[3,3] Sigmatropic Rearrangement of Boron-Containing Allyl Alcohols: Synthesis of Allyl Addition Reagents

Article abstract of DOI:10.1002/anie.200352210

Enantiomerically pure reagents for allyl additions were prepared by [3,3] sigmatropic rearrangements (see scheme) followed by a separation of the diastereoisomers. The highly stable allylboronic esters with a stereogenic center α to a boron atom were used to synthesize Z-configured homoallylic alcohols with an enantiomeric excess > 94%.

Full text of DOI:10.1002/anie.200352210

Communications
Allylation Reagents
[3,3] Sigmatropic Rearrangement of Boron-
Containing Allyl Alcohols: Synthesis of Allyl
Addition Reagents**
Jörg Pietruszka* and Niklas Schöne
Over the past decades a major effort has been directed toward
the selective formation of homoallylic alcohols by the
addition of allylmetal compounds to aldehydes and ketones.
Allylboron reagents have proved to be especially versatile: a
closed, chairlike transition structure with the boron atom
coordinated to the carbonyl oxygen atom is responsible for
the highly selective transformations.[1] While auxiliary-con-
trolled reactions are well established, the use of reagents with
a stereogenic center in the position a to the boronic ester
moiety (structure 1; Figure 1) is reported less often.[2]
Hoffmann et al. have developed a family of derivatives and
Figure 1. Retrosynthesis of allylboronic esters 4. X=OEt, NMe2.
[*] Priv.-Doz. Dr. J. Pietruszka, N. Schöne
Institut für Organische Chemie
Universität Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
Fax: (+49)711-685-4269
E-mail: joerg.pietruszka@po.uni-stuttgart.de
[**] The authors thank the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie, the Otto-Röhm-Gedächtnisstif-
tung, and Novartis AG for their generous support. We are grateful to
Dr. Wolfgang Frey for performing the X-ray structure analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
5638
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200352210
Angew. Chem. Int. Ed. 2003, 42, 5638 –5641

Angewandte
Chemie
have demonstrated their versatility in the synthesis of
complex (polypropionate-derived) natural products.[3] It was
shown that a high degree of enantioselectivity can be
observed, but a drawback is the problem of preparing a-
chiral 2-allylboronic esters in an enantiomerically pure form.
The fact that boronic esters 2—derived from an “inverse-
TADDOL”—show remarkable stability towards a variety of
reaction conditions, and in addition allow the chromato-
graphic separations of diastereoisomers,[4] started our inves-
tigation to synthesize a new type of reagent. Furthermore,
since preliminary results with allylboronic ester 3 showed that
the auxiliary has only a minor influence on the stereo-
selection,[5] it was envisaged that the allyl addition should
almost exclusively be controlled by an additional stereogenic
center in the a-position.
In connection with an ongoing problem in a natural
product synthesis, we were especially interested in developing
a method to synthesize enantiomerically pure reagents of the
general type 4 (Figure 1). A simple retrosynthetic analysis of
this g,d-unsaturated carbonyl compound revealed a possible
[3,3]sigmatropic rearrangement for the conversion, [6] another
key reaction in organic synthesis that has already been used
for the corresponding Si or Sn derivatives.[7] However, an
application to boron chemistry was not known. It is important
to note that the E/Z selectivity of the reaction with boronic
esters depends on the substituent in the a-position and the
steric bulk of the ester, thus enabling the stereochemical
course of the reaction to be directed.[8] Furthermore, our
approach should easily allow the introduction of additional
substituents in the 2- or 5-position of reagent 4 by altering
either the reagent for the rearrangement or using a modified
allyl alcohol 5.
Scheme 1. Synthesis of starting materials for the [3,3] sigmatropic
rearrangements: a) 1. Catecholborane, cat. [Rh(cod)Cl]2, (iPr)3P, Et3N,
cyclohexane, RT; 2. 8, RT (63%); b) HCl, EtOH (62%). Cod=cyclo-
octa-1,5-diene.
The starting materials are readily available from silyl-
protected propargyl alcohol 6 (Scheme 1): Direct hydrobora-
tion with 1,3,2-dioxaborolane 7—derived from the BH3·SMe2
complex and diol 8—yielded the allyl alcohol (E)-5 after
deprotection. Regioisomer 9 was also isolated as a minor by-
product.[4] For the initial step in the improved synthesis of the
olefin (Z)-5[4d] we followed the procedure reported by
Miyaura and co-workers;[9] the consecutive transesterification
with diol 8 and deprotection furnished the allyl alcohol (Z)-5.
Transformation to the esters 10—starting materials for the
envisaged Claisen–Ireland or Carroll rearrangement—pro-
ceeded smoothly under standard conditions.
Initial attempts to perform rearrangements under basic
conditions (as required for Claisen–Ireland or Carroll reac-
tions) failed, no matter which variation was used. Reactions
under acidic conditions were more successful: The best results
were obtained by using the standard procedure under the
harsh conditions of the Johnson rearrangement.[10] The allyl
alcohol (E)-5 reacted with triethyl orthoacetate at 1358C in
the presence of catalytic amounts of propionic acid to yield
the g,d-unsaturated esters 4a in 71% yield as a 1:1 mixture of
readily separable diastereoisomers (Scheme 2). Similar
results were obtained with the alternative starting materials
(Z)-5 and 9. Ester 11a was isolated in 64% yield (from 9). The
transformation of (Z)-5 gave the same products as the olefin
(E)-5, however, quite unexpectedly an increase of selectivity
was observed [(3S)-4a:(3R)-4a 30:70, 76% yield].
Scheme 2. [3,3] Sigmatropic rearrangement of boron-containing
allyl alcohols. Conditions: “a”: MeC(OEt)3, 1358C, cat. EtCO2H;
“b”: Me(OMe)2NMe2, toluene, 808C.
Eschenmoser rearrangements[7a,11] gave similar results: At
808C allyl alcohol (E)-5 reacted with the orthoamide to
furnish the diastereoisomeric amides 4b (70% yield of a 1:1
mixture, separated by medium-pressure liquid chromatogra-
Angew. Chem. Int. Ed. 2003, 42, 5638 –5641
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5639

Communications
phy (MPLC)), while compound 9 gave product 11b in
moderate yield (44%). No formation of products 4b was
detected when olefin (Z)-5 was exposed to the same reaction
conditions. Instead, the only compound isolated was the
homoenolate equivalent 12 as a single, configurationally
stable diastereoisomer. One possible explanation for this
could be that an intramolecular occurred complexation
through the amino group (for example, intermediate 13)
which prevented the rearrangement, but also favored the
substitution by the released methanol. A similar intramolec-
ular activation was previously observed when attempting a
cyclopropanation of the olefin (Z)-5.[4d]
Figure 2. Left: Favored transition state for the allyl addition of (3S)-4a
to benzaldehyde; right: X-ray structure analysis of (3R)-4a.
The absolute configuration of the new reagents was
assigned after the allyl addition of pure diastereoisomer (3S)-
4a (configuration determined after this sequence) to benzal-
dehyde (Scheme 3). Homoallyl alcohol (S)-14a was obtained
Figure 3. Allyl addition products—influence of a stereogenic center in
the aldehyde moiety.
In our initial studies, we applied all new reagents 4 to
some simple allyl additions (Figure 3). It was generally shown
that the reactions with benzaldehyde could be performed in
good yield (78–91%) and enantiomeric excess (> 94% ee as
determined as the Mosher ester). An attempt at a kinetic
resolution by introducing a 1:1 mixture of diastereoisomers
(3S)- and (3R)-4a (2 equiv reagent used for 1 equiv of
benzaldehyde) failed: Homoallylalcohol 14 was obtained as
a racemic mixture and the ratio of the recovered allylboronic
esters (3S)- and (3R)-4a did not change. We could not observe
a reagent-controlled addition when introducing aldehydes
with an additional stereogenic center, for example, 2,3-O-
isopropylidene-d-glyceraldehyde, instead a mismatched (with
(3R)-4 to syn-product 16) and a matched (with (3S)-4 to anti-
product 17) interaction occurred.[15] Nevertheless, the anti
alcohols 17a/b were obtained in high yield and in no case was
a second diastereoisomer detected.
In conclusion, we have synthesized a new type of allyl
addition reagent. For the first time, Johnson and Eschenmoser
rearrangements were used to obtain enantiomerically pure
allylboronic esters. The synthesis of homoenolate equivalent
12 as a single diastereoisomer in good yield from (Z)-5 was an
especially pleasant surprise. We unequivocally assigned the
absolute configuration of all reagents by means of chemical
correlation or X-ray structure analysis, and successfully
performed allyl additions.
Scheme 3. Assignment of absolute configuration: a) PhCHO, toluene,
ꢀ100!RT; b) 1. CH2Cl2, O3, ꢀ788C; 2. Me2S, RT; c) LiAlH4, THF, 08C.
15: [a]2D0 =ꢀ70 (c=0.1 in CHCl3) [ref.[13]: ꢀ70.5 (c=1.0 in CHCl3)].
in 91% yield; the enantiomeric excess was determined
(ca. 96% ee) by the Mosher method.[12] It is important to
note that the Z-configured olefin was formed exclusively and
no traces of the diastereoisomer could be detected in the crude
product. This also has important implications for the preferred
transition state of the addition (see below). An analytical
sample was further converted into diol 15, and the config-
uration determined by comparing the optical rotation with the
literature data.[13] The same sequence was used to ascertain
both the configuration and diastereomeric purity of 12.
The stereochemical assignment of the allyl addition
product (S)-14a enabled the configurations of all products 4
to be deduced: In full agreement with the work of Hoffmann
et al.,[8] the outcome of the reaction between benzaldehyde
and (S)-14a can be explained by a favored chairlike transition
state (Figure 2, left). The phenyl group would—as expected—
preferentially take up an equatorial position, whereas bulky
boronic ester moieties would favor the substituent a to the
boron atom to be in an axial position. Indeed, this reasoning
was later indirectly confirmed by an X-ray structure analysis
of the second diastereoisomer (3R)-4a (Figure 2, right).[14]
The configuration of amide 4b were assigned by comparison
of the NMR data as well as by an X-ray structure analysis of
(3S)-4b.
Received: June 24, 2003
Revised: September 15, 2003 [Z52210]
5640
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 5638 –5641

Angewandte
Chemie
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
Keywords: allyl additions · boronic esters · rearrangements ·
sigmatropic reactions · stereoselectivity
.
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[15]For other investigations on matched/mismatched interactions of
allyl additions to 2,3-O-isopropylidene-d-glyceraldehyde with
boron reagents see, for example, a) I. Chataigner, J. Lebreton, F.
Zammattio, J. Villiꢀras, Tetrahedron Lett. 1997, 38, 3719 – 3722;
b) W. R. Roush, L. K. Hoong, M. A. J. Palmer, J. C. Park, J. Org.
Chem. 1990, 55, 4109 – 4117; c) W. R. Roush, L. K. Hoong,
M. A. J. Palmer, J. A. Straub, A. D. Palkowitz, J. Org. Chem.
1990, 55, 4117 – 4126; d) R. W. Hoffmann, B. Landmann, Chem.
Ber. 1986, 119, 2013 – 2024; and references therein.
[1]a) D. Hoppe in Stereoselective Synthesis, Vol. E21, 3rd ed (Eds.:
G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann),
Thieme, Stuttgart, 1996, pp. 1357 – 1409; b) W. R. Roush, in
Stereoselective Synthesis, Vol. E21, 3rd ed (Eds.: G. Helmchen,
R. W. Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart,
1996, pp. 1410 – 1486; c) S. E. Denmark, N. G. Almstead, in
Modern Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH,
Weinheim, 2000, pp. 299 – 401; d) S. R. Chemler, W. R. Roush,
in Modern Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH,
Weinheim, 2000, pp. 403 – 490; e) Y. Yamamoto, N. Asao, Chem.
Rev. 1993, 93, 2207 – 2293.
[2]For recent publications, see a) E. M. Flamme, W. R. Roush, J.
Am. Chem. Soc. 2002, 124, 13644 – 13645; b) A. Schlapbach,
R. W. Hoffmann, Eur. J. Org. Chem. 2001, 323 – 328; c) J.
Mortier, M. Vaultier, B. Plunian, L. Toupet, Heterocycles 1999,
50, 703 – 711; d) J.-Y. Lallemand, Y. Six, L. Ricard, Eur. J. Org.
Chem. 2002, 503 – 513.
[3]Review: a) R. W. Hoffmann, Pure Appl. Chem. 1988, 60, 123 –
130; synthesis by Matteson homologation (D. S. Matteson,
Tetrahedron 1998, 54, 10555 – 10607): b) R. W. Hoffmann, K.
Ditrich, G. Köster, R. Stürmer, Chem. Ber. 1989, 122, 1783 –
1789; c) R. Stürmer, R. W. Hoffmann, Synlett 1990, 759 – 761;
synthesis by allylic rearrangement with SOCl2: d) R. W. Hoff-
mann, S. Dresely, Angew. Chem. 1986, 98, 186 – 187; Angew.
Chem. Int. Ed. Engl. 1986, 25, 189; e) R. W. Hoffmann, S.
Dresely, Chem. Ber. 1989, 122, 903 – 909; synthesis by Diels–
Alder reactions: f) M. Vaultier, F. Truchet, B. Carboni, R. W.
Hoffmann, I. Denne, Tetrahedron Lett. 1987, 28, 4169 – 4172.
[4]a) J. E. A. Luithle, J. Pietruszka, Liebigs Ann. 1997, 2297 – 2302;
b) J. E. A. Luithle, J. Pietruszka, J. Org. Chem. 1999, 64, 8287 –
8297; c) J. E. A. Luithle, J. Pietruszka, J. Org. Chem. 2000, 65,
9194 – 9200; d) J. E. A. Luithle, J. Pietruszka, Eur. J. Org. Chem.
2000, 2557 – 2562.
[5]With benzaldehyde and 3: 30% ee (T. Wilhelm, J. Pietruszka,
Universität Stuttgart).
[6]Recent review: U. Nubbemeyer, Synthesis 2003, 961 – 1008, and
references therein.
[7]Si derivatives: a) P. R. Jenkins, R. Gut, H. Wetter, A. Eschen-
moser, Helv. Chim. Acta 1979, 62, 1922 – 1931; b) G. Procter,
A. T. Russel, P. J. Murphy, T. S. Tan, A. N. Mather, Tetrahedron
1988, 44, 3953 – 3973; c) J. S. Panek, R. Beresis, F. Xu, M. Yang, J.
Org. Chem. 1991, 56, 7341 – 7344; d) R. T. Beresis, J. S. Solomon,
M. G. Yang, N. F. Jain, J. S. Panek, Org. Synth. 1998, 75, 78 – 88,
and references therein; Sn derivatives: e) K. Ritter, Tetrahedron
Lett. 1990, 31, 869 – 872; f) J. C. Anderson, C. A. Roberts,
Tetrahedron Lett. 1998, 39, 159 – 162; g) U. Kazmaier, D.
Schauß, S. Raddatz, M. Pohlmann, Chem. Eur. J. 2001, 7, 456 –
464.
[8]R. W. Hoffmann, U. Weidmann, J. Organomet. Chem. 1980, 195,
137 – 146.
[9]T. Ohmura, Y. Yamamoto, N. Miyaura, J. Am. Chem. Soc. 2000,
122, 4990 – 4991.
[10]W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Brockson, T.-
T. Li, D. J. Faulkner, M. R. Petersen, J. Am. Chem. Soc. 1970, 92,
741 – 743.
[11]a) H. Meerwein, W. Florian, N. Schön, G. Stopp, Justus Liebigs
Ann. Chem. 1960, 641, 1 – 39; b) A. E. Wick, D. Felix, K. Steen,
A. Eschenmoser, Helv. Chim. Acta 1964, 47, 2425 – 2429.
[12]J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34,
2543 – 2549.
[13]N. W. Boaz, J. Org. Chem. 1992, 57, 4289 – 4292.
[14]CCDC-212769 [(3 R)-4a]contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
Angew. Chem. Int. Ed. 2003, 42, 5638 –5641
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5641