A short and efficient synthesis of N-Cbz-galantinic acid under promoter control on enantioselective acyclic stereoselection based on chiral oxazaborolidinone-promoted aldol reactions

Article abstract of DOI:10.1016/S0040-4039(00)01124-2

An effective 'promoter control' on enantioselective acyclic stereoselection based on chiral oxazaborolidinone-promoted asymmetric aldol reactions has been found in the case of chiral N-protected α-amino aldehydes. An enantioselective synthesis of the title compound has been efficiently accomplished by using a sequence of the aldol reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01124-2

Tetrahedron Letters 41 (2000) 6599±6603
A short and ecient synthesis of N-Cbz-galantinic acid under
promoter control on enantioselective acyclic stereoselection
based on chiral oxazaborolidinone-promoted aldol reactions
Syun-ichi Kiyooka,* Kazuki Goh, Yuri Nakamura, Hironori Takesue
and Mostofa A. Hena
Department of Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
Received 1 May 2000; revised 27 June 2000; accepted 30 June 2000
Abstract
An e€ective `promoter control' on enantioselective acyclic stereoselection based on chiral oxazaboro-
lidinone-promoted asymmetric aldol reactions has been found in the case of chiral N-protected a-amino
aldehydes. An enantioselective synthesis of the title compound has been eciently accomplished by using a
sequence of the aldol reaction. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric aldol reaction; chiral borane; promoter control; a-amino aldehydes.
A large number of reactions with N-protected a-amino aldehydes as a chiral pool available for
natural product synthesis have received widespread attention in recent years.1 Most addition
reactions lead mainly to high diastereoselectivity through chelated and/or non-chelated transition
states, which are assisted by various types of Lewis acids.2 However, the subject dealt with in this
report is not the case. The chiral oxazaborolidinone-promoted asymmetric aldol reaction
developed by us was known to show excellent `promoter control' on enantioselective acyclic
stereoselection even in the case of a-chiral aldehydes, e.g. a-phenylpropanal, where the
stereochemistry of the newly-created stereocenter depends on only the stereochemistry of the
chiral borane used.3 If the promoter control is valid in the case of chiral N-protected a-amino
aldehydes, the aldol reaction might be potentially useful in the development of new ®elds of
application.
A non-proteinogenic a-amino acid, (^)-galantinic acid, as a constituent amino acid of the
peptide antibiotic galantin I, was selected as a suitable synthetic target in order to test whether the
chiral N-protected a-amino aldehydes are really appropriate for the asymmetric aldol reaction in
the sense of promoter control or not.4 The aldol strategy applied to an enantioselective synthesis
* Corresponding author. Fax: +81 (0) 88 844 8360; e-mail: kiyo@cc.kochi-u.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01124-2

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Scheme 1. Retrosynthesis of N-Cbz-galantinic acid
of N-Cbz-galantinic acid 2 is outlined in the retrosynthetic format of Scheme 1. It was planned
for the fundamental carbon±carbon bonds of the skeleton to be constructed by chiral
oxazaborolidinone-promoted asymmetric aldol reactions with the protected l-serinal 3 as the
starting aldehyde. Slant lines indicate the positions suitable for the two expected aldol reactions,
depicted in Scheme 1.
First we carried out a model reaction of N-Cbz-leucinal 4 with unsubstituted silyl nucleophile
55 in order to explore the level of `promoter control' in the chiral oxazaborolidinone-promoted
asymmetric aldol reaction with N-Cbz-a-amino aldehydes. The reaction smoothly proceeded to
give a mixture of diastereomer 66 without racemization of the starting aldehyde in the presence of
a stoichiometric amount of chiral boranes, (S)-7 and (R)-7. The results are summarized in Scheme
2. The reaction with (S)-7 resulted in high syn diastereoselectivity (13:1), while the reaction with
(R)-7 gave moderate anti diastereoselectivity (3:1). The most important feature of the above
results is that the promoter control could be surely observed even in the case of chiral aldehydes
having a nitrogen substituent. The di€erence in the level of the observed promoter control
depending on the stereochemistry of the chiral boranes used can be attributable to the di€erent
steric interactions between the existing a-stereocenter of the aldehyde and the stereocenter of the
chiral boranes.7 A matching case to the syn structure is presumably rationalized by using a model
of the transition state assembly; the si facial selectivity with (S)-7 leads to syn diastereoselectivity
without serious a€ection of the a-stereocenter of the aldehyde, as shown in Fig. 1.8
Scheme 2. Diastereoselectivity found in the chiral oxazaborolidinone-promoted asymmetric aldol reaction of N-Cbz-
leucinal 4 with unsubstituted silyl nucleophile 5

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Figure 1. Si facial selectivity with (S)-7 leads to syn diastereoselectivity (a matching case)
The above high syn preference allowed us to use the reaction in the presence of (S)-7 for the
®rst aldol reaction with aldehyde 3 toward the enantioselective synthesis of N-Cbz-galantinic acid
2. The protected serinal 3 was prepared as follows: Silyl protection of N-Cbz-serine methyl ester
was done with TBSOTf/2,6-lutidine/CH2Cl2 (89% yield) and the di-protected ester was directly
reduced with DIBAL-H/CH2Cl2 at ^78ꢀC to give the expected aldehyde 3 (80% yield) which is
prone to racemize9 so that the crude product was used immediately for the following reaction
(Scheme 3) without further puri®cation. The ®rst aldol reaction of 3 with silyl nucleophile 5 in the
presence of (S)-7 predominantly furnished the desired syn-aldol product (syn-8) in a ratio of 10:1,
which was puri®ed by ¯ash column chromatography (10% AcOEt in hexane).10 Further protec-
tion of syn-8 to the acetonide 9 was carried out with 2,2-dimethoxypropane/CSA followed by
reduction with DIBAL-H under the conditions (^78ꢀC, 2 h) to give the corresponding alcohol 10
in 94 yield. The second aldol reaction of aldehyde 11, which was obtained by Swern oxidation of
10 (88% yield), with 125 took place in nitroethane instead of dichloromethane11 in the presence of
Scheme 3. Enantioselective synthesis of N-Cbz-galantinic acid, based on the reiterative chiral oxazaborolidinone-pro-
moted aldol reaction

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(R)-7 to give the desired 1,3-anti diol essentially as a single isomer in 76% yield. This is an
excellent example of simple promoter control on the newly-created stereocenter because the
existing chiral centers of 11 are far (b and g) from the reaction site.12 Desulfurization with
n-Bu3SnH and AIBN quantitatively gave anti-13.10 After puri®cation by ¯ash column
chromatography (10% AcOEt in hexane), the protected groups of anti-13 were cleaved upon
treatment with 80% AcOH at room temperature for 2 days to give N-Cbz-galantinic acid 2 in
75% yield.10
Thus, the enantioselective synthesis of N-Cbz-galantinic acid 2 was accomplished in a very
short way according to a strategy characterized by the reiterative chiral oxazaborolidinone-
promoted aldol reactions under promoter control.
Acknowledgements
This work was supported by a Grant-in-Aid for Scienti®c Research (Grant No. 9554046 and
10640525) from the Ministry of Education, Science, Culture and Sports.
References
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Chem. 1994, 59, 5139±5140. (f) Mikami, K.; Kaneko, M.; Loh, T.-P.; Terada, M.; Nakai, T. Tetrahedron Lett.
1990, 31, 3909±3912. (g) Takemoto, Y.; Matsumoto, T.; Ito, Y.; Terashima, S. Tetrahedron Lett. 1990, 31, 217±
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4. (a) Sakai, N.; Ohfune, Y. Tetrahedron Lett. 1990, 31, 4151±4154. (b) Sakai, N.; Ohfune, Y. J. Am. Chem. Soc.
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5. The most reliable silyl nucleophile for the enantioselective incorporation of an acetate synthon in our aldol
reaction is 1-ethoxy-2,2-(ethylenedithio)-1-trimethylsiloxyethane 12 (Ref. 3b), but the silyl nucleophile did not
work in the reaction with N-Cbz-a-amino aldehydes presumably owing to the total steric hindrances caused from
the interaction of the nucleophile and the aldehyde.
6. The oxazolidinones, 14 and 15, were derived from syn-6 and anti-6, respectively, after reduction of the ester
function, TBS protection, followed by cyclization, see: (a) Kiyooka, S.-i.; Suzuki, K.; Shirouchi, M.; Kaneko, Y.;
Tanimori, S. Tetrahedron Lett. 1993, 34, 5729±5732. (b) Ref. 4a.
7. The reaction of N-Cbz-leucinal 4 with silyl nucleophile 5 in the presence of BF3 resulted in a slight excess of the
syn isomer so that the level of `substrate control' is not high in this system.
8. Kiyooka, S.-i.; Hena, M. A. J. Org. Chem. 1999, 64, 5511±5523.

6603
9. Kang, M.; Park, J.; Konradi, A. W.; Pedersen, S. F. J. Org. Chem. 1996, 61, 5528±5531.
24
10. Selected physical data: compound syn-8: ‰ꢀŠ ^46.7 (c 0.30, CHCl3); IR (neat) 3437, 1723 cm^1; 1H NMR (CDCl3,
D
400 MHz): ꢁ (ppm) 7.09±7.40 (m, 10H), 5.40 (d, J=9.3 Hz, 1H), 5.15 (s, 2H), 4.56 (brs, 1H), 3.86 (d, J=4.2 Hz,
2H), 3.78 (dt, J=3.9, 4.0 Hz, 1H), 3.48 (d, J=2.0 Hz, 1H), 2.80 (dd, J=8.8, 16.6 Hz, 1H), 2.78 (dd, J=4.4, 16.3
Hz, 1H), 0.89 (s, 9H), 0.07 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 100 MHz): ꢁ (ppm) 170.6, 156.4, 150.4, 136.3,
24
D
129.4, 128.5, 128.2, 128.1, 125.9, 121.5, 68.6, 66.9, 65.0, 54.2, 38.8, 25.8, 18.1, ^5.6. Compound anti±13: ‰ꢀŠ +16.7
1
(c 0.60, CHCl3); IR (neat) 3449, 1731, 1707 cm^1; H NMR (CDCl3, 400 MHz), which showed a mixture of the
rotamers related to the ring at room temperature so that the following data were measured at 50ꢀC with D2O: ꢁ
(ppm) 7.18±7.28 (m, 5H), 5.05 (ABq, J=12.2 Hz, Áꢂ=24.2 Hz, 2H), 4.31 (dt, J=4.60, 7.81 Hz, 1H), 4.18 (m, 1H),
4.09 (q, J=7.1 Hz, 2H), 3.69 (m, 1H), 3.59 (dd, J=5.4, 9.3 Hz, 2H), 3.01 (d, J=4.2 Hz, 1H), 2.46 (dd, J=4.2, 16.1
Hz, 1H), 2.40 (dd, J=8.1, 16.1 Hz, 1H), 1.77 (m, 2H), 1.68 (m, 1H), 1.47 (brs, 3H), 1.42 (s, 3H), 1.19 (t, J=7.1 Hz,
22
D
1
3H), 0.79 (s, 9H), ^0.07 (s, 6H). Compound 2: ‰ꢀŠ +18.8 (c 0.16, CHCl3); IR (neat) 3412, 1716, 1697 cm^1; H
NMR (CDCl3, 400 MHz): ꢁ (ppm) 9.00 (brs, 1H), 7.32±7.39 (m, 5H), 5.38 (d, J=8.8 Hz, 1H), 5.12 (s, 2H), 4.55 (d,
J=11.7 Hz, 1H), 4.30 (brs, 1H), 3.66±3.87 (m, 4H), 2.87 (dd, J=5.4, 16.8 Hz, 1H), 2.55 (brs, 1H), 2.48 (dd, J=7.6,
17.1 Hz, 1H), 2.24 (brd, J=13.4 Hz, 1H), 1.74±1.82 (m, 1H); 13C NMR (CDCl3, 100 MHz): ꢁ (ppm) 170.9, 156.9,
136.0, 128.6, 128.3, 128.0, 75.6, 67.2, 63.3, 61.6, 54.6, 39.2, 34.3.
11. The condensation reaction of 11 and 12 proceeded in dichloromethane but the yield was low (20%) even in an
overnight reaction.
12. (a) Kiyooka, S.-i.; Maeda, H. Tetrahedron: Asymmetry 1997, 8, 3371±3374. (b) Kiyooka, S.-i.; Yamaguchi, T.;
Maeda, H.; Kira, H.; Hena, M. A.; Horiike, M. Tetrahedron Lett. 1997, 38, 3553±3556.