Direct C-allylation of aryl-alkyl/glycosyl carbinols: Facile synthesis of C-linked carbo-β2-/γ2-/δ2- amino acids

Article abstract of DOI:10.1021/jo052418r

A facile ZrCl₄-catalyzed direct allylation of the p-methoxyphenyl-alkyl/glycosyl carbinols at room temperature, and the conversion of the derived aryl-glycosyl-alkenes into hitherto unknown C-linked carbo-β²-/γ²-/δ²-amino acids is reported.

Full text of DOI:10.1021/jo052418r

CHART 1. General Reaction of Allylationa
Direct C-Allylation of Aryl-Alkyl/Glycosyl
Carbinols: Facile Synthesis of C-linked
Carbo-â2-/γ2-/δ2-Amino Acids†
Gangavaram V. M. Sharma,* Katta Laxmi Reddy,
P. Sree Lakshmi, R. Ravi, and Ajit C. Kunwar
a Reagents and conditions: (a) Mg, 4-bromoanisole, dry THF, reflux;
(b) allyltrimethylsilane (2 equiv), ZrCl4 (2 mol %), CH3CN, rt; (c) several
reagents.
D-211, DiscoVery Laboratory, Organic Chemistry
DiVision III, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
the course of our studies, we felt the imminent need to develop
flexible protocols for the preparation of a variety of Caa
monomers to further expand the horizon of unnatural peptides.
Herein, we describe a facile ZrCl4-catalyzed direct allylation
of the p-methoxyphenyl-alkyl/glycosyl carbinols at room tem-
perature, and the conversion of the derived p-methoxyphenyl-
glycosyl-alkenes into hitherto unknown C-linked carbo-â2-/γ2-/
δ2-amino acids (Caas), wherein, the p-methoxyphenyl and allyl
groups are envisaged as masked acid and amine functionalities,
respectively.
esmVee@iict.res.in;sharmagVm@yahoo.com
ReceiVed NoVember 23, 2005
The nucleophilic substitution of the hydroxy group in
carbinols with allylsilane in the presence of a catalytic amount
of acid under nearly neutral conditions would be a very fasci-
nating and ideal C-C bond-forming protocol to generate aryl-
alkyl/glycosyl olefins. Earlier reports on such transformations
A facile ZrCl4-catalyzed direct allylation of the p-meth-
oxyphenyl-alkyl/glycosyl carbinols at room temperature, and
the conversion of the derived aryl-glycosyl-alkenes into
hitherto unknown C-linked carbo-â2-/γ2-/δ2-amino acids is
reported.
5d
used BF3/CH2Cl2,5a B(C6F5)3,5b InBr3,5c or HN(SO2F)2 for
allylation of acetates with allyltrimethylsilane, while the InCl3-
mediated6 allylation of carbinols in dichloroethane was achieved
on limited substrates by reacting at 80 °C for 3 h. In view of
the fact that the success of the allylation process of carbinols
depends on the delicate balance of cation stability and acidity
of the Lewis acid, we chose a p-methoxyphenyl group as an
Introduction
7
aryl variant and ZrCl4 as a new catalyst for the allylation of
Peptides play an important role in many physiological
processes,1 hence, their de novo design has emerged as a
valuable tool to critically evaluate the rules of folding and
structural stabilization. A variety of secondary structures have
been found in â- as well as in homologous γ- and δ-peptides
derived from unnatural amino acids,2 providing a promising
class of peptidomimetics. The presence of additional C atoms
in â-amino acids2 increases the structural diversity, which raises
exponentially in γ- and δ-amino acids. Though â-amino acids
are ubiquitous in nature, â-, γ-, and δ-peptides are not. In recent
years, we have developed3 C-linked carbo-â-amino acids (â3-
Caas) as a new class of â-amino acids and utilized them to
prepare â-peptides4 with helical diversity and robustness. During
carbinols (Chart 1).
Results and Discussions
According to the above strategy, 1 was treated with allylsilane
in the presence of ZrCl4 (2 mol %) in CH3CN at room
temperature to afford 1a (98%) in 15 min (Table 1). On the
contrary, when 2 was allowed to react with allylsilane-ZrCl4,
no product formation was observed even after 24 h, thus
asserting a mismatch between the phenyl group and the acid
catalyst for carbocation formation. However, carbinol 3,8 with
a p-methoxyphenyl group, reacted smoothly with allylsilane and
furnished 3a in 96% yield in 25 min. To investigate the scope
and limitations of the present protocol of direct allylation of
† IICT Communication No. 050803.
(1) Nielsen, P. E. Pseudo-peptides in Drug DiscoVery; Wiley-VCH
(5) (a) Cella, J. A. J. Org. Chem. 1998, 47, 2125-2134. (b) Rubin, M.;
Gevorgyan, V. Org. Lett. 2001, 3, 2705-2707. (c) Kim, S. H.; Shin, C.;
Pae, A. N.; Koh, H. Y.; Chang, M. H.; Chung, B. Y.; Cho, Y. S. Synthesis
2004, 1581-1584. (d) Kaur, G.; Kaushik, M.; Trehan, S. Tetrahedron Lett.
1997, 38, 2521-2524.
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(2) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219-3232. (b) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem.
BiodiVersity 2004, 1, 1111-1239.
(3) Sharma, G. V. M.; Goverdhan Reddy, V.; Subhash Chander, A.;
Ravinder Reddy, K. Tetrahedron: Asymmetry 2002, 13, 21-24.
(4) (a) Sharma, G. V. M.; Ravinder Reddy, K.; Radha Krishna, P.; Ravi
Sankar, A.; Narsimulu, K.; Kiran Kumar, S.; Jayaprakash, P.; Jagannadh,
B.; Kunwar, A. C. J. Am. Chem. Soc. 2003, 125, 13670-13671. (b) Sharma,
G. V. M.; Ravinder Reddy, K.; Radha Krishna, P.; Ravi Sankar, A.;
Jayaprakash, P.; Jagannadh, B.; Kunwar, A. C. Angew. Chem. 2004, 116,
4051-4055; Angew. Chem., Int. Ed. 2004, 43, 3961-3965. (c) Sharma, G.
V. M.; Nagender, P.; Radha Krishna, P.; Jayaprakash, P.; Ramakrishna, K.
V. S.; Kunwar, A. C. Angew. Chem., Int. Ed. 2005, 44, 6028-6032.
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Ed. 2004, 43, 1414-1416. (b) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A.
Synlett 2005, 1737-1739.
(7) (a) Sharma, G. V. M.; Reddy, Ch. G.; Krishna, P. R. J. Org. Chem.
2003, 68, 4574-4575. (b) Sharma, G. V. M.; Goverdhan Reddy, Ch.;
Radhakrishna, P. Synlett 2003, 1728-1730. (c) Sharma, G. V. M.; Srinivas,
B.; Radhakrishna, P. Tetrahedron Lett. 2003, 44, 4689-4691. (d) Sharma,
G. V. M.; Janardhan Reddy, J.; Sree Lakshmi, P.; Radhakrishna, P.
Tetrahedron Lett. 2004, 45, 6963-6965.
(8) For details, please see Supporting Information.
10.1021/jo052418r CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/12/2006
J. Org. Chem. 2006, 71, 3967-3969
3967

SCHEME 1. Conversion of 8a to Lactonea
TABLE 1. ZrCl4-Catalyzed Allylation of Carbinols with
Allyltrimethylsilane
a Reagents and conditions: (a) O3, CH2Cl2, rt; (b) NaClO2, H2O2,
t-BuOH/H2O (7:3), 0 °C-rt; (c) 10% Pd-C, EtOAc, rt.
a No product formation was observed even after 24 h.
FIGURE 1. (A) Characteristic NOE of 15 and (B) energy minimization
structure of 15.
1
TABLE 2. ZrCl4-Catalyzed Allylation of p-Methoxyphenyl-glycosyl
Carbinols with Allyltrimethylsilane
chemical shift patterns in their respective H NMR spectra.
Further studies on the allylation of glycosyl carbinols 11 and
12, prepared from a known aldehyde9b derived from D-ribose,
resulted in the exclusive formation of olefins 11a and 12a, re-
spectively. Thus, the allylation method is amenable to p-meth-
oxyphenyl-glycosyl carbinols with different glycosyl side chains.
To ascertain the absolute stereochemistry at the new stereo-
center in the olefins 7a, 9a, 11a, and 12a, a fused lactone 15
was prepared from 8a. Carbinols 8 and 10,8 on reaction with
allylsilane-ZrCl4, furnished 8a and 10a (Table 2), respectively,
as exclusive products. Ozonolysis of 8a (Scheme 1) gave the
aldehyde 13 (92%), which on further oxidation afforded the acid
14 (93%). Compound 14, on reaction with Pd-C (10%) in
EtOAc, underwent debenzylation along with concomitant cy-
clization to give the lactone 15 (92%). The structure and the
stereochemistry at the C5 stereocenter was unambiguously
assigned through NMR studies.
The conformational analysis of 15 (Figure 1) showed NOEs
between H3/H5 and H6/H1, reflecting the presence of H-3 and
H-5, similarly, H-6 and H-1 on the same face. A coupling
constant of 13.7 Hz for J5,6 suggests a dihedral angle value of
about 180° for H6-C6-C5-H5. Other couplings, namely, J5,6′
) 5.0 Hz, J4,5 ) 1.7 Hz, and J3,4 ) 2.9 Hz, supported the
proposed structure. These data unequivocally proves that the
configuration at C5 in 8a is R. The structure was further
supported by the energy minimization calculations (Figure 1)
obtained from the SYBYL 6.8 program.10
carbinols, 4-6 were prepared and subjected to a reaction with
allylsilane-ZrCl4 to furnish the respective olefins 4a-6a (Table
1) in more than 95% yields within 20-30 min at room
temperature.
Our recent interest on the synthesis of Caa containing robust
peptide helices4 prompted us to study the direct allylation of
p-methoxyphenyl-glycosyl carbinols8 as a novel stereoselective
variant to generate new Caas. Thus, the carbinols 7 and 9 (Table
2), obtained from the known aldehyde9a by a Grignard reaction,
were treated with allylsilane-ZrCl4. They underwent facile
allylation and gave the olefins 7a and 9a, respectively, as
exclusive products having R′ and S′ configurations at the C-5
stereocenter. Olefins 7a and 9a displayed distinctly different
Having successfully developed a protocol for the direct
allylation of carbinols using ZrCl4 as a Lewis acid, our next
goal was to convert these systems into Caas with diversity.
(9) (a) Inch, T. D. Carbohydrate Res. 1967, 5, 45-52. (b) Radha Krishna,
P.; Ramana Reddy, V. V.; Sharma, G. V. M. Synlett 2003, 1619-1622.
(10) (a) SYBYL Force Field Manual, version 6.6, 1999; pp 217-229.
(b) Evans, J. N. S. Biomolecular NMR Spectrocopy, Oxford University
Press: Oxford, 1995.
3968 J. Org. Chem., Vol. 71, No. 10, 2006

SCHEME 2. Conversion of 7a to Amino Acidsa
a Reagents and conditions: (a) O3, CH2Cl2, rt; (b) NaClO2, H2O2, t-BuOH/H2O (7:3), 0 °C-rt; (c) ClCOOEt, NaN3, acetone, t-BuOH, toluene, 0 °C-
reflux; (d) RuCl3, NaIO4, CH3CN/H2O/CCl4 (1:1:2), 25 °C; (e) CH2N2, MeOH, rt; (f) BnNH2, anhyd MgSO4, CH2Cl2, NaBH4, MeOH, 0 °C-rt; (g) 10%
Pd-C, EtOAc, rt; (h) (Boc)2O, THF, Et3N, 0 °C-rt; (i) BH3-DMS, dry THF, rt; (j) TsCl, Et3N, CH2Cl2, 0 °C-rt; (k) NaN3, DMF, 65 °C.
Accordingly, olefin 7a (Scheme 2) was subjected to ozonolysis
to give 16, which on oxidation afforded the corresponding acid
17 (95%). Acid 17 on reaction with ClCO2Et-NaN3 underwent
a facile Curtius rearrangement to install amine functionality and
furnished 18 (63%). Similarly, 16 on reductive amination gave
21, which on debenzylation and subsequent reaction with
(Boc)2O afforded 23 (92%). Likewise, 7a on reaction with
BH3-DMS gave alcohol 26 (73%), which on treatment with
TsCl afforded 27. Displacement of the tosyl group in 27 with
NaN3 and subsequent hydrogenation to amine 29 and protection
afforded amide 30 (89%).
Thus, after the successful conversion of the olefin into amine
functionality, the amides 18, 23, and 30 (Scheme 2) were
subjected to aromatic ring oxidative cleavage11 with RuCl3-
NaIO4 at room temperature to give the corresponding acids 19,
24, and 31, respectively. Finally, the acids were allowed to react
with diazomethane to afford a novel class of the â2-, γ2-, and
δ2-Caas 20, 25, and 32, respectively.
carbocation-forming capability of the p-methoxyphenyl group
is efficiently exploited to conduct the direct allylation at room
temperature in short reaction times. The scope of the reaction
is not restricted to the p-methoxyphenyl-alkyl carbinols and has
been extended to other substrates. Further, it is demonstrated
that the p-methoxyphenyl and olefinic groups act as masked
acid and amine functionalities and have been effectively utilized
to result in a variety of C-linked carbo-â2, γ2, and δ2 classes of
unnatural amino acids of significant current interest. The use
of such monomers not only creates an opportunity for the design
diversity but also the structural diversity, leading to the
development of peptidomimetics and peptide-based drugs.
Acknowledgment. K.L.R and R.R. are thankful to UGC,
and P.S.L. is thankful to CSIR, New Delhi, for financial support.
Supporting Information Available: Spectral data for all
compounds along with experimental procedure. This material is
available free of charge via the Internet at http://pubs.acs.org.
In summary, we have demonstrated a facile direct substitution
of carbinols with an allyl group, thus converting a C-O bond
into a C-C bond using ZrCl4 (2 mol %) as a Lewis acid. A
delicate balance between the Lewis acidity of ZrCl4 and the
JO052418R
(11) Boger, D. L.; Lee, R. J.; Bounaud, P.-Y.; Meier, P. J. Org. Chem.
2000, 65, 6770-6772.
J. Org. Chem, Vol. 71, No. 10, 2006 3969