Acyclic 1,4-stereocontrol via reductive 1,3-transpositions

Article abstract of DOI:10.1021/ol702921x

(Chemical Equation Presented) One-pot reduction/allylic diazene rearrangement of lactic acid- and mandelic acid-derived α,β- unsaturated tosyl hydrazones leads to 1,4-syn-or 1,4-anti-E-2-alkenyl arrays in high yield and diastereoselectivity. Either the syn or the anti diastereomer can be prepared by choosing the appropriate alkene stereoisomer of the hydrazone. The E-alkenes led to the 1,4-syn isomers, while the Z-alkenes led to the 1,4-anti isomers, both with ≥20:1 diastereoselectivity.

Full text of DOI:10.1021/ol702921x

ORGANIC
LETTERS
2008
Vol. 10, No. 2
357-359
Acyclic 1,4-Stereocontrol via Reductive
1,3-Transpositions
Wei Qi and Matthias C. McIntosh*
119 Chemistry Building, UniVersity of Arkansas, FayetteVille, Arkansas 72701
mcintosh@uark.edu
Received December 3, 2007
ABSTRACT
One-pot reduction/allylic diazene rearrangement of lactic acid- and mandelic acid-derived
r,â-unsaturated tosyl hydrazones leads to 1,4-syn-
or 1,4-anti-E-2-alkenyl arrays in high yield and diastereoselectivity. Either the syn or the anti diastereomer can be prepared by choosing the
appropriate alkene stereoisomer of the hydrazone. The E-alkenes led to the 1,4-syn isomers, while the Z-alkenes led to the 1,4-anti isomers,
both with
g20:1 diastereoselectivity.
The allylic diazene rearrangement (ADR) in its simplest form
is the retro ene reaction of 1-diazo-2-propene to afford
molecular nitrogen and propene (Scheme 1).1 The ADR is
ployed in reductive Mitsunobu reactions,3 reductive alkyla-
tions,4 and in reductive transpositions of Diels-Alder adducts
of 1-hydrazino dienes.5,6
If the terminal carbon of the alkene of the allylic diazene
is prochiral, a stereocenter can be installed via the ADR.
Indeed, the ADR has been employed in a variety of cyclic
systems to establish sp3 stereocenters.2,5,6 However, to our
knowledge there have been no reports of the use of the
reaction to install sp3 stereocenters in acyclic systems.
We envisioned that diastereoselective reduction of an R,â-
unsaturated tosylhydrazone could be achieved under the
influence of an R-alkoxy stereocenter (Scheme 2). An
unsaturated sulfonyl hydrazone containing an alkoxy group
at the R-stereocenter might participate in either Felkin-
Anh or Cram chelation-controlled reduction of the hydra-
zone imine. The suprafacial nature of the rearrangement,
coupled with allylic strain-induced conformational con-
straints,4a,7 should result in diastereoselective transfer of
Scheme 1. Allylic Diazene Rearrangement
often encountered as the final step in the reductive 1,3-
transposition of R,â-unsaturated tosylhydrazones to the
reduced alkenes.2 More recently, the ADR has been em-
(1) Bumgardner, C. L.; Freeman, J. P. J. Am. Chem. Soc. 1964, 86, 2233;
Jabbari, A.; Sorensen, E. J.; Houk, K. N. Org. Lett. 2006, 8, 3105.
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see: Ripoll, J.-L.; Valle´e, Y. Synthesis 1993, 659.
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10.1021/ol702921x CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/20/2007

Thus, tosyl hydrazone 1a was prepared in four steps from
(S)-(+)-lactic acid (Scheme 3).16 During optimization studies
Scheme 2. Acyclic Diastereoselective Reductive Transposition
Scheme 3. Reductive Transposition of Hydrazone 1a
on the reductive transposition, we found that a modification
(addition of 2 weight equiv of silica gel) of the Kabalka
conditions17 greatly accelerated the hydrazone reduction step.
After addition of NaOAc and heating of the reaction mixture,
the 1,4-syn-E-2-alkenyl product 2a was isolated in high yield
and diastereoselectivity (g20:1 dr based on 1H NMR
analysis).18 Importantly, Mosher ester analysis of a derivative
of 2a revealed that no detectable racemization of the R-alkoxy
stereocenter had occurred during the entire reaction se-
quence from (S)-(+)-lactic acid to 2a.16
the diazene hydrogen to one face of the prochiral alkene
carbon.
Hydroxy and alkyl groups possessing 1,4-syn and/or 1,4-
anti relationships are encountered in a variety of biologically
significant marine natural products, including amphidinolide
J,8 reidispongiolide A,9 mycoticin,10 okadaic acid,11 hali-
chlorine,12 pinnaic acid13 and many others. A diastereose-
lective acyclic reductive 1,3-transposition would greatly
expand the utility of the reaction. We report herein the
realization of this transformation in the generation of both
1,4-syn and 1,4-anti constructs.
The 1,4-syn adducts 2b and 2c were prepared in a directly
analogous fashion (Figure 1). Each was isolated in very good
A necessary first step of the proposed reductive transposi-
tion is the diastereoselective reduction of acyclic R-alkoxy
sulfonyl hydrazones (Scheme 2). Although there was little
precedent for this transformation,14 we were encouraged by
a number of reports of diastereoselective reduction of acyclic
R-hydroxy or R-alkoxy oximes using a variety of reducing
agents.15
We chose to test the viability of the reductive transposition
on lactic acid- and mandelic acid-derived substrates (Scheme
2, R 2 ) Me or Ph). Siloxymethyl, siloxyethyl, and ethenyl
were chosen as the R4 substituents, since these groups would
be useful in post-rearrangement manipulations that might be
employed in natural product synthesis.
Figure 1. Reductive transposition products 2b-f.
(7) For reviews of allylic strain directed reactions, see: Hoffman, R.
W. Chem. ReV. 1989, 89, 1841; Hoveyda, A. H.; Evans, D. A.; Fu, G. C.
Chem. ReV. 1993, 93, 1307.
(8) Kobayashi, J.; Sato, Ishibashi, M. J. Org. Chem. 1993, 58, 2645.
(9) D’Auria, M. V.; Gomez-Paloma, L.; Minale, L.; Zampella, A.;
Verbist, J.-F.; Roussakis, C.; Dibitus, C.; Patissou, J. Tetrahedron 1994,
50, 4829.
(10) Wasserman, H. H.; Van Verth, J. E.; McCaustland, D. J.; Borowitz,
I. J.; Kamber, B. J. Am. Chem. Soc. 1967, 89, 1535.
(11) Tachibana, K.; Scheuer, P. J.; Tsukitani, Y.; Kikuchi, H.; Van Engen,
D.; Clardy, J.; Gopichand, Y.; Schmitz, F. J. J. Am. Chem. Soc. 1981, 103,
2469.
(12) Kuramoto, M.; Tong, C.; Yamada, K.; Chiba, T.; Hayashi, Y.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3867.
(13) Chou, T.; Kuramoto, M.; Otani, Y.; Shikano, M.; Yazawa, K.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3871.
(14) Goma, Yuki; Matsumoto, Yoichi. Reduction of optically actiVe
imines. Jpn. Kokai Tokkyo Koho 2001064244, 2001.
(15) Iida, H.; Yamazaki, N.; Harada, K.; Shiono, S. Bull. Chem. Soc.
Jpn. 1984, 57, 1040; Kibayashi, C. J. Chem. Soc., Chem. Commun. 1987,
746; Fujita, M.; Hiyama, T. J. Org. Chem. 1988, 53, 5415; Williams, D.
R.; Osterhout, M. H.; Reddy, J. P. Tetrahedron Lett. 1993, 34, 3271;
Uneyama, K.; Hao, J.; Amii, H. Tetrahedron Lett. 1998, 39, 4079; Shimizu,
M.; Tsukamoto, K.; Matsutani, T.; Fujisawa, T. Tetrahedron 1998, 54,
10265; Boukhris, S.; Souizi, A. Tetrahedron Lett. 1999, 40, 1669; Miyata,
O.; Koizumi, T.; Asai, H.; Iba, R.; Naito, T. Tetrahedron 2004, 60, 3893.
yield and uniformly high level of isomeric purity (dr g 20:
1). Solely the E-alkene isomer was detected by H NMR
analysis.
1
The mandelic acid-derived hydrazones afforded equally
high levels of diastereoselectivity in the reductive transposi-
tion to give adducts 2d-f (Figure 1). The er of adduct 2d
was identical to that of its Weinreb amide precursor,16,19
indicating that no detectable racemization of the alkoxy-
bearing stereocenter had occurred in its conversion to 2d.
In order to access the corresponding 1,4-anti diastereomers,
tosyl hydrazones 2g and 2h possessing Z-alkenes were
(16) See Supporting Information.
(17) Kabalka, G. W.; Yang, D. T. C.; Baker, J. D., Jr. J. Org. Chem.
1976, 41, 574.
(18) The 1,4-cis configuration of 2a was confirmed by its conversion to
the known cis-2-methyl-5-hexanolide (see Supporting Information).
(19) The er of the Weinreb amide leading to 2d was 3:1.
358
Org. Lett., Vol. 10, No. 2, 2008

This method described herein is complementary to other
methods used for acyclic 1,4-stereocontrol, such as the
Claisen20 and 2,3-Wittig21 rearrangements, and the SN2′
reactions of organometals.22 Our own applications to complex
molecule synthesis will be reported in due course.
Scheme 4. Preparation of 1,4-anti Adducts 2g,h
Acknowledgment. We thank the NSF (CHE-0616154),
the NIH (RR-15569), and the Arkansas Biosciences Institute
for support of this work, and Gavin D. Jones (Arkansas Tech
University) and David A. Vicic (University of Hawaii) for
X-ray crystallographic analysis.
Supporting Information Available: Experimental pro-
cedures, characterization data, 1H- and 13C NMR spectra of
compounds 1a-h and 2a-h, X-ray crystal structure data of
the hydrazone leading to 2f, Mosher ester analyses of 2a,d.
This material is available free of charge via the Internet at
http://pubs.acs.org.
prepared (Scheme 4). Although the stereoselectivity in the
hydrazone formation step was not as high (70:30 and 65:35
E:Z, respectively), the E-hydrazone isomer could nevertheless
be crystallized in isomerically pure form from the mixture.
Gratifyingly, treatment of hydrazones 1g and 1h under the
same conditions as before yielded the 1,4-anti-E-2-alkenyl
diastereomers 2g and 2h in good yield and g20:1 dr. As
OL702921X
1
with 2a-f, only the E-alkene isomer was detected by H
(20) See, for example: Cywin, C. L.; Kallmerten, J. Tetrahedron Lett.
1993, 34, 1103; Kim, D.; Shin, K. J.; Kim, I. Y.; Park, S. W. Tetrahedron
Lett. 1994, 35, 7957. For reviews, see: Hiersemann, M., Nubbemeyer, U.,
Eds. The Claisen Rearrangement: Methods and Applications; Wiley-
VCH: Weinheim, 2007.
(21) For a review, see: Nakai, T.; Mikami, K. Chem. ReV. 1986, 86,
885.
(22) Ibuka, T.; Tanaka, M.; Nishii, S.; Yamamoto, Y. J. Am. Chem. Soc.
1989, 111, 4864; Ibuka, T.; Nakai, K.; Habashita, H.; Bessho, K.; Fujii, N.
Tetrahedron 1993, 49, 9479.
NMR analysis.
The reductive transposition described herein has several
features that recommend its use: (i) the ready accessibility
of the R-alkoxy tosylhydrazone precursors,16 (ii) the mild
reaction conditions for effecting the transformation, and (iii)
the ability to prepare either the 1,4-syn or 1,4-anti diaster-
eomers.
Org. Lett., Vol. 10, No. 2, 2008
359