Sterically biased 3,3-sigmatropic rearrangement of azides: Efficient preparation of nonracemic α-amino acids and heterocycles

Article abstract of DOI:10.1021/ol052034n

(Chemical Equation Presented) Homochiral α-amino acids, heterocycles, and carbocycles are efficiently constructed via a short sequence of reactions starting from the chiral auxiliary p-menthane-3-carboxaldehyde. The key feature of the sequence is a highly selective tandem Mitsunobu/3,3-sigmatropic rearrangement of hydrazoic acid that procures enantiomerically enriched allylic azides. The sequence is either terminated by oxidative cleavage to provide amino acids or by ring-closing metathesis to provide heterocycles or carbocycles bearing nitrogen.

Full text of DOI:10.1021/ol052034n

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4769-4771
Sterically Biased 3,3-Sigmatropic
Rearrangement of Azides: Efficient
Preparation of Nonracemic
Acids and Heterocycles
r-Amino
David Gagnon, Sophie Lauzon, Ce´drickx Godbout, and Claude Spino*
De´partement de Chimie, UniVersite´ de Sherbrooke, Sherbrooke, QC, Canada J1K 2R1
claude.spino@usherbrooke.ca
Received August 23, 2005
ABSTRACT
Homochiral
r-amino acids, heterocycles, and carbocycles are efficiently constructed via a short sequence of reactions starting from the chiral
auxiliary p-menthane-3-carboxaldehyde. The key feature of the sequence is a highly selective tandem Mitsunobu/3,3-sigmatropic rearrangement
of hydrazoic acid that procures enantiomerically enriched allylic azides. The sequence is either terminated by oxidative cleavage to provide
amino acids or by ring-closing metathesis to provide heterocycles or carbocycles bearing nitrogen.
p-Menthane-3-carboxaldehyde 1 is a useful chiral auxiliary
used for the construction of chiral R-alkylated carbonyl
compounds,1 including quaternary carbons.2 Effecting ste-
reoselective C-N bond formation from allylic alcohol 2 with
complete transposition of the double bond would usefully
expand our methodology to make nitrogen-containing prod-
ucts (Scheme 1).3
in 3 should be amenable to a ring-closing metathesis (RCM)
reaction such that carbo- or heterocycles could be formed
concomitantly (Scheme 1).
With regard to the C-N bond formation, allylic azides
are known to rearrange at temperatures ranging from below
0 to 100 °C.4 However, Trost and Pulley pointed out that
(2) (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. (c) Spino,
C.; Godbout, C. J. Am. Chem. Soc. 2003, 125, 12106-12107.
(3) For selected examples of C-N bond formation from allylic alcohols,
including those with double bond transposition, see: (a) Johannsen, M.;
Jorgensen, K. A. Chem. ReV. 1998, 98, 1689-1708. Imidate rearrange-
ment: (b) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125,
12412-12413. (c) Jiang, Y.; Longmire, J. M.; Zhang, X. Tetrahedron Lett.
1999, 40, 1449-1450. (d) Kang, J.; Yew, K. H.; Kim, T. H.; Choi, D. H.
Tetrahedron Lett. 2002, 43, 9509-9512. (e) Savage, I.; Thomas, E. J.;
Wilson, P. D. J. Chem. Soc., Perkin Trans. 1 1999, 3291-3303. (f) Metz,
P.; Mues, C.; Schoop, A. Tetrahedron 1992, 48, 1071-1080. (g) Overman,
L. E. Acc. Chem. Res. 1980, 13, 218-224. (h) Eguchi, T.; Koudate, T.;
Kakinuma, K. Tetrahedron 1993, 49, 4527-4540. (i) Chen, Y. K.; Lurain,
A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 12225-12231.
Phosphorimidate rearrangement: (j) Chen, B.; Mapp, A. K. J. Am. Chem.
Soc. 2005, 127, 6712-6718. (k) Lee, E. E.; Batey, R. A. Angew. Chem.,
Int. Ed. 2004, 43, 1865-1868. Pd-catalyzed nucleophilic displacement: (l)
Godleski, S. A. In Comprehensive Organic Synthesis, 1st ed.; Semmelhack,
M. F., Ed.; Pergamon Press: New York, 1991; Vol. 4, p 585. (m) Trost, B.
M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173-1192. (n) Trost, B. M.;
Van Vranken, D. L. Chem. ReV. 1996, 96, 395-422.
Scheme 1. Intended C-N bond formation from 1
Cleavage of the auxiliary on this system is usually done
by ozonolysis such that alcohol, aldehyde, or acid products
are obtained. We surmised that the transposed double bond
(1) For a review on chiral enolate alkylation equivalents, see: Spino, C.
Org. Proc. Prepr. Int. 2003, 35, 1-133.
10.1021/ol052034n CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/10/2005

the reaction has not been used very often because its synthetic
utility depends on the ability to control the thermodynamic
ratio of the two regioisomeric azides.5 This is infrequently
observed as it is normally substrate-dependent. Herein, we
report the successful execution of this transposition via a
Mitsunobu reaction of 2 with hydrazoic acid followed by a
sterically biased 3,3-sigmatropic rearrangement of the result-
ing allylic azide with extraordinarily good thermodynamic
selectivity. Amino acids6,7 or N-heterocycles8 are obtained
depending on the method of cleavage of the chiral auxiliary.
Metal-halogen exchange reaction of vinyl iodides 4a-d
or vinyl bromide 4e furnished the corresponding vinyllithi-
ums. Each was added separately and stereoselectively to 1
Table 1. Selectivities in the Mitsunobu/Azide Rearrangement
of 5
9
in the presence of AlMe3 to give 5a-e in 54-67% yields
and excellent isomeric ratios (Scheme 2). In all cases, the
diastereomeric alcohols were separable by silica gel column
chromatography.
a Isolated yield. b Measured by HPLC against authentic mixtures of 7
1
and 8. c Measured by H NMR.
Scheme 2. AlMe3-Promoted Vinyllithium Addition to 1
It is unusual for the Mitsunobu reaction of allylic alcohols
to give SN2′-displacement products. There are known cases
of SN2′ regioselectivity in that reaction, but in most of these
cases the alkene is electronically biased.11 Mulzer and co-
workers have performed Mitsunobu reactions of several
chiral allylic alcohols with phthalimide and reported that
regioselectivities depended on the substitution pattern of the
alkene (electronic and steric biases).12
Mitsunobu10 reaction of allylic alcohols 5a-e with hy-
drazoic acid gave exclusively azides 7a-e and no detectable
amount of SN2 product 9a-e (Table 1). The stereoselectivity
(7/8) of the reaction varied from very good (92:8) to excellent
(98:2).
Azides 7 are thus more likely formed via a normal SN2-
selective Mitsunobu reaction followed by a 3,3-sigmatropic
rearrangement of the resulting allylic azides. The rearrange-
ment, we believe, is under thermodynamic control, and the
steric bulk of the menthyl moiety destabilizes regioisomers
9 (or 10). Also, the stereochemical integrity of the initially
formed azides 9 is preserved during the concerted rearrange-
ment.13 We believe that the minor isomer 10 arises from
some SN2′ displacement by the azide. Preliminary evidence
for this mechanistic rational comes from the Mitsunobu
reactions of 5f (R ) Ph, entry 6), which gave predominantly
9f, presumably because of its increased stability due to
conjugation of the double bond with the phenyl ring.14 In
this case, the reaction was much less selective giving a 3:1
ratio of 9f/10f. More importantly, when the diastereomeric
alcohol 6f was submitted to the Mitsunobu conditions, the
ratio of 9f/10f was now reversed (1:3). The rearrangement
being concerted, this lower diastereoselectivity cannot be
explained by an SN2 displacement followed by rearrange-
ment. The identical but reversed ratios observed from 5f and
6f rules out an SN1 mechanism to explain the lower
(4) (a) Gagneux, A.; Winstein, S.; Young, W. G. J. Am. Chem. Soc.
1960, 82, 5956-5957. (b) Chida, N.; Tobe, T.; Murai, K.; Yamazaki, K.;
Ogawa, S. Heterocycles 1994, 38, 2383-2388. (c) Murahashi, S.-I.;
Taniguchi, Y.; Imada, Y.; Tanigawa, Y. J. Org. Chem. 1989, 54, 3292-
3303. (d) Panek, J. S.; Yang, M.; Muler, I. J. Org. Chem. 1992, 57, 4063-
4064. (e) Cardillo, G.; Fabbroni, S.; Gentilucci, L.; Perciaccante, R.;
Piccinelli, F.; Tolomelli, A. Org. Lett. 2005, 7, 533-536. (f) Capaccio, C.
A. I.; Varela, O. Tetrahedron: Asymmetry 2000, 11, 4945-4954. (g) Fava,
C.; Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron: Asymmetry 2001,
12, 273-2741. (h) Safi, M.; Fahrang, R.; Sinou, D. Tetrahedron Lett. 1990,
31, 527-530.
(5) Trost, B. M.; Pulley, S. R. Tetrahedron Lett. 1995, 36, 8737-8740.
(6) (a) Barret, G. C.; Elmore, D. T. Amino Acids and Peptides; University
Press: Cambridge, U.K., 1998. (b) Sardina, F. J.; Rapoport, H. Chem. ReV.
1996, 96, 1825-1872; (c) Williams, R. M. In Organic Chemistry Series
Volume 7: Synthesis of Optically ActiVe R-Amino-Acids; Baldwin, J. E.,
Magnus, P. D., Eds.; Pergamon Press: Oxford, 1989. (d) Duthaler, R. O.
Tetrahedron 1994, 50, 1539-1650. (e) Lescrinier, T.; Busson, R.; Rozenski,
J.; Janssen, G.; Aerschot, A.; Herdewijin, P. Tetrahedron 1996, 52, 6965-
6972.
(7) Amino acids are used as key structural units of chiral catalysts for
enantioselective synthesis. See: (a) List, B.; Pojarliev, P.; Biller, W. T.;
Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833. (b) Priem, G.; Pelotˆıer,
B.; Macdonald, S. J. F.; Anson, M. S.; Campbell, I. B. J. Org. Chem. 2003,
68, 3844-3848.
(8) (a) Hesse, M. In The Alkaloids, Nature’s Curse or Blessing?; Wiley-
VCH: Zu¨rich, 2002; 413 pp. (b) Yamamura, S.; Hirata, Y. In The Alkaloids;
Manske, R. H. F., Ed.; Academic Press: New York, 1975; Vol. 15, p 41.
(c) Yamamura, S. In The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1986; Vol, 29, p 265.
(11) (a) Charrette, A. B.; Coˆte´, B.; Monroc, S.; Prescott, S. J. Org. Chem.
1995, 60, 6888-6894. (b) Sobti, A.; Sulikowski, G. A. Tetrahedron Lett.
1994, 35, 3661-3664. (c) Ramesh, N. G.; Balasubramanian, K. K.
Tetrahedron 1995, 51, 255-272.
(12) Mulzer, J.; Funk, G. Synthesis 1995, 101-112.
(13) Evidence for a concerted mechanism for azide rearrangement was
provided by Padwa and co-workers. See: Padwa, A.; Sa`, M. M. Tetrahedron
Lett. 1997, 38, 5087-5090.
(14) Further discussion on the mechanism will be presented in the full
account of this work.
(9) Spino, C.; Granger, M.-C. Org. Lett. 2002, 4, 4735-4737.
(10) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L. Org.
React. 1992, 42, 335-656. (c) Hughes, D. L. Org. Prep. Proc. Int. 1996,
28, 127-164.
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Org. Lett., Vol. 7, No. 21, 2005

diastereoselectivity. Moreover, according to the work of
Mulzer, a Mitsunobu reaction on 5f without the possibility
of rearrangement should have given predominantly the SN2′
displacement product 7f because of the aromatic ring.12
Therefore, we propose that an increased amount of SN2′
displacement occurs in the case of 5f and 6f because of the
phenyl ring. The SN2′ is less selective and gives a lower
ratio of 7f and 8f, which then rearrange to 9f and 10f,
respectively, with preservation of their stereochemical in-
tegrity. This explains why 5f leads to a 3:1 ratio of 9f/10f
while 6f affords a 1:3 ratio of those same compounds.
The azides 7a-e were then reduced to the corresponding
amines 11a-e with lithium aluminum hydride or using
Staudinger’s reaction (Scheme 3). Protection as a 9-fluore-
Scheme 4. Synthesis of Heterocycles and Carbocycles
Scheme 3. Synthesis of R-Amino Acids 13a-d
was performed using the Grubbs or the Grubbs-Nolan
catalyst in refluxing dichloromethane (dichloroethane for
18).17 Gratifyingly, these RCM were highly efficient and gave
pyrrolidine (15c), piperidines (15a, 15d), or carbo- and
heterocycles bearing an exocyclic nitrogen (17, and 19).
Compound 15d was hydrogenated to give (+)-N-Boc-
coniine.18
In summary, we have developed a short and highly
selective synthesis of R-amino acids and heterocycles. The
excellent regioselectivity of the azide rearrangement and the
efficient cleavage of the chiral auxiliary by RCM is of note.
We are currently applying the methodology to the synthesis
of more complex alkaloid natural products.
nylmethyl (9-Fm) carbamate proceeded in excellent yield to
give 12a-d. Oxidative cleavage of the auxiliary in 12a,b,d
afforded the amino acids 13a,b,d in good to excellent yields.
In the case of N-protected tert-leucine 13c, we isolated the
sensitive R-amino aldehyde and then oxidized it with Jones’
reagent without racemization. This is significant because
R-amino aldehydes are difficult to obtain in the nonracemic
form. They are used as starting material for the synthesis of
complex amino alcohols.15 Enantiomeric ratios (HPLC) were
consistent with the % dr obtained for azides 7b-d, 13a
having suffered a slight loss of enantiomeric purity. The sign
of optical rotation of amino acids 13a-d confirmed their
absolute stereochemistries and thus our stereochemical
assignments of 7a-d.
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-
1
cedures, characterization data, and H NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL052034N
(16) Salvatore, R. N.; Nagle, A. S.; Schmidt, S. E.; Jung, K. W. Org.
Lett. 1999, 1, 1893-1896.
(17) (a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003. (b) Huang, J.; Stevens, E. D.; Nolan, S. P.;
Peterson, J. L. J. Am. Chem. Soc. 1999, 121, 2674-2678. (c) Scholl, M.;
Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40,
2247-2250.
(18) (a) Reding, M. T.; Buchwald, S. L. J. Org. Chem. 1998, 63, 6344-
6347. (b) Bois, F.; Gardette, D.; Gramain, J.-C. Tetrahedron Lett. 2000,
41, 8769-8772. (c) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett.
2000, 2, 155-158.
Alternatively, amines 11b-d were monoalkylated with
4-bromo-1-butene or allyl bromide (Scheme 4).16 Ring-
closing metathesis (RCM) cleavage of the chiral auxiliairy
(15) (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576. (b) Ager,
D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835-875.
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