Effective procedure for selective ammonolysis of monosubstituted oxiranes: application to E7389 synthesis

Article abstract of DOI:10.1016/j.tetlet.2007.10.116

A highly effective procedure is reported to synthesize 1,2-aminoalcohols by regio- and chemo-selective ammonolysis of mono-substituted epoxides. Additive- and concentration-effects were studied, revealing that (1) methanesulfonic acid is most effective among the additives tested and (2) formation of bis-adducts is practically eliminated at [C] ≤ 40 mM. The optimum condition thus identified was successfully applied to the final step of the synthesis of potent anti-tumor compound E7389.

Full text of DOI:10.1016/j.tetlet.2007.10.116

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8967–8971
Effective procedure for selective ammonolysis of monosubstituted
oxiranes: application to E7389 synthesis
Yosuke Kaburagi and Yoshito Kishi*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA
Received 7 September 2007; revised 22 October 2007; accepted 23 October 2007
Available online 26 October 2007
Abstract—A highly effective procedure is reported to synthesize 1,2-aminoalcohols by regio- and chemo-selective ammonolysis of
mono-substituted epoxides. Additive- and concentration-effects were studied, revealing that (1) methanesulfonic acid is most effec-
tive among the additives tested and (2) formation of bis-adducts is practically eliminated at [C] 6 40 mM. The optimum condition
thus identified was successfully applied to the final step of the synthesis of potent anti-tumor compound E7389.
Ó 2007 Elsevier Ltd. All rights reserved.
1,2-Aminoalcohols 2 (Scheme 1) are important building
blocks in the synthesis of natural products, pharmaceu-
ticals, and other substances.1 Among several synthetic
methods known, ammonolysis of 1,2-epoxides 1 is one
of the most attractive and commonly used methods,2
coupled with the fact that optically active 1,2-epoxides
have become readily available in recent years.3–6 How-
ever, there are three intrinsic limitations that could
potentially make this process impractical. First, the
nucleophilic attack of ammonia can take place at
the 1- or 2-position, that is, 1!2 versus 1!3. Second,
the resultant 1,2-aminoalcohols 2 can react with the
starting material 1, to yield the corresponding secondary
amines 4. Because a primary amine is more nucleophilic
than ammonia, this side reaction often presents a
problem. Usually, this problem is circumvented by use
of a large excess of ammonia at low concentration,
which is not necessarily ideal for a large-scale synthesis.
Third, the ammonolysis is usually slow and often suffers
from low conversion. To overcome this difficulty, the
microwave assisted method has been reported in recent
years.7 Overall, although ammonolysis of 1,2-epoxides
is a direct and attractive synthetic route to 1,2-amino-
alcohols, problems still remain to achieve this chemical
transformation effectively and economically.
Related to the ammonolysis summarized in Scheme 1,
we should note that aminolysis of epoxides with primary
and secondary amines has been a subject for extensive
research. To overcome the intrinsic limitations noted
above, three type of approaches, that is, (1) use of metal
amides (aluminum,8 magnesium,9 lead,10 tin,11 and
silicon12), (2) use of metal salts such as LiClO4 and
13
lanthanide(III) triflates,14 and (3) use of amines
absorbed on alumina,15 have been introduced.
The potential problems associated with the ammonoly-
sis of epoxides came to our attention in connection with
the synthesis of an anti-tumor drug candidate E7389 (7),
a structurally simplified analog of the marine natural
product halichondrins (Scheme 2).16–18 Namely, the last
step in the synthesis of E7389 (7) is the ammonolysis of
epoxide 6, generated in situ from the mono-mesylate 5.16
Based on the published experimental procedure, we
speculate that this step most likely suffers from the prob-
lems discussed in a general context.
O
R
1
NH
3
HO
H N
2
HO
OH
H
H N
2
+
+
HO
N
R
R
R
R
2
3
4
Scheme 1.
Basically, we were curious about the possibility of acti-
vating 1,2-epoxides by an acid. In this connection, the
reports by Crotti and co-workers are instructive; they
*
Corresponding author. Tel.: +1 617 495 4679; fax: +1 617 495
5150; e-mail: kishi@chemistry.harvard.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.116

8968
Y. Kaburagi, Y. Kishi / Tetrahedron Letters 48 (2007) 8967–8971
and regio-selective manner.14 Reymond and co-workers
MeO
HO
extended the Yb(OTf)3-mediated method to ammonoly-
sis of 1,2-epoxides in ethanol, to obtain the desired
aminoalcohols in high yields.19 In addition, Koyama
and Fujikawa claimed in their patent that ammonium
halide improves the ammonolysis of epoxides.20
MsO
H
O
O
O
H
O
O
H
O
O
O
Me
O
5
In terms of the enhancement of reactivity and the
improvement of regioselectivity, the examples cited
above suggest that lanthanide(III) triflates appear to
give a solution for the ammonolysis/aminolysis of 1,2-
epoxides. To the best of our knowledge, however, there
is no study reported to suppress the formation of dimer
4 and conduct the ammonolysis in a practically accept-
able concentration. Thus, we decided to study the
ammonolysis of a 1,2-epoxide in the presence of acids.
Using the epoxide 1a (Table 1), we examined the effect
of acids and concentrations on the product distribution.
a
MeO
O
O
6
MeO
HO
.
MsOH H N
H
O
2
O
O
H
O
O
H
O
O
O
Me
O
To begin with, we examined the effects of Yb(OTf)3 on
the ammonolysis of 1a. Thus, 1a was treated with
ammonia in ethanol (ammonia-saturated EtOH,
[C] = 40 mM) in the presence and absence of Yb(OTf)3
(10 mol %) at 70 °C and the product analysis was con-
ducted after acetylation of the crude product (entry 3a
vs entry 13a in Table 1), thereby revealing the following.
First, no significant difference in the ammonolysis rate
was noticed between the two cases. Considering that a
large excess of ammonia was used for these experiments,
this observation was not totally unexpected. Second, the
E7389 (7)
Scheme 2. Reagents and conditions: (a) EtOH saturated with NH3,
MsOH (5 equiv), [C] = 40 mM, rt, 3.5 days, 93% yield.
demonstrated that lanthanide(III) triflates such as
Yb(OTf)3, Nd(OTf)3, and Gd(OTf)3 catalyze the ami-
nolysis of 1,2-epoxides in a non-protic solvent, to yield
the corresponding aminoalcohols in a highly stereo-
Table 1. Effect of additive and concentration on product distribution
O
OTBS
1a
NH sat. in EtOH
3
Additive
HO
H N
2
HO
H
OH
H N
2
+
+
HO
N
R
R
R
R
2a
3a
4a
R = (CH ) OTBS
2 3
Entry
Additive
Concentration (mM)
Temperaturea
Ratio 2a:4a
1
2
3a
3b
4
Yb(OTf)3ÆnH2O (0.1 equiv)
Yb(OTf)3ÆnH2O (0.1 equiv)
Yb(OTf)3ÆnH2O (0.1 equiv)
160
80
40
70
70
70
rt
70
70
70
rt
70
rt
70
rt
100:12
100:11
100:3
100:8
100:2
100:4
100:8
100:9
100:2
100:3
100:1.5
100:2
100:4.5
100:5
100:5
100:6
Yb(OTf)3ÆnH2O (0.1 equiv)
Sc(OTf)3 (0.1 equiv)
MsOH (5 equiv)
20
20
80
5
6a
6b
7a
7b
8a
8b
9
10
11
12
MsOH (5 equiv)
MsOH (5 equiv)
40
20
MsOH (3 equiv)
MsOH (1 equiv)
NH4Cl (5 equiv)
NH4OAc (5 equiv)
40
40
40
40
rt
rt
70
70
13a
13b
No additive
40
70
rt
100:4
100:8
a Reaction time at 70 °C and at rt was 10 h and 82 h, respectively.

Y. Kaburagi, Y. Kishi / Tetrahedron Letters 48 (2007) 8967–8971
8969
aminoalcohol corresponding to 3a was not detected in
the crude product for both cases (1H NMR). Third,
Yb(OTf)3 appeared to have a small effect on the 2a:4a
ratio, that is, the ratio was slightly better for entry 3a
than for entry 13a. Interestingly, at room temperature,
the Yb(OTf)3-effect on the ratio was not seen (entry 3b
vs entry 13b).
presence of 5 equiv of MsOH at 70 °C27 and at room
temperature at [C] = 40 mM, to furnish E7389 (7) meth-
1
anesulfonate16 in 93% yield.28 The H NMR analysis of
7 and its O,N-diacetate revealed that the product thus
obtained was not contaminated with a detectable
amount of side-product(s).
In summary, we reported an effective MsOH-mediated
ammonolysis of mono-substituted epoxides. Under the
optimum condition, that is, EtOH saturated with NH3
in the presence of MsOH (5 equiv) at [C] 6 40 mM,
the ammonolysis of 1a can be achieved in a highly selec-
tive manner, to furnish the desired 1,2-aminoalcohol 2a
in excellent chemical yields. The usefulness of this proce-
dure was demonstrated by the case of E7389 (7)
synthesis.
We then studied the concentration effect on the dimer
formation in the presence of Yb(OTf)3 (entries 1–4),
thereby revealing that only a very small amount of 4a
was detected at [C] 6 40 mM, whereas a significant
amount of dimer 4a was found at [C] P 80 mM.21
Encouraged by these results, we tested other Lewis and
Brønsted acids. Sc(OTf)3 (10 mol %) gave the result sim-
ilar, but slightly inferior, to that with Yb(OTf)3 (entry
5). Among the Brønsted acids tested, methanesulfonic
acid (MsOH)22 was found to be slightly more effective
than Yb(OTf)3, but hydrochloric acid (NH4Cl) and ace-
tic acid (NH4OAc) were found to be less effective (entry
11 and 12). Notably, 10 mol % of Yb(OTf)3 was suffi-
cient to cause the optimum effect, whereas more than
a stoichiometric amount of MsOH was required (entries
7ab, 9, and 10). Practically, approximately 5 equiv of
MsOH seemed to be required to achieve the maximum
2a:4a ratio. Overall, the effectiveness order of tested-
acids is as follows: MsOH (5 equiv) P Yb(OTf)3
(0.1 equiv) > NH4Cl (5 equiv) > NH4OAc (5 equiv) >
Sc(OTf)3 (0.1 equiv). Considering the cost effective-
ness and operational simplicity, we recommend the
ammonolysis in the presence of excess MsOH over
Yb(OTf)3.
Acknowledgments
We are grateful to the National Institutes of Health (CA
22215) and Eisai Research Institute for generous finan-
cial support.
Supplementary data
1H NMR spectra of 5 and 7 can be found in the online
version. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2007.10.116.
References and notes
The concentration dependency of the product distribu-
tion in the presence of MsOH (entries 6–8) was found
to be similar to that in the presence of Yb(OTf)3.
Namely, only a very small amount of 4a was detected
at [C] 6 40 mM, whereas a significant amount of dimer
4a was found at [C] P80 mM. The temperature effect on
the 2a:4a ratio was found to be negligibly small,
although the ratio at 70 °C appeared to be very slightly
better than that at room temperature (entries 6a vs 6b,
7a vs 7b, 8a vs 8b). Finally, it is worthwhile noting that
no detectable regioisomer 3a was detected in the crude
product (1H NMR).23 Overall, this ammonolysis can
best be achieved in NH3-saturated EtOH in the presence
of MeOH (5 equiv) at [C] 6 40 mM. Under this condi-
tion, additional two epoxides were selectively converted
into the corresponding aminoalcohols in high yields.24
1. Mo¨ller, F. In Methoden der Organischen Chemie (Houben-
Weyl), 4th ed.; Muller, E., Ed.; Thieme-Verlag: Stuttgart,
¨
1957; Vol. 11/1, pp 311–326.
2. For selected examples since 2001, see: (a) Gautier, A.;
Mulatier, J.-C.; Crassous, J.; Dutasta, J.-P. Org. Lett.
2005, 7, 1207; (b) Shimogawa, H.; Kwon, Y.; Mao, Q.;
Kawazoe, Y.; Choi, Y.; Asada, S.; Kigoshi, H.; Uesugi,
M. J. Am. Chem. Soc. 2004, 126, 3461; (c) Liu, C.-H.;
Wang, B.; Li, W.-Z.; Yun, L.-H.; Liu, Y.; Su, R.-B.; Li, J.;
Liu, H. Bioorg. Med. Chem. 2004, 12, 4701; (d) Stachel, S.
J.; Coburn, C. A.; Steele, T. G.; Jones, K. G.; Loutzenh-
iser, E. F.; Gregro, A. R.; Rajapakse, H. A.; Lai, M.-T.;
Crouthamel, M.-C.; Xu, M.; Tugusheva, K.; Lineberger,
J. E.; Pietrak, B. L.; Espeseth, A. S.; Shi, X.-P.; Chen-
Dodson, E.; Holloway, M. K.; Munshi, S.; Simon, A. J.;
Kuo, L.; Vacca, J. P. J. Med. Chem. 2004, 47, 6447; (e)
Guangyou, Z.; Yuquing, L.; Zhaohui, W.; Nohira, H.;
Hirose, T. Tetrahedron: Asymmetry 2003, 14, 3297; (f) Hu,
B.; Ellingboe, J.; Gunawan, I.; Han, S.; Largis, E.; Li, Z.;
Malamas, M.; Mulvey, R.; Oliphant, A.; Sum, F.-W.;
Tillett, J.; Wong, V. Bioorg. Med. Chem. Lett. 2001, 11,
757.
3. Several well-developed methods are now available to
obtain optically active epoxides, including asymmetric
epoxidation of olefins,4 asymmetric dihydroxylation of
olefins,5 asymmetric reduction of ketones,6 and others.
4. Chiral epoxides are available via asymmetric epoxidation
of allylic alcohols pioneered by Sharpless (Katsuki, T.;
Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974),
(salen)manganese complex-based asymmetric epoxidation
With these results in hand, we then applied the MsOH-
mediated ammonolysis to the synthesis of E7389 (7). In
this case, epoxide 6 was prepared in situ by ammonia
treatment of the corresponding mono-mesylate 5;16 with
respect to the amount of MsOH present in the reaction
media, the reported ammonolysis condition corresponds
to entry 10 in Table 1. In extrapolating the optimal con-
ditions found in substrate 1a, we anticipated the opti-
mum condition for the ammonolysis of 5 to be ‘in the
presence of additional four or more equivalents of
MsOH in EtOH at [C] = 40 mM’.25 Thus, the mono-
mesylate 5 was treated with ammonia in ethanol in the

8970
Y. Kaburagi, Y. Kishi / Tetrahedron Letters 48 (2007) 8967–8971
developed by Jacobsen (Jacobsen, E. N.; Zhang, W.;
Nowak, P.; Wan, Z.-K.; Xie, C. Pure Appl. Chem. 2003,
75, 1, and the references cited therein; (c) Namba, K.; Jun,
H.-S.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 7770; (d)
Namba, K.; Kishi, Y. J. Am. Chem. Soc. 2005, 127, 15382;
(e) Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723, and
references cited therein.
Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc.
1991, 113, 7063) and by Katsuki (Irie, R.; Noda, K.; Ito,
Y.; Matsumoto, N.; Katsuki, T. Tetrahedron Lett. 1990,
31, 7345), hydrolytic kinetic resolutions of racemic epox-
ides pioneered by Jacobsen (Tokunaga, M.; Larrow, J. F.;
Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936), and
chiral ketone-based asymmetric epoxidation developed by
Shi (Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996,
118, 9806) and others. There are numerous reviews
published to cover these subjects. For a recent review,
see: Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su,
K.-X. Chem. Rev. 2005, 105, 1603. For recent monographs,
see: Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.
Ed.; Wiley-VCH: New York, 2000; Comprehensive Asym-
metric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer: New York, 1999; Comprehensive
Organometallic Chemistry II; Abel, E. W., Stone, F. G.
A., Wilkinson, G., Eds.; Pergamon: New York, 1995; Vol.
12. (volume edited by Hegedus, L. S.). For asymmetric
epoxidation of homoallylic alcohols, see: Zhang, W.;
Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286.
18. Jordan and co-workers recently reported that the primary
antimitotic mechanism of action of E7389 is suppression
of microtubule growth; see: Jordan, M. A.; Kamath, K.;
Manna, T.; Okouneva, T.; Miller, H. P.; Davis, C.;
Littlefield, B. A.; Wilson, L. Mol. Cancer Ther. 2005, 4,
1086.
19. Wahler, D.; Badalassi, F.; Crotti, P.; Reymond, J.-L.
Chem. Eur. J. 2002, 8, 3211.
20. Koyama, H.; Fujikawa, H. Japan Patent # 2618713, 1997.
21. The concentration of ammonolysis reported by Reymond
and co-workers was approximately 125 mM.19
22. p-Toluenesulfonic acid was shown to be as effective as
MsOH.
23. As anticipated, stylene oxide gave a significant amount of
the regioisomer, along with the dimers. Even for this case,
the effect of MsOH on the formation of both regioisomer
and dimers was noticed.
5. For chiral epoxide synthesis via chiral dihydroxylation,
see: Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48,
10515, and references cited therein.
6. For chiral epoxides via asymmetric reduction of ketones,
see: (a) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1993,
34, 5227; (b) Ramachandran, P. V.; Gong, B.; Brown, H.
C. J. Org. Chem. 1995, 60, 41; (c) Kitamura, M.;
Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
2931, and references cited therein.
7. For the microwave-assisted ammonolysis/aminolysis, see:
(a) Sabitha, G.; Subba Reddy, B. V.; Abraham, S.; Yadav,
J. S. Green Chem. 1999, 251; (b) Favretto, L.; Nugent, W.
A.; Licini, G. Tetrahedron Lett. 2002, 43, 2581; (c)
Wellner, E.; Sandin, H.; Swanstein, M.-L. Synlett 2004,
1817; (d) Sello, G.; Orsini, F.; Bernasconi, S.; Di Gennaro,
P. Tetrahedron: Asymmetry 2006, 17, 372.
OH
NH
2
sat. NH
in EtOH
O
3
H N
2
HO
dimers
[C]=40 mM
MsOH (5eq) added: product ratio
No MsOH added: product ratio
=
=
100
100
:
:
20
30
:
:
5
10
24. Additional two substrates a and b were subjected to
ammonolysis under the optimum condition, to give the
expected aminoalcohols in almost quantitative yields.
Me
Me
Me
Me
O
O
Me
a
b
8. Overman, L. E.; Flippin, L. A. Tetrahedron Lett. 1981, 22,
195.
9. Carre, M. C.; Houmounou, J. P.; Caubere, P. Tetrahedron
Lett. 1985, 26, 3107.
10. Yamada, J.; Yumoto, M.; Yamamoto, Y. Tetrahedron
Lett. 1989, 30, 4255.
11. Fiorenza, M.; Ricci, A.; Taddei, M.; Tassi, D. Synthesis
1983, 640.
12. Papini, A.; Ricci, A.; Taddei, M. J. Chem. Soc., Perkin
Trans. 1 1984, 2261.
13. Chini, M.; Crotti, P.; Macchia, F. Tetrahedron Lett. 1990,
31, 4661.
14. Chini, M.; Crotti, P.; Favero, L.; Macchia, F.; Pineschi,
M. Tetrahedron Lett. 1994, 35, 433.
25. Two model substrates c and d were first used to demon-
strate that the identified optimum condition is effective for
the transformation of 5 into 7. Substrates c and d were
synthesized from the known crystalline dibenzoate, that is,
dibenzoate 15 reported in Ref. 17b, in 3 (1. BnBr/TBAI/
Ag2O/CH2Cl2/rt, 2. aq KOH/MeOH–THF/rt, 3. p-TsCl/
n-Bu2SnO/Et3N/CH2Cl2/rt26) and 4 (1. H2/Pd(OH)2 on C/
˚
EtOH/rt, 2. MeI/Ag2O/MS 4A/rt, 3. aq KOH/MeOH–
THF/rt, 4. p-TsCl/n-Bu2SnO/Et3N/CH2Cl2/rt26) steps,
respectively.
BnO
OBn
MeO
HO
OMe
HO
TsO
TsO
Me
O
O
15. (a) Posner, G. H.; Rogers, D. Z. J. Am. Chem. Soc. 1977,
99, 8208; (b) Posner, G. H. Angew. Chem., Int. Ed. Engl.
1978, 17, 487.
c
d
26. Martinelli, M. J.; Vaidyanathan, R.; Pawlak, J. M.;
Nayyar, N. K.; Dhokte, U. P.; Doecke, C. W.; Zollars,
L. M. H.; Moher, E. D.; Van Khau, V.; Kosˇmrlj, B. J. Am.
Chem. Soc. 2002, 124, 3578.
27. This ammonolysis was conducted also at 70 °C for 10 h at
[C] = 20 mM in a 9.4-mg scale, to furnish the desired
product over 95% yield. The purity of the crude product
thus obtained was found to be as good as that of the
product obtained at room temperature (1H NMR analysis
of the crude product and its O,N-diacetate).
28. A 10-mL vial equipped with a magnetic stirbar and a
rubber septum fitted with an ammonia inlet needle and a
pressure equilibrating needle was charged with 5 (18.8 mg,
0.0232 mmol, 1.0 equiv) and EtOH (0.58 mL). Ammonia
gas was bubbled through the needle for 5 min, and then
16. (a) Zheng, W.; Seletsky, B. M.; Palme, M. H.; Lydon, P.
J.; Singer, L. A.; Chase, C. E.; Lemelin, C. A.; Shen, Y.;
Davis, H.; Tremblay, L.; Towle, M. J.; Salvato, K. A.;
Wels, B. F.; Aalfs, K. K.; Kishi, Y.; Littlefield, B. A.; Yu,
M. J. Bioorg. Med. Chem. Lett. 2004, 14, 5551; (b)
Littlefield, B. A.; Palme, M. H.; Seletsky, B. M.; Towle,
M. J.; Yu, M. J.; Zheng, W. U.S. Patent 6,214,865,
6,365,759, and International Patent WO99/65894.
17. For the synthetic work on the marine natural product
halichondrins from this laboratory, see: (a) Aicher, T. D.;
Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.;
Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.;
Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162; (b) Choi,
H.-w.; Demeke, D.; Kang, F.-A.; Kishi, Y.; Nakajima, K.;

Y. Kaburagi, Y. Kishi / Tetrahedron Letters 48 (2007) 8967–8971
8971
MsOH (10 vol % in EtOH, 75 lL, 0.116 mmol, 5 equiv)
was added. The vial was tightly capped. The mixture was
stirred at room temperature for 3.5 days. All volatiles were
removed under reduced pressure. To the residue was
added EtOAc, and the suspension was passed through a
pad of Celite. The filtrate was concentrated and dried
under vacuum to give 7 (17.8 mg, 93%) as a colorless
amorphous solid.