A versatile approach to N-Boc-statine and N-Boc-norstatine based on the reduction of 1-trialkylsilyl acetylenic ketones. Strong remote effect of the C(1) substituent on the stereoselectivity

Article abstract of DOI:10.1021/ol991098t

(formula presented) An efficient, unified approach to chiral, protected β-hydroxy γ-amino and α-hydroxy β-amino acids derived from Boc-L-leucine has been accomplished on the basis of the oxazaborolidine-controlled, stereoselective reduction of 1-trialkyls

Full text of DOI:10.1021/ol991098t

ORGANIC
LETTERS
1999
Vol. 1, No. 11
1831-1834
A Versatile Approach to N-Boc-statine
and N-Boc-norstatine Based on the
Reduction of 1-Trialkylsilyl Acetylenic
Ketones. Strong Remote Effect of the
C(1) Substituent on the Stereoselectivity
Carme Alemany, Jordi Bach,* Jaume Farra`s,* and Jordi Garcia*
Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona, 08028 Barcelona,
Catalonia, Spain
jgg@gsaa1.qo.ub.es
Received September 29, 1999
ABSTRACT
An efficient, unified approach to chiral, protected â-hydroxy γ-amino and r-hydroxy â-amino acids derived from Boc-L-leucine has been
accomplished on the basis of the oxazaborolidine-controlled, stereoselective reduction of 1-trialkylsilyl acetylenic ketones; stereoselectivity in
the reduction step has shown strong dependence upon C(1) substitution.
In recent years, syn-â-hydroxy γ-amino acids (1) have
received much attention since compounds as statine (1, R )
i-Bu) or cyclohexylstatine (1, R ) cyclohexylmethyl) became
key components of peptidomimetic protease inhibitors.1
Interestingly, the syn (threo) relative configuration of the
amino and hydroxy groups in 1, which mimics the tetrahedral
transition state for peptide bond hydrolysis, has been found
to be essential for their bioactivity. However, several
members of the corresponding diastereomeric anti (erythro)
series (2) are also of natural occurrence.2 Representative
exemples of those substructures can be found in the bioactive
depsipeptides didemnins A-C3 and hapalosin4 inter alia. On
the other hand, both syn- and anti-R-hydroxy â-amino acid
units (3 and 4) are constituents of many natural products
including paclitaxel (taxol), the immunological response
modifier bestatin, several biologically active metabolites
isolated from lithistid sponges,5 and a number of protease
inhibitors.6 Thus, for example, norstatine (3, R ) i-Bu) is
present in KRI-1230, a human renin inhibitor peptide,6b
whereas its enantiomer has been found in the natural peptide
amastatine.6c
(3) Hossain, H. B.; van der Helm, D.; Antel, J.; Sheldrick, G. M.; Sanduja,
S. K.; Weinheimer, A. J. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 4118;
Banaigs, B.; Jeanty, G.; Francisco, C.; Jouin, P.; Poncet, J.; Heitz, A.; Cave,
A.; Prome, J. C.; Wahl, M.; Lafargue, F. Tetrahedron 1989, 45, 181. For
nordidemnin B, a closely related natural product, see: Jouin, P.; Poncet,
J.; Dufour, M.; Pantaloni, A.; Castro, B. J. Org. Chem. 1989, 54, 617.
(4) Stratmann, K.; Burgoyne, D. L.; Moore, R. E.; Patterson, G. M. L.
J. Org. Chem. 1994, 59, 7219.
(5) Bewley, C. A.; Faulkner, D. J. Angew. Chem. Int. Ed. 1998, 37, 2163.
(6) (a) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 117. (b) Iizuka,
K.; Kamijo, T.; Kubota, T.; Akahane, K.; Umeyama, Y.; Kiso, Y. J. Med.
Chem. 1988, 31, 701. (c) Aoyagi, T.; Tobe, H.; Kojima, F.; Hamada, M.;
Takeuchi, T.; Umezawa J. Antiobiot. 1978, 31, 636.
(1) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(2) Aoyagi, Y.; Williams, R. M. Tetrahedron 1998, 54, 10419 and
references therein.
10.1021/ol991098t CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/24/1999

According to this strategy and bearing in mind that Boc-D-
leucine is also commercially available, a judicious combina-
tion of the starting leucine, the proper configuration of the
oxazaborolidine 7, and the final treatment (hydroboration/
oxidation against oxidative cleavage of the triple bond) could
ultimately allow us to obtain any of the eight possible
stereoisomers of 8 and 9. Herein, we wish to report our
findings in this connection.
A series of acetylenic ketones derived from Boc-L-leucine
were synthesized in 70-85% yield12 by reaction of Weinreb
amide 11 with different lithium acetylides,13 in order to
investigate their performance in oxazaborolidine-mediated
reductions (Scheme 2). Besides the aforementioned 1-tri-
The importance of amino acids 1-4 has fueled intensive
search for synthetic approaches, both in academic and
industrial laboratories, over the past decade.6,7 As the result
of this effort, there are now suitable methods for the
preparation of some of these compounds in reasonable yields
and stereoselectivities,8 but there is not a general and unified
route to all of them.
Scheme 2
In particular, several groups have reported the reduction
of suitable chiral R-amino ketones (such as 5) to obtain 1 or
2, with modest to good diastereoselectivities for a number
of amine protecting groups and achiral reducing agents,9 the
anti isomer generally prevailing.10 Taking advantage of our
previous experience in the reduction of acetylenic ketones
with BH3:SMe2 in the presence of oxazaborolidines (R)- or
(S)-7,11 we envisaged that a single ketone (either 6a or 6b)
derived from Boc-L-leucine could be a potentially versatile
gateway to N-Boc-statine (syn-8) and protected N-Boc-
norstatine (threo-9) as well as to their respective diastereo-
mers anti-8 and erythro-9, as outlined in Scheme 1.
alkylsilyl acetylenic ketones, a number of other 1-substituted-
1-alkyn-3-ones (6d-f) were included since the corresponding
propargylic alcohols are also amenable to transformation into
protected amino acids 9 by oxidative cleavage of the triple
bond.
Reductions of 6 were performed by slow addition (∼20
min) of the ketone (1 mmol) to a solution of BH3:SMe2 (1.2
mmol) in THF (2 mL) with 0.2-1.0 mmol of (R)- or (S)-7
under Ar at 0 °C. We were gratified to observe that, as shown
in Table 1, when R′ was a bulky, quaternary substituent
(ketones 6a-d), the oxazaborolidine 7 largely overcame the
intrinsic facial bias of the carbonyl group of 6; good to
Scheme 1
Table 1. Reduction of Ketones 6 with BH3:SMe2 in the
Presence of Oxazaborolidines 7
1832
Org. Lett., Vol. 1, No. 11, 1999

excellent diastereoselectivities were obtained even in the
mismatched cases. In sharp contrast, reduction of ketones
with lower steric requeriments on C(1), such as 6e-f, was
much more disappointing. For the sake of comparison,
reductions of 6 with NaBH4 (MeOH, 0 °C) were also
performed, leading to a mixture of diastereomeric amino
alcohols 10 (from 1.5:1 to 3.5:1 anti/syn ratio) in all cases.
According to the mechanism proposed by Corey et al.,14
this remarkable effect of the C(1) substituent, R′, on the
stereoselectivity was unexpected since it is distant from the
oxazaborolidine ring, avoiding any repulsive interaction with
the B-Me group; the stereoselectivity observed for analogous
oxazaborolidine-mediated reductions is usually explained in
this way. However, a closer analysis of molecular models
reveals that an “endo” arrangement, as in 12, may be dis-
favored, since the rigid linear nature of the triple bond puts
the SiR′3 and the R-phenyl group in close proximity; the
i-Bu group and the Boc-amino moiety (shown as a ball in
Figure 1) are then pushed near to the borane-oxazaboroli-
To assess this assumption, a series of ab initio 3-21G
calculations15 have been undertaken. In our preliminary
results for the BH3-6a-(R)-7 complex, the arrangement of
the most stable exo conformation (which would lead to syn-
10a) is ca. 1.85 kcal mol-1 more stable than the endo
conformation of lowest energy (Figure 2, 13a and 12a
Figure 1. Complexes of ketones 6a-c with (R)-7.
dine complex, destabilizing that arrangement. This repulsive
interaction becomes more important when R′ is bulky,
encouraging the pathway that proceeds via “exo” complex
13.
(7) For a review on syntheses of â-amino acids, see: Cole, D. C.
Tetrahedron 1994, 50, 9517. For a discussion of the synthetic approaches
to â-hydroxy γ-amino acids, see: Castejo´n, P.; Moyano, A.; Perica`s, M.
A.; Riera, A. Tetrahedron 1996, 52, 7063. See also: Pasto´, M.; Moyano,
A.; Perica`s, M. A.; Riera, A. Tetrahedron: Asymmetry 1996, 7, 243.
(8) For example, see: Merino, P.; Castillo, E.; Franco, S.; Mercha´n, F.
L.; Tejero, T. Tetrahedron 1998, 54, 12301. See also: Jost, S.; Gimbert,
Y.; Greene, A. E.; Fotiadu, F. J. J. Org. Chem. 1997, 62, 6672.
(9) For example, see: Harris, B. C.; Joullie´, M. M. Tetrahedron 1988,
44, 3489. Good results have been also reported with bulky N,N-dibenzyl-
protected compunds, but the deprotection step was troublesome: Reetz,
M. T.; Drewes, M. W.; Matthews, B. R.; Lennick, K. Chem. Commun.
1989, 1474. See also: Hoffman, R. V.; Tao, J. J. Org. Chem. 1997, 62,
2292 and references therein.
(10) For a review on the synthesis of diastereomeric amino alcohols,
see: Tramontini, M. Synthesis 1982, 605. See also ref 9.
(11) Bach, J.; Berenguer, R.; Garcia, J.; Loscertales, T.; Vilarrasa, J. J.
Org. Chem. 1996, 61, 9021. Bach, J.; Garcia, J. Tetrahedron Lett. 1998,
39, 6761. Bach, J.; Galobardes, M.; Garcia, J.; Romea, P.; Tey, C.; Urp´ı,
F.; Vilarrasa, J. Tetrahedron Lett. 1998, 39, 6765.
(12) Compound 6c was obtained in only 30% yield.
(13) Cupps, T. L.; Boutin, R. H.; Rapoport, H. J. Org. Chem. 1985, 50,
3972.
(14) For a review on oxazaborolidine-mediated reductions, see: Corey,
E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986. Remote repulsive
interactions with the B-alkyl group in the reduction of R,â-ynones have
been reported: Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem.
Soc. 1996, 118, 10938.
Figure 2. Ab initio 3-21G geometries for BH3-6a-(R)-7 com-
plexes.
respectively), in agreement with the experimental results.
Having in hand stereochemically enriched amino alcohols
10, we undertook their transformation into acids 8 and 9 (see
Scheme 3). Thus, hydroboration16 of syn-10a (or syn-10b)
with dicyclohexylborane followed by oxidative workup
afforded protected statine (syn-8). In a similar way, anti-8
was obtained from anti-10a or anti-10b.
On the other hand, treatment of amino alcohols 10 with
2,2-dimethoxypropane and a catalytic amount of PPTS
provided a mixture of oxazolidines 14 from which the minor
(15) All ab initio calculations were carried out using the GAUSSIAN-
94 (rev. E.1) series of programs (Gaussian, Inc., Pittsburgh, PA, 1995).
(16) Midland, M. M.; Lee, P. E. J. Org. Chem. 1981, 46, 3933.
Org. Lett., Vol. 1, No. 11, 1999
1833

In summary, we have demonstrated that all the stereo-
isomers of the 4-(N-tert-butoxycarbonylamino)-3-hydroxy-
6-methylheptanoic acid (8) as well as of the protected 3-(N-
tert-butoxycarbonylamino)-2-hydroxy-5-methylhexanoic acid
(9) can be efficiently prepared from the appropiate enanti-
omer of Boc-leucine with the aid of oxazaborolidines (R)-
or (S)-7. It is likely that this strategy can be applied to prepare
a variety of other protected â-hydroxy γ-amino and R-hy-
droxy â-amino acids. Work is in progress in this connection.
Scheme 3
Acknowledgment. Calculations described in this work
were performed on a HP-V2250 at the Centre de Supercom-
putacio´ de Catalunya. Thanks are due to the Universitat de
Barcelona for financial support of the calculations. We also
thank the DGICYT, Ministerio de Educacio´n y Cultura
(Grant PM95-0061), the Direccio´ General de Recerca,
Generalitat de Catalunya (1996SGR00102), for financial
support and Prof. J. Vilarrasa for reading the draft.
Supporting Information Available: General experimen-
tal procedures and spectroscopic data for compounds 6a, anti-
8, threo-9, anti-10a, and erythro-14a. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL991098T
(17) Samples of stereochemically pure alcohols 10 were available by
deprotection (aqueous MeOH, catalytic p-TsOH, rt) of pure oxazolidines
14.
(18) Carlsen, H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936.
stereoisomer could be removed17 by flash chromatography.
Finally, protected R-hydroxy â-amino acids 9 were readily
obtained by Ru-mediated oxidation18 of the triple bond.
1834
Org. Lett., Vol. 1, No. 11, 1999