Stereocontrolled formation of amino acids and N-heterocycles bearing a quaternary chiral carbon

Article abstract of DOI:10.1021/ol053061g

Stereocontrolled formation of tertiary or quaternary chiral carbons bearing nitrogen was achieved using the [3,3]-sigmatropic rearrangement of cyanate to isocyanate as a key element. A short and highly selective sequence of reactions, starting from p-ment

Full text of DOI:10.1021/ol053061g

ORGANIC
LETTERS
2006
Vol. 8, No. 5
939-942
Stereocontrolled Formation of Amino
Acids and N-Heterocycles Bearing a
Quaternary Chiral Carbon
Ste´phanie Roy and Claude Spino*
De´partement de Chimie, UniVersite´ de Sherbrooke, Sherbrooke, QC, Canada J1K 2R1
claude.spino@usherbrooke.ca
Received December 18, 2005
ABSTRACT
Stereocontrolled formation of tertiary or quaternary chiral carbons bearing nitrogen was achieved using the [3,3]-sigmatropic rearrangement
of cyanate to isocyanate as a key element. A short and highly selective sequence of reactions, starting from p-menthane-3-carboxaldehyde,
was developed leading to
r,r-dialkylated r-amino acids or N-heterocycles, depending on the method of cleavage of the auxiliary.
Quaternary carbons bearing a nitrogen atom are fairly
ubiquitous in nature, being found in many natural alkaloids
such as daphniphylline and (-)-adaline (Figure 1).1 In
The stereoselective preparation of quaternary carbons
bearing nitrogen is a particularly difficult task.5,6 We recently
published6 a stereodivergent approach to R,R-dialkylated
amino acids that takes advantage of two stereospecific events,
namely, the SN2′ displacement of allylic esters by cuprates
and the Curtius rearrangement, using p-menthane-3-carbox-
aldehyde 17 as a recyclable chiral auxiliary. The linear
(1) For selected books and reviews, see: (a) Ohfune, Y.; Shinada, T.
Eur. J. Org. Chem. 2005, 5127-5143 (b) Hesse, M. In The Alkaloids,
Nature’s Curse or Blessing? Wiley-VCH: Zu¨rich, 2002. (c) Cordell, G. A.
In The Alkaloids: Chemistry and Biology; Elsevier: San Diego, 2003; Vol.
60. (d) Ramon, D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149-183. (e)
Kobayashi, J.; Morita, H. Alkaloids 2003, 60, 165-205. (f) Yamamura, S.
In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1986; Vol.
29. (g) Moldvai, I.; Temesvari-Major, E.; Incze, M.; Doernyei, G.;
Szentirmay, E.; Szantay, C. HelV. Chim. Acta 2005, 88, 1344-1356. (h)
Reynolds, T. Phytochemistry 2005, 66, 1399-1406.
(2) (a) Hsieh, K. H.; Marsall, G. R. J. Med. Chem. 1986, 29, 1968-
1971. (b) Samanen, J.; Narindray, D.; Adams, Jr., W.; Cash, T.; Yellin, T.;
Regoli, D. J. Med. Chem. 1988, 31, 510-516. (c) Formaggio, F.; Pantano,
M.; Crisma, M.; Toniolo, C.; Boesten, W. H. J.; Schoemaker, H. E.;
Kamphuis, J.; Becker, E. L. Bioorg. Med. Chem. Lett. 1993, 3, 953-956.
(d) Bellier, B.; McCort-Tranchepain, I.; Ducos, B.; Danascimento, S.;
Meudal, H.; Noble, F.; Garbay, C.; Roques, B. P. J. Med. Chem. 1997, 40,
3947-3956.
(3) (a) Karle, I.; Kaul, R.; Roa, R. B.; Raghothama, S.; Balaram, P. J.
Am. Chem. Soc. 1997, 119, 12048-12054. (b) Karle, I.; Roa, R. B.; Prasad,
S.; Kaul, R.; Balaram, P. J. Am. Chem. Soc. 1994, 116, 10355-10361. (c)
Toniolo, C.; Crisma, M.; Formaggio, F.; Valle, G.; Cavicchioni, G.;
Pre´cigoux, G.; Aubry, A.; Kamphuis, J. Biopolymers 1993, 33, 1061-1072.
(d) Hodgkin, E. E.; Clark, J. D.; Miller, K. R.; Marshall, G. R. Biopolymers
1990, 30, 533-546.
Figure 1. Natural products containing a quaternary chiral carbon
bearing nitrogen.
addition, R,R-dialkylated amino acids such as methylphen-
ylalanine are useful molecular building blocks for the
synthesis of peptides with specific properties.2 Such peptides
possessing constrained conformations due to the additional
substituent may change their secondary or tertiary structure.3
In addition, some R,R-dialkylated amino acids are powerful
enzyme inhibitors.4
10.1021/ol053061g CCC: $33.50
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Published on Web 02/09/2006

sequence included seven chemical steps, and we felt it could
be improved. We now disclose a shorter sequence of
reactions that starts with p-menthane-3-carboxaldehyde 1 and
generates, in five steps, amino acids or N-heterocycles,
depending on the method of cleavage, bearing a tertiary or
quaternary chiral carbon.
R2 * H). Contrary to azides, cyanates rearrange irreversibly
to the corresponding isocyanates because of the strength of
the carbonyl double bond. In addition, unlike the azide,
making the cyanate does not require displacing the stereo-
chemically pure alcohol (cf. alcohols 8), thus eliminating a
step that can potentially scramble stereochemistry.
The strategy is based on the stereospecific [3,3]-sigma-
tropic rearrangement of allylic cyanates 5 to allylic isocy-
anates 6 (Scheme 1, eq 2).8,9 In an earlier communication,
The sequence starts with the stereoselective preparation
of allylic alcohols 8 using either a trimethylaluminum-
catalyzed11 addition of vinyllithium (method A) or the direct
addition of vinylalanes12 (method B) to p-menthane-3-
carboxaldehyde 4 (Table 1). Either of these methods proceeds
Scheme 1. Stereocontrolled Formation of the C-N Bond
Table 1. Stereoselective Addition of Vinylmetals to 4
entry
R1
R2
product
yield of 8 (%)a
ratio 8:9b
1
2
3
4
5
6
H
H
H
Me
Me
Me
n-Pr
t-Bu
TMS
n-Pr
Ph
a
b
c
d
e
f
72
66
69
87
69
81
99:1
200:1
6:1c
30:1
49:1
24:1
we described the reversible [3,3]-sigmatropic rearrangement
of allylic azides 2 to give principally compound 3 thanks to
the steric bias provided by the menthyl fragment (Scheme
1, eq 1).10 However, substituents capable of conjugation such
as the phenyl group favored regioisomer 2, and in addition,
the method was not applicable to quaternary azides (3, R1,
Bn
a Isolated yield of pure 8. b Measured by GC against authentic material.
c Prepared without AlMe3 as additive.
(4) (a) Shirlin, D.; Gerhart, F.; Hornsperger, J. M.; Harmon, M.; Wagner,
I.; Jung, M. J. Med. Chem. 1988, 31, 30-36. (b) Zhelyaskov, D. K.; Levitt,
M.; Uddenfriend, S. Mol. Pharmacol. 1968, 4, 445-451. (c) Kiick, D. M.;
Cook, P. F. Biochemistry 1983, 22, 375-382.
with high stereoselectivity, providing allylic alcohols 8a-f
in good yields and excellent diastereomeric ratios. The
addition of vinyllithiums without AlMe3 as additive usually
proceeds with much lower selectivity (cf. entry 3). The
formation of the major alcohol 8 can be rationalized using
the Felkin-Anh model of addition to R-chiral carbonyls.13
The diastereomeric alcohols were easily separated by flash
chromatography in all cases to yield diastereomerically pure
allylic alcohols 8a-f.
Treatment of these allylic alcohols 8a-f with trichloro-
acetyl isocyanate in dichloromethane at 0 °C followed by
hydrolysis using potassium carbonate in an aqueous metha-
nolic solution provided the corresponding carbamates 11a-f
in excellent yields (88% to >99%).14 The carbamates 11a-f
were then treated with trifluoroacetic anhydride and triethyl-
amine in dichloromethane at 0 °C to generate the isocyanates
6a-f in only 10 min (Table 2), presumably via the
intermediacy of the corresponding cyanates 5a-f that
rearranged in situ. The lower-energy transition state 5A with
(5) For selected examples of the construction of chiral quaternary carbon
bearing nitrogen, see: (a) Shaw, S. A.; Alema´n, P.; Vedejs, E. J. Am. Chem.
Soc. 2003, 125, 13368-13369. (b) Garc´ıa Ruano, J. L; Alema´n, J.; Parra,
A. J. Am. Chem. Soc. 2005, 127, 13048-13054. (c) Ikeda, D.; Kawatsura,
M.; Uenishi, J. Tetrahedron Lett. 2005, 46, 6663-6666. (d) Carlier, P. R.;
Zhao, H.; DeGuzman, J.; Lam P. C.-H. J. Am. Chem. Soc. 2003, 125,
11482-11483. (e) Masaki,_ Y.; Arasaki, H.; Iwata, M. Chem. Lett. 2003,
32, 4-5. (f) Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem.
2001, 66, 2667-2673. R,R-Dialkylated-R-amino acids: (g) Cativiela, C.;
D.-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517-3599. (h)
Cativiela, C.; D.-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11,
645-732. (i) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2708-2748. (j) Wirth, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 225-227. (k) M.-Manas, M.; Trepat, E.; Sebastian, R. M.;
Vallribera, A. Tetrahedron: Asymmetry 1999, 10, 4211-4224. (l) Berkow-
itz, D. B.; McFadden, J. M.; Sloss, M. K. J. Org. Chem. 2000, 65, 2907-
2918.
(6) Spino, C.; Godbout, C. J. Am. Chem. Soc. 2003, 125, 12106-12107.
(7) (a) Spino, C.; Beaulieu, C. Angew. Chem., Int. Ed. 2000, 39, 1930-
1932. (b) Spino, C.; Godbout, C.; Beaulieu, C.; Harter, M.; Mwene-Mbeja,
T. M.; Boisvert, L. J. Am. Chem. Soc. 2004, 126, 13312-13319.
(8) (a) Christophersen, C.; Holm, A. Acta Chem. Scand. 1970, 24, 1512-
1526. (b) Banert, K.; Groth, S. Angew. Chem., Int. Ed. Engl. 1992, 31,
866-868.
(9) During the course of our work a conceptually similar approach was
divulged; see: (a) Ichikawa, Y.; Yamauchi, E.; Isobe, M. Biosci. Biotechnol.
Biochem. 2005, 69, 939-943. (b) Ichikawa, Y.; Ito, T.; Isobe, M. Chem.
Eur. J. 2005, 11, 1949-1957. (c) Matsukawa, Y.; Isobe, M.; Kotsuki, H;
Ichikawa Y. J. Org. Chem. 2005, 70, 5339-5341. (d) Nishiyama, T.; Isobe,
M.; Ichikawa, Y. Angew. Chem., Int. Ed. 2005, 44, 4372-4375.
(10) Gagnon, D.; Lauzon, S.; Godbout, C.; Spino, C. Org. Lett. 2005, 7,
4769-4771.
(11) Spino, C.; Granger, M.-C.; Tremblay, M.-C. Org. Lett. 2002, 4,
4735-4737.
(12) Negishi, E.-I.; Kondalov, D. Y. Chem. Soc. ReV. 1996, 417-426.
(13) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191-1223.
(14) Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4,
1109-1111.
940
Org. Lett., Vol. 8, No. 5, 2006

Table 2. [3,3]-Rearrangement of Allylic Cyanates from 11a-f
entry
R1
R2
product
yield (%)a
dr 6b
Figure 3. Possible cationic intermediates.
1
2
3
4
5
6
H
H
H
Me
Me
Me
n-Pr
t-Bu
TMS
n-Pr
Ph
a
b
c
d
e
f
96
93
93
99
80
99
>99:1
>99:1
>98:2c
>99:1
97:3
Isocyanates 6c-e were further reacted with 9-fluor-
enemethanol in the presence of a catalytic amount of
Ti(Ot-Bu)4 in benzene at 45 °C, providing Fmoc-protected
allylic amines 14c-e (Scheme 2). This catalyst is particularly
Bn
>99:1
a Isolated yield. b Measured by GC against authentic diastereomeric
mixtures. c Measured by HPLC.
Scheme 2. Synthesis of R-Amino Acids 15
minimum A1,3 strain leads to the major isocyanate with a
E-double bond (Figure 2). The higher-energy transition state
useful when dealing with sterically crowded isocyanates.16
Oxidative cleavage of the auxiliary afforded amino acids 15d
and 15e in good to excellent yields and without loss of
stereochemical purity. Ozonolysis of 14c followed by a
reductive workup provided Fmoc-protected 2-hydroxy-1-
(trimethylsilyl)ethylamine 16c in 60% yield. Compounds of
this type could be useful as chiral oxazolidinones. Although
15c could not be oxidized to the amino acid because of the
labile trimethylsilyl group, amino-alcohols substituted with
larger silyl groups can.17
Alternatively, isocyanate 6d was treated with vinylmag-
nesium bromide in THF at 0 °C to afford acrylamide 17
(Scheme 3). Cleavage of the auxiliary18 was then achieved
using the second generation Grubbs19 catalyst and afforded
pyrrolone 18 in 60% yield. Compounds of type 18 are highly
suited for the synthesis of more complex alkaloids possessing
a quaternary carbon bearing nitrogen. The alkene 19 is highly
Figure 2. Possible transition states for the rearrangement.
5B with maximum A1,3 strain would lead to an isocyanate
having a Z-double bond, which was never observed. Isocy-
anates can be purified on silica gel and proved to be stable
at room temperature for an extended period of time. Other
conditions of dehydration were tried but invariably led to
mixtures of products (see Supporting Information). Promi-
nent in those mixtures were products resulting from elimina-
tion reactions. Importantly, carbamates 11d-f possessing
trisubstituted double bonds gave excellent yields and dia-
stereomeric ratios of products having a chiral quaternary
isocyanate.
With this method, compounds such as 6c and 6e possess-
ing phenyl or silyl substituents, which were not previously
accessible,10 are now easily prepared in high stereoisomeric
purity. However, in the case of 6e, the diastereomeric excess
of the isocyanate was slighly lower than for the other
substrates. We believe that this could arise from a partial
nonstereoselective collapse of the stabilized cationic inter-
mediate 12 (Figure 3).15 The isolation of a 3% yield of the
regioisomer 13e together with small amounts of elimination
products is supportive of this hypothesis.
(15) Similar intermediates were previously suggested. See: Overman,
L. E. J. Am. Chem. Soc. 1976, 2901-2910.
(16) Spino, C.; Joly, M.-A.; Godbout, C.; Arbour, M. J. Org. Chem.
2005, 70, 6118-6121.
(17) Liu, G.; Sieburth, S. McN. Org. Lett. 2005, 7, 665-668.
(18) Boisvert, L.; Beaumier, F.; Spino, C. Can. J. Chem. 2006, in press.
(19) (a) Scholl, M.; Ding, S.; Lee C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953-956. Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999,
1, 1751-1753. Trnka, T. T.; Grubbs, R. B. Acc. Chem. Res. 2001, 34,
18-29.
Org. Lett., Vol. 8, No. 5, 2006
941

ogy gives rapid access to tertiary and quaternary centers in
good to excellent yields and diastereomeric excesses. We
have developed a short and highly selective synthesis of R,R-
dialkylated amino acids and N-heterocycles possessing a
chiral quaternary carbon atom, which are interresting building
blocks for the synthesis of more complex peptides and
alkaloids. This methodology is now being applied toward
the synthesis of complex natural alkaloids.
Scheme 3. Synthesis of Pyrrolone 18
Acknowledgment. The financial support of the Natural
Sciences and Engineering Council of Canada, AstraZeneca
(Canada) Inc., and the Universite´ de Sherbrooke is gratefully
acknowledged.
Supporting Information Available: Experimental pro-
cedures and H NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
volatile and can be easily removed from 18 under vacuum.
Chiral auxiliary 1 can be recovered simply by ozonolysis
of 9.
In summary, we have achieved the stereocontrolled
formation of chiral carbons bearing nitrogen. Our methodol-
1
OL053061G
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Org. Lett., Vol. 8, No. 5, 2006