An easy and stereoselective synthesis of N-Boc-dolaproine via the Baylis-Hillman reaction

Article abstract of DOI:10.1016/S0040-4039(02)02765-X

In this communication we report a stereoselective total synthesis of N-Boc-dolaproine (Dap), an amino acid residue of the antineoplastic pentapeptide Dolastatin 10. Our strategy is based on a Baylis-Hillman reaction between N-Boc-prolinal and methyl acrylate, followed by a diastereoselective double bond hydrogenation and hydrolysis of the ester function.

Full text of DOI:10.1016/S0040-4039(02)02765-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 937–940
An easy and stereoselective synthesis of N-Boc-dolaproine via
the Baylis–Hillman reaction
Wanda P. Almeidaa,b,* and Fernando Coelhoc,*
aCREUPI, Esp´ırito Santo do Pinhal, 13990-000-SP, Brazil
bCurso de Po´s-Graduac¸a˜o em Biologia Celular e Estrutural, IB/Unicamp, PO Box 6109, 13084-971-Campinas-SP, Brazil
cDQO/IQ, UNICAMP, PO Box 6154, 13083-970-Campinas-SP, Brazil
Received 7 November 2002; revised 4 December 2002; accepted 4 December 2002
Abstract—In this communication we report a stereoselective total synthesis of N-Boc-dolaproine (Dap), an amino acid residue of
the antineoplastic pentapeptide Dolastatin 10. Our strategy is based on a Baylis–Hillman reaction between N-Boc-prolinal and
methyl acrylate, followed by a diastereoselective double bond hydrogenation and hydrolysis of the ester function. © 2003 Elsevier
Science Ltd. All rights reserved.
Dolastatin 10 (1, Fig. 1) has been reported to exhibit a
remarkable antineoplastic activity1 and is now in Phase
II human cancer clinicals trials.2 Its structure and abso-
lute configuration were ascertained by total synthesis
some years ago.3a The unusual b-methoxy-g-amino acid
dolaproine (Dap) comprises the most complex unit of
the pentapeptide 1, and has been synthesized by several
groups employing aldol condensation,3a–c addition of a
crotylboronate to N-Boc-prolinal3e,f and a cobalt-cata-
lyzed Reformatsky reaction.4 More recently, Genet et
al.5 reported a new strategy based on a dynamic kinetic
resolution of a b-keto ester derivative.
A careful search of the literature pointed out that
Drewes and Roos8 have already reported that chiral
a-amino aldehydes such as L-prolinal provided a mod-
erate anti diastereoselectivity in the Baylis–Hillman
reaction with methyl acrylate, but the specific rotation
of the product is low (ca. 1°), suggesting that racemiza-
tion of the starting aldehyde had occurred.
It seems likely that under extended period of reaction
DABCO is sufficiently basic to abstract the a carbonyl
proton thus leading to a loss of chirality. Besides this,
the presence of a strong electron-attracting N-protect-
ing groups (p-nitrobenzoyl or sulfonyl) should con-
tribute to increase the acidity of the a hydrogen. Our
interest was to overcome the problem of racemization
by shortening the reaction time and changing the N-
protecting group.
In an ongoing research program focused on the utiliza-
tion of Baylis–Hillman adducts6 for the total synthesis
of biologically active products,7 we decided to propose
an alternative strategy for the preparation of this
important non proteinogenic amino acid.
In a recent report, we demonstrated that the use of
ultrasound radiation significantly decreases the Baylis–
Hillman reaction time.9 It is worth mentioning that
other alternatives to accelerate the Baylis–Hillman reac-
tion time have already been related, such as the use of
Lewis acid (alone)-catalyzed or -promoted reaction,10
microwaves,11 salts and metals,12 ionic liquids13 and an
aqueous medium.14
Figure 1. Dolastatin 10.
Then, we decided to apply ultrasound radiation to the
DABCO-catalyzed coupling between N-Boc-prolinal
(3) and an acrylate (4 or 5). If it was possible to achieve
good control in the racemization reaction, a subsequent
diastereoselective hydrogenation of intermediates 6 or 7
should guarantee access to our target (Scheme 1).
Keywords: dolaproine; Baylis–Hillman; hydrogenation; amino alde-
hydes.
* Corresponding authors. Tel.: +55-19-3788-3015; fax: +55-19-3788-
3023; e-mail: wciuffo@aol.com, coelho@iqm.unicamp.br
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02765-X

938
W. P. Almeida, F. Coelho / Tetrahedron Letters 44 (2003) 937–940
Scheme 2. Diastereoselective hydrogenation of 8a. Reagents
and conditions: (a) H2, Pd/C 5%; EtOAC, rt, atmospheric
pressure, 91% of a 83:17 diastereoisomeric mixture; (b) flash
chromatography (EtOAc–hexane 1:9; major isomer: 79%
yield).
Scheme 1. Retrosynthetic analysis for N-Boc-dolaproine (2).
In this communication, we report a successful and
simple approach for the total synthesis of N-Boc-
dolaproine (2), employing a Baylis–Hillman reaction as
the key step. N-Boc-prolinal was prepared following a
well established procedure described in the literature.15
the methyl derivative 8a was measured (−32.5°, c 1,
MeOH) and strongly suggested that the Baylis–Hillman
reaction had occurred without extensive racemization
(Scheme 2).
Unfortunately, the relative stereochemistry of the
phenyl derivative was uncertain (8c and 8d, see Table
1). The diastereoisomers could not be easily separated
For the two acrylates examined (4 and 5), the Baylis–
Hillman reactions we performed without and with soni-
cation. The results obtained are summarized in Table 1.
1
on a silica gel chromatographic column and their H
NMR spectra were undistinguishable. The planned syn-
thetic pathway was followed subjecting only 8a (anti
methyl derivative, enantiomerically enriched) to the
hydrogenation step (Scheme 2).
As expected, the reactions with an aromatic acrylate
were faster than those in which methyl acrylate was
used. From Table 1, it is clear that the ultrasound
technique has a significant effect on the time of reac-
tion; however, the nature of acrylate moiety has a
major effect on both the reaction time and the stereo-
selectivity (entry 4).
Ester 9 was obtained in a 83:17 diastereomeric ratio
determined by GC–MS of the crude product. To define
the stereochemistry of the major isomer, after purifica-
tion by flash chromatography, ester 9 was subjected to
deprotection and a cyclization sequence to yield lactam
10 (Scheme 3).11 NOE experiments supported the stereo-
chemical assignment: the cyclic product did not show
increment of signals, suggesting a trans CH–CH3 rela-
tionship (lactam 10a). Similarly, the same experiment
on the lactam derived from the minor diastereoisomer
showed a signal increment of ꢀ10%, suggesting a cis
CH–CH3 relationship. These observations confirmed
the anti–syn (C2ꢀC3%ꢀC2%, Scheme 3) configuration of
ester 9a.
Diastereoisomers obtained from methyl acrylate (8)
were chromatographically separable and the stereo-
1
chemistry of the major one, determined by H NMR
and proved to be anti (8a, Scheme 2), as expected.7 The
anti diastereoselectivity may be rationalized in terms of
the Felkin–Ahn open-chain model.16 The hD value of
Table 1. Baylis–Hillman reaction of N-Boc-prolinal
Then, ester 9a was subjected to the next synthetic step.
To confirm, as quickly as possible, if we were in the
right direction, we decided, in this stage of the work, to
Entry
Acrylate
Conditions
Time (% yield) Ratiod
1
2
3
4
Methyl
Methyl
Phenyla
Phenyl
Standardb
Ultrasoundc
Standard
7 days (70)
5 days (75)
4 days (65)
2 days (70)
3:1
3:1
8:1
8:1
Ultrasound
a CAUTION: Phenyl acrylate is both an irritant and toxic.
b Room temperature, CH2Cl2; DABCO/aldehyde (equimolar ratio)
and 4-fold excess of the acrylate.
Scheme 3. Relative stereochemistry determination of 9a.
Reagents and conditions: (a) CF3CO2H/CH2Cl2, 68% yield; (b)
K2CO3/MeOH, overnight (9a“10a: 82% yield; 9b“10b: 71%
yield).
c Ultrasonic cleaner, 1000 W, 40 kHz.
d Determined by CG–MS.

W. P. Almeida, F. Coelho / Tetrahedron Letters 44 (2003) 937–940
939
Acknowledgements
This work was supported by a grant from FAPESP
(grant 98/14640-0). We also thank the Brazilian
National Research Council (CNPq-301369/1987–9) for
a research fellowship to F.C.
References
1. Pettit, G. R.; Kamano, Y.; Herald, C. L.; Tuinman, A.
A.; Boettner, F. E.; Kizu, H.; Schmidt, J. M.; Baczyn-
skyz, L.; Tomer, K. B.; Bontems, R. J. J. Am. Chem. Soc.
1987, 109, 6883–6885.
2. Madden, T.; Tran, H. T.; Beck, D.; Huie, R.; Newman,
R. A.; Pusztai, L.; Wright, J. J.; Abbruzzese, J. L. Clin.
Cancer. Res. 2000, 6, 1293–1301.
Scheme 4. Synthesis of N-Boc-dolaproine (2). Reagents and
conditions: (a) LiOH/THF, rt, 16 h, 87%; (b) Me3OBF4,
CH2Cl2, proton sponge, rt, 18 h, 70%.
transform 9a into a compound with well established
relative and absolute configurations. Thus, treatment
of ester 9a with LiOH–H2O/THF, at room tempera-
ture, gave N-Boc-nordolaproine (11) in 87% yield
(Scheme 4).
3. (a) Pettit, G. R.; Singh, S. B.; Hogan, F.; Lloyd-Williams,
P.; Herald, D. L.; Burkett, D. D.; Clewlow, P. J. J. Am.
Chem. Soc. 1989, 111, 5463–5645; (b) Hamada, Y.;
Hayashi, K.; Shioiri, T. Tetrahedron Lett. 1991, 32, 931–
934; (c) Tomioka, K.; Kanai, M.; Koga, K. Tetrahedron
Lett. 1991, 32, 2395–2398; (d) Shioiri, T.; Hayashi, K.;
Hamada, Y. Tetrahedron 1993, 49, 1913–1924; (e) Roux,
F.; Maugras, I.; Poncet, J.; Niel, G.; Jouin, P. Tetra-
hedron 1994, 50, 5345–5360; (f) Niel, G.; Roux, F.;
Maisonnasse, Y.; Maugras, I.; Ponet, J.; Jouin, P. J.
Chem. Soc., Perkin Trans. 1 1994, 1275–1280; (g) Shiori,
T. J. Synth. Org. Chem. Jpn. 1994, 52, 392–402; (h)
Miyazaki, K.; Kobayashi, M.; Natsume, T.; Gondo, M.;
Mikami, T.; Sakakibara, K.; Tsukagoshi, S. Chem.
Pharm. Bull. 1995, 43, 1706–1718; (i) Pettit, G. R.; Sri-
rangam, J. K.; Singh, S. B.; Williams, M. D.; Herald, D.
L.; Barkoczy, J.; Kantoci, D.; Hogan, F. J. Chem. Soc.,
Perkin Trans. 1 1996, 8, 859–863 and references cited
therein; (j) Pettit, G. R.; Burkett, D. D.; Barko´czy, J.;
Breneman, G. L.; Pettit, W. E. Synthesis 1996, 719–719;
(k) For a recent review, see: Shioiri, T.; Hamada, Y.
Synlett 2001, 184–201.
The hD value of 11 (−55.8°, c 0.71, MeOH) was
nearly identical to that reported in literature17 and,
therefore, confirmed that the absolute configuration
had been retained in all steps.
Then, the synthesis of N-Boc-dolaproine was achieved
in two subsequent steps from ester 9a. First, O-
methylation of the hydroxy moiety with MeO3BF4
and proton sponge afforded the methoxy ester 6 in
70% yield. Saponification of the methyl ester function
with LiOH in THF/H2O led to N-Boc-protected
dolaproine (2) in 86% yield.18 Since the removal of
Boc protective group is well documented in litera-
ture,1 the preparation of dolaproine has been formally
achieved from a Baylis–Hillman adduct.
4. Pettit, G. R.; Grealish, M. P. J. Org. Chem. 2001, 66,
8640–8642.
5. Lavergne, D.; Mordant, C.; Ratovelomanana-Vidal, V.;
The synthesis of N-Boc-dolaproine 2 was achieved in
four steps from N-Boc-prolinal, with an overall yield
of 27%.19 Despite moderate selectivities, this simple
and efficient synthetic strategy, associated with the
ready chromatographic separation of the diastereoiso-
mers, provided a new entry to N-Boc-dolaproine. As
far as we know this is the first report concerning the
asymmetric total synthesis of a dolaproine derivative
from a Baylis–Hillman adduct. Our results demon-
strate clearly that it is possible to retain the configu-
ration of the a-carbonyl center in N-Boc-prolinal,
using a Baylis–Hillman coupling carried out in the
presence of ultrasound.20,21
Genet, J.-P. Org. Lett. 2001, 3, 1909–1912.
6. For comprehensive reviews on the Baylis–Hillman reac-
tion, see: (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
Tetrahedron 1996, 52, 8001–8062; (b) Ciganek, E. Org.
React. 1997, 51, 201–350; (c) Almeida, W. P.; Coelho, F.
Quim. Nova 2000, 23, 98–101; Chem. Abstr. 2000, 132,
236562e.
7. (a) Almeida, W. P.; Mateus, C. R.; Coelho, F. Tetra-
hedron Lett. 2000, 41, 2533–2536; (b) Coelho, F.;
Almeida, W. P.; Mateus, C. R.; Feltrin, M.; Costa, A. M.
Tetrahedron 2001, 57, 6901–6908; (c) Masunari, A.;
Trazzi, G.; Ishida, E.; Almeida, W. P.; Coelho, F. Synth.
Commun. 2001, 31, 2127–2136; (d) Coelho, F.; Rossi, R.
C. Tetrahedron Lett. 2002, 43, 2797–2800.
8. (a) Roos, G.; Manickum, T. Synth. Commun. 1991, 21,
2269–2274; (b) Drewes, S. E.; Khan, A. A.; Rowland, K.
Synth. Commun. 1993, 23, 183–188.
9. (a) Almeida, W. P.; Coelho, F. Tetrahedron Lett. 1998,
39, 8609–8612; (b) Coelho, F.; Almeida, W. P.; Veronese,
D.; Mateus, C. R.; Lopes, E. C. S.; Silveira, G. P. C.;
In summary, this reaction sequence is very easy to
implement and did not require anhydrous solvents,
a
temperamental boron enolate or a low reac-
tion temperature. Additional studies focusing on
the generalization of this method for other chiral a-
amino aldehydes using other activated acrylates are
ongoing in our laboratory and will be reported in due
course.

940
W. P. Almeida, F. Coelho / Tetrahedron Letters 44 (2003) 937–940
Rossi, R. C.; Pavam, C. H. Tetrahedron 2002, 58, 7437–
7447.
10. (a) Pei, W.; Wei, H. X.; Li, G. G. Chem. Commun. 2002,
20, 1856–1857 and references cited therein; (b) Li, G. G.;
Wei, H. X.; Gao, J. J.; Caputo, T. D. Tetrahedron Lett.
2001, 41, 1–5.
427–430; (g) Aggarwal, V. K.; Mereu, A.; Tarver, G. J.;
McCague, R. J. Org. Chem. 1998, 63, 7183–7189.
13. Rosa, J. N.; Afonso, C. A. M.; Santos, A. G. Tetrahedron
2001, 57, 4189–4193.
14. (a) Yu, C. Z.; Liu, B.; Hu, L. Q. J. Org. Chem. 2001, 66,
5413–5418; (b) Auge´, J.; Lubin, N.; Lubineau, A. Tetra-
hedron Lett. 1994, 35, 7947–7948.
15. Pettit, G. R.; Singh, S. B.; Herald, D. L.; Williams, P. L.;
Kantoci, D.; Burkett, D. D.; Barkbczy, J.; Hogan, F.;
Wardlaw, T. R. J. Org. Chem. 1994, 59, 6287–6295.
16. (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron
Lett. 1968, 18, 2199; (b) Ahn, N. T. Top. Curr. Chem.
1980, 88, 144–162; (c) Hoffmann, R. W. Chem. Rev.
1989, 89, 1841–1860.
11. (a) Basavaiah, D.; Sreenivasulu, B.; Reddy, R. M.;
Muthukumaran, K. Synth. Commun. 2001, 31, 2987–
2995; (b) Yadav, J. S.; Reddy, B. V. S.; Madan, C. New
J. Chem. 2001, 25, 1114–1117; (c) Shanmugam, P.; Singh,
P. R. Synlett 2001, 8, 1314–1316; (d) Ravichandran, S.
Synth. Commun. 2001, 31, 2055–2057; (e) Shi, M.; Feng,
Y. S. J. Org. Chem. 2001, 66, 406–411; (f) Micuch, P.;
Fisera, L.; Cyranski, M. K.; Krygowski, T. M.; Krajcik,
J. Tetrahedron 2000, 56, 5465–5472; (g) Kataoka, T.;
Kinoshita, H.; Kinoshita, S.; Iwamura, T.; Watanabe, S.
Angew. Chem., Int. Ed. 2000, 39, 2358–2360; (h) Micuch,
P.; Fisera, L.; Cyranski, M. K.; Krygowski, T. M. Tetra-
hedron Lett. 1999, 40, 167–170; (i) Iwama, T.; Tsujiyama,
S.; Kinoshita, H.; Kanematsu, K.; Tsurukami, Y.; Iwa-
mura, T.; Watanabe, S.; Kataoka, T. Chem. Pharm. Bull.
1999, 47, 956–961; (j) Basavaiah, D.; Muthukumaran, K.;
Sreenivasulu, B. Synlett 1999, 8, 1249–1250; (k) Iwama,
T.; Kinoshita, H.; Kataoka, T. Tetrahedron Lett. 1999,
40, 3741–3744; (l) Kundu, M. K.; Mukherjee, S. B.; Balu,
N.; Padmakumar, R.; Bhat, S. V. Synlett 1994, 6, 444–
444; (m) Cablewski, T.; Faux, A. F.; Strauss, C. R. J.
Org. Chem. 1994, 59, 3408–3412.
17. Nakai, T.; Mikami, K.; Terada, M. Tetrahedron Lett.
1991, 32, 937.
18. Ref. 3g: [h]2D6=−56.8° (c 0.52, MeOH); Ref. 3i: [h]2D5=
−57.0° (c 0.81, MeOH); Ref. 3b: [h]2D7=−54.5° (c 1,
MeOH).
19. All spectral data were compatible with those related
previously for N-Boc-dolaproine (2). A colorless viscous
oil, which crystallize on standing. Recrystallization
(twice) from acetone–hexane produced needles: mp 138–
142°C; [h]2D5=−60.2° (c 0.5, CH3OH); (lit.9 [h]2D5=−61.4°
(c 0.5, CH3OH); lit. [h]2D5=−57.0° (c 2.08, CH3OH);
EIMS m/z 287 (M+), 255, 214, 170, 114, 70; IR (KBr,
umax): 3084, 2978, 2938, 2884, 1736, 1696, 1402, 1167,
1
1167, 1099 cm−1; H NMR (500 MHz, CD3CN, 50°C) l
12. For some examples of metal catalysis in Baylis–Hillman
reaction, see: (a) Shi, M.; Jiang, J. K.; Cui, S. C. Tetra-
hedron 2001, 57, 7343–7347; (b) Akiyama, H.; Fujimoto,
T.; Ohshima, K.; Hoshino, K.; Saito, Y.; Okamoto, A.;
Yamamoto, I.; Kakehi, A.; Iriye, R. Eur. J. Org. Chem.
2001, 12, 2265–2272; (c) Comins, D. L.; Hiebel, A. C.;
Huang, S. L. Org. Lett. 2001, 3, 769–771; (d) Shi, M.;
Feng, Y. S. J. Org. Chem. 2001, 66, 406–411; (e)
Kataoka, T.; Kinoshita, H.; Kinoshita, S.; Iwamura, T.;
Watanabe, S. Angew. Chem., Int. Ed. 2000, 39, 2358–
2360; (f) Akiyama, H.; Fujimoto, T.; Ohshima, K.;
Hoshino, K.; Yamamoto, I.; Iriye, R. Org. Lett. 1999, 1,
3.80 (m, 2H), 3.44 (m, 1H), 3.39 (s, 3H, OCH3), 3.16 (m,
1H), 2.47 (m, 1H), 1.96–1.82 (m, 4H), 1.72 (m, 1H), 1.44
(s, 9H), 1.18 (d, 3H, J=7 Hz).
20. For an example of a Baylis–Hillman reaction with 4-
oxoazetidine-carboaldehydes without racemization, see:
Alcaide, B.; Almendros, P.; Aragoncillo, C. J. Org.
Chem. 2001, 66, 1612–1620 and references cited therein.
21. For an example of a Baylis–Hillman reaction using a
configurational restricted amino aldehyde without race-
mization, see: Nayak, S. K.; Thijs, L.; Zwanenburg, B.
Tetrahedron Lett. 1999, 40, 981–984.