedex, France
M. Taddei
Dipartimento di Chimica, Universita` di Sassari,
I-07100 Sassari, Italy
Received March 13, 1996
Mycrocystins, nodularin and motuporin, both cyclic
peptides from cyanobacteria, have a common feature, a
unique C20 amino acid ADDA (1) that seems to be
essential for their biological functions.1 In the reported
syntheses of ADDA, the E,E-dienic system present in
1 was prepared via J ulia-Wittig-type chemistry, which
did not allow for the complete control of the stereochem-
istry of the double bonds.2-5
Sch em e 2a
We designed an alternative strategy to 1, which is
depicted in retrosynthetic Scheme 1. In this strategy,
the disconnection of the C5-C6 bond of 1 suggested two
fragments, C1-C5 (2) and C6-C10 (3), which, in a forward
synthetic direction, could be coupled together under Stille
conditions to give ADDA (1).6 We envisioned that the
C1-C5 fragment (2) could be derived from the â alkylated
R-amino aldehyde 4, which in turn could originate from
(R)-aspartic acid. For fragment C6-C10 (3), a disubsti-
tuted chiral alkyne, we believed the stereochemistry of
the stereogenic center at carbon C-8 could be controlled
via SN2′ alkylation of chiral bromoallene 5, derived from
enantiomerically pure phenyllactic acid (6) (Scheme 1).
A similar diastereoselectivity has been demonstrated in
our recent work.7
a
Key: (a) EtSH, DCC, DMAP, CH2Cl2, rt (81%); (b) Et3SiH,
Pd/C, acetone, rt (82%); (c) CHI3, CrCl2, THF (75%); (d)
Me3SnSnMe3, Pd(PPh3)4, THF, 50 °C (74%).
in 2 was exclusively trans as suggested by the coupling
constant of the two vinylic protons (J ) 19 Hz).
The preparation of the C6-C10 fragment is depicted in
Scheme 3.8 Commercially available (S)-phenyllactic acid
(6) was transformed into the Weinreb amide 9 using
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexaflu-
orophosphate (py-BOP) as a coupling reagent (72% yield
over the two steps).12 The N-methyl-N-methoxy group
worked first as a protecting group during the methylation
Scheme 2 outlines the elaboration of C1-C5 frag-
ment.4,8,9 To selectively reduce the carboxylic group to
an aldehyde in the presence of a methyl ester, we decided
to convert acid 7 into the corresponding ethylthioester.
Subsequent reduction with triethylsilane in the presence
of catalytic amounts of Pd/C gave aldehyde 4 in 66% yield
over the two steps.10 Further elaboration of aldehyde 4
into vinylstannane 2 was done using the following
sequence: reaction with CHI3 in the presence of CrCl2
gave trans vinyl iodide 8,11 and stannylation with hexa-
methyldistannane in the presence of freshly prepared Pd-
(PPh3)4, yielded trans vinylstannane 2 (56% yield over
the two steps).6 The geometry of the vinylic hydrogens
(8) Physical data for 2, 3, 5, and 12: 2: 1H NMR (200 MHz, CDCl3,
50 °C, TMS) δ ) 0.09 (s, J ) 27 Hz, 9 H, coupling with 119Sn), 1.19 (d,
J ) 7.1 Hz, 3 H), 1.42 (s, 9 H), 2.69-2.79 (m, 1 H), 3.62 (s, 3 H), 4.29-
4.33 (m, 1 H), 5.30 (d, J ) 9.2 Hz, 1 H), 5.85 (dd, J ) 19, 4.2 Hz, 1 H),
6.15 (d, J ) 19 Hz, 1 H); 13C NMR (50 MHz, CDCl3, 50 °C, TMS) δ )
-9.7 (t, J ) 173 Hz), 14.2, 28.2, 43.1, 51.4, 56.2, 79.2, 130.7, 145.2,
155.5, 175.2. 3: 1H NMR (200 MHz, CDCl3, 25 °C, TMS) δ ) 1.19 (d,
J ) 7 Hz, 3 H), 1.84 (d, J ) 2.4 Hz, 3 H), 2.52-2.60 (m, 1 H), 2.80-
3.04 (m, 2 H), 3.21-3.33 (m, 1 H), 3.28 (s, 3 H), 7.20-7.30 (m, 5 H);
13C NMR (50 MHz, CDCl3) δ ) 3.6, 17.4, 30.1, 37.8, 58.4, 65.8, 81.1,
85.8, 126.0, 128.1, 129.5, 139.1; IR (CCl4) ν ) 3034, 2926, 1939, 1453,
1119 cm-1; MS (EI) m/z 202 (3) [M+], 170 (7), 155 (4), 135 (100), 111
* To whom correspondence should be addressed. Tel: (33) 88 45 66
84. FAX: (33) 88 60 08 10. E-mail: mann@neurochem.u-strasbg.fr.
(1) Goldberg, J .; Huang, H.; Kwon, Y.; Greengard, P.; Nairn, A. C.;
Kuriyan, J . Nature 1995, 376, 745 and references cited therein.
(2) Namikoshi, M.; Rinehart, K. L.; Dahlem, A. M.; Beasley, V. R.;
Carmichael, W. W. Tetrahedron Lett. 1989, 30, 4349.
(3) Chakraborty, T. K.; J oshi, S. P. Tetrahedron Lett. 1990, 31, 2043.
(4) Beatty, M. F.; J ennings-White, C.; Avery, M. A. J . Chem. Soc.,
Perkin Trans. 1 1992, 1637.
(5) Schreiber, S. L.; Valentekovich, R. J . J . Am. Chem. Soc. 1995,
117, 9069.
(6) Stille, J . K.; Groh, B. L. J . Am. Chem. Soc. 1987, 109, 813.
(7) D’Aniello, F.; Mann, A.; Taddei, M. Tetrahedron Lett. 1994, 35,
7775.
(56), 103 (30), 91 (29), 77 (10); [R]20 ) -60.2 (c ) 1, CHCl3). 5: 1H
D
NMR (200 MHz, CDCl3, 25 °C, TMS) δ ) 2.25 (d, J ) 3 Hz, 3 H), 2.82-
3.03 (m, 2 H), 3.34 (s, 3 H), 3.93-4.04 (m, 1 H), 5.10-5.18 (m, 1 H),
7.18-7.35 (m, 5 H); 13C NMR (50 MHz, CDCl3, 25 °C, TMS) δ ) 25.1,
41.8, 56.8, 65.8, 79.8, 97.8, 126.3, 128.2, 129.4, 137.5, 203.3; IR (CCl4)
ν 3069, 2928, 1958, 1604, 1454, 1105 cm-1; MS (IE) m/z 268 (0.3) [MH+],
186 (13), 175 (74), 155 (77), 135 (100), 103 (31), 91 (63), 77 (13). 12:
1H NMR (200 MHz, CDCl3, 25 °C, TMS) δ ) 1.05 (d, J ) 6.8 Hz, 3 H),
2.26 (d, J ) 1.4 Hz, 3 H), 2.43-2.55 (m, 1 H), 2.66-2.89 (m, 2 H),
3.15-3.25 (m, 1 H), 3.28 (s, 3 H), 6.11 (dd, J ) 1.4, 10 Hz, 1 H), 7.18-
7.35 (m, 5 H); 13C NMR (50 MHz, CDCl3, 25 °C, TMS) δ ) 15.4, 27.7,
37.7, 39.0, 58.5, 85.9, 94.1, 126.0, 128.2, 129.3, 138.8, 143.7; IR (CCl4)
ν ) 3033, 2933, 1635, 1454, 1100 cm-1; [R]20 ) -48 (c ) 1, CHCl3).
D
S0022-3263(96)00500-2 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 15, 1996 4871
Sch em e 3a
bromoallene (epi-5), present in ca. 5%, was detected by
1H NMR (200 MHz) and could not be separated by TLC.
We suspect that to some extent direct substitution of the
transient tosylate by bromine occurred, producing a
propargylic bromide that in turn was converted into the
bromoallene identified as epi-5 (see below). Alkylation
of the mixture of 5 and its anti isomer epi-5 was
performed with the organocopper reagent MeCuCNLi in
THF and afforded a separable mixture of two compounds
identified as 3 (syn: J ) 6 Hz, 76%) and its anti isomer
epi-3 (anti: J ) 3.5 Hz, 5%). The reaction with the
copper reagent proceeded through a pure SN2′ mechanism
introducing the methyl group on the side of the allene
opposite to that of the bromine, producing alkylalkyne 3
as the sole adduct.7 No trace of the direct substitution
product resulting from attack of the copper reagent was
1
detected by H and 13C NMR.
For the selective formation of the E iodide 12, the triple
bond in 3 was subjected to hydrozirconation followed by
quenching with iodine.17 This sequence installed the
halogen at the less hindered side of the triple bond in 3
and defined the geometry of the double bond for Stille
coupling with compound 2. The protected ADDA frag-
ment 13 with the correct E,E stereochemistry was finally
obtained by reaction of iodide 12 and vinyl stannnane 2
in dry DMF in the presence of Pd(CH3CN)2Cl2 (5%) in
an acceptable yield (60%).6,18 During the cross coupling
reaction, 5% of the corresponding E,Z isomer was formed
but subsequently separated from 13 by column chroma-
tography. Finally, saponification of the methyl ester in
13 with LiOH afforded the N-Boc amino acid 14 ready
to be used for the synthesis of the phosphatase inhibitors
mentioned above. Compound 14, obtained in this way,
was fully characterized and found to have the same
physical and spectroscopic properties previously de-
scribed for N-Boc ADDA.4,19,20 In conclusion, we have
demonstrated that homochiral bromoallenes are reliable
intermediates for the regio- and diastereocontrolled
preparation of disubstituted alkylalkynes.
a
Key: N,O-dimethylhydroxylamine‚HCl, triethylamine, pyBOP,
CH2Cl2, rt (81%); (b) CH3I, Ag2O, DMF, rt (88%); (c) MeCtCLi,
THF, -78 °C, (89%); (d) K-Selectride, THF, -100 °C (72%); (e)
BuLi, LiBr, TosCl, THF, then CuBr‚DMS, LiBr, -60 °C (75%: 5
and epi-5); (f) MeCuCNLi, THF, -78 °C (76% of 3 and 4% of epi-
3); (g) Cp2ZrCl(H), C6H6, 43 °C, then I2 in CCl4 (70%); (h) 2,
PdCl2(CH3CN)2, DMF, rt (58%); (i) LiOH, dimethoxyethane-H2O
1/1, rt (70%).
of the secondary alcohol using silver oxide and methyl
iodide and after as a carbonyl activating group for the
preparation of propargylic ketone 10.
Compound 9 was reacted with lithium propyne (ob-
tained by reaction of 1-bromopropene and 2.2 equiv of
BuLi)13 to give 10 in 89% yield. Syn stereoselective
reduction of the carbonyl group of 10 was performed with
potassium tri-sec-butyl borohydride (K-Selectride, Ald-
rich) at -100 °C in THF.14 The resulting propargylic
alcohol 11 was isolated isomerically pure after column
chromatography in 72% yield. The stereochemistry of
this product was confirmed by analyzing the value of the
coupling constant between the protons attached to the
stereogenic centres (J ) 5.8 Hz), typical for a syn
arrangement. Propargylic alcohol 11 was transformed
into the bromoallene 5 through reaction of LiBr and CuBr
in THF at -60 °C with the corresponding tosylate.15,16
This reaction is highly regio- and stereoselective, giving
the desired compound 5 with 90% de. The epimeric
Ack n ow led gm en t. We thank the Lilly laboratories
and the “Socie´te´ de Secours des Amis des Sciences” for
grants to F. D’Aniello.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all compounds (8 pages).
(9) (a) For convenience, we used this tedious procedure in place of
the recently reported stereoselective alkylation of aspartic derivatives,9b
because of the drastic conditions needed to remove the nitrogen
protecting group. (b) Humphrey, J . M.; Bridges, R. J .; Hart, J . A.;
Chamberlin, A. R. J . Org. Chem. 1994, 59, 2467.
(10) Fukuyama, T.; Lin, S.; Li, L. J . Am. Chem. Soc. 1990, 112, 7050.
(11) Takai, T.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408.
(12) Coste, J .; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990,
31, 205.
(13) Suffert, J .; Toussaint, D. J . Org. Chem. 1995, 60, 3550.
(14) (a) Takahashi, T.; Miyazawa, M.; Tsuji, T.; Ueno, H. Tetrahe-
dron Lett. 1985, 26, 5139. (b) Takahashi, T.; Miyazawa, M.; Tsuji, T.;
Ueno, H. Ibid. 1985, 26, 4463.
J O9605004
(16) If the reaction was conducted at room temperature, a mixture
of regio- and diastereoisomers of propargylic and allenyl bromides was
observed by 1H NMR.
(17) Buchwald, S. L.; Lamaire, S. J .; Nielsen, R. B.; Watson, B. T.;
King, S. M. Org. Synth. 1992, 71, 77.
(18) The coupling reaction must be conducted in completely degassed
solvent (freezing technique).
(19) Namikoshi, M.; Choi, B. W.; Sakai, R.; Sun, F.; Rinehart, K. L.
J . Org. Chem. 1994, 59, 2349.
(20) Note a d d ed in P r oof: A synthesis of ADDA was recently
reported. Kim, H. Y.; Toogood, P. L. Tetrahedron Lett. 1996, 37, 2349.
(15) Montmury, M.; Gore, J . Synth. Commun. 1980, 10, 873.