Through-bond/through-space anion relay chemistry exploiting vinylepoxides as bifunctional linchpins

Article abstract of DOI:10.1002/anie.201309270

The development of new bifunctional linchpins that permit the union of diverse building blocks is essential for the synthetic utility of anion relay chemistry (ARC). The design, synthesis, and validation of three vinylepoxide linchpins for through-bond/through-space ARC are now reported. For negative charge migration, this class of bifunctional linchpins employs initial through-bond ARC by an SN2' reaction, followed by through-space ARC exploiting a 1,4-Brook rearrangement. The trans-disubstituted vinylepoxide linchpin yields a mixture of E/Z isomers, whereas the cis-disubstituted and the trans-trisubstituted vinylepoxide linchpins proceed to deliver three-component adducts with excellent E selectivity.

Full text of DOI:10.1002/anie.201309270

Angewandte
Chemie
DOI: 10.1002/anie.201309270
Synthetic Methods
Through-Bond/Through-Space Anion Relay Chemistry Exploiting
Vinylepoxides as Bifunctional Linchpins**
Ming Z. Chen, Osvaldo Gutierrez, and Amos B. Smith III*
Abstract: The development of new bifunctional linchpins that
permit the union of diverse building blocks is essential for the
synthetic utility of anion relay chemistry (ARC). The design,
synthesis, and validation of three vinylepoxide linchpins for
through-bond/through-space ARC are now reported. For
negative charge migration, this class of bifunctional linchpins
employs initial through-bond ARC by an SN2’ reaction,
followed by through-space ARC exploiting a 1,4-Brook
rearrangement. The trans-disubstituted vinylepoxide linchpin
yields a mixture of E/Z isomers, whereas the cis-disubstituted
and the trans-trisubstituted vinylepoxide linchpins proceed to
deliver three-component adducts with excellent E selectivity.
negative charge through the bonding system of a molecule
(e.g., conjugate addition reactions), whereas in through-space
ARC, a carrier species is employed to facilitate negative
charge migration (e.g., Brook rearrangement). Over the past
decade, we have reported extensive studies in the area of
through-space ARC employing Brook rearrangements, which
led to the discovery of Type I and Type II ARC.[2] The
synthetic utility of both Type I and Type II ARC tactics has
been demonstrated in a number of completed or ongoing
synthetic ventures, including those on (+)-spongistatins 1 and
2,[3] (+)-rimocidin,[4] (+)-spirastrellolide A and B,[5] the indo-
lizidine alkaloids (À)-223AB and (À)-205B,[6] and the Cryp-
tocarya family of polyhydroxylated pyrone natural products.[7]
For the future, the development of new bifunctional linchpins
that permit the reaction of diverse building blocks is essential
for the synthetic utility of the ARC method.
M
ulti-component anion relay chemistry (ARC) holds great
promise for the construction of architecturally complex
natural and unnatural products of biological significance.[1]
This strategy permits the rapid and efficient assembly of
molecular complexity in a “single flask” with precise stereo-
control. The ARC tactic can be broadly divided into two
classes based on the mode of negative charge migration, that
occurs either “through-bond” or “through-space” (Fig-
ure 1).[1b] Through-bond ARC is defined as the transfer of
With this goal in mind, we now present for the first time
the combination of through-bond and through-space ARC
with a new class of bifunctional linchpins, namely vinyl-
epoxides 1, for the propagation of negative charge to deliver
structural motifs that were previously not readily accessible
(Figure 2). Specifically, addition of an external nucleophile to
Figure 2. Through-bond/through-space ARC exploiting vinylepoxides as
bifunctional linchpins. TMS=trimethylsilyl.
Figure 1. Classification of anion relay chemistry.
vinylepoxide linchpin 1 in an SN2’ fashion first generates an
alkoxide anion upon negative charge migration through the
bonding system (“through-bond”). Subsequent 1,4-Brook
rearrangement, triggered by the addition of a polar additive
[e.g., hexamethylphosphoramide (HMPA)], relays the neg-
ative charge to a new carbon center (“through-space”).
Trapping of the resultant dithiane anion with an electrophile
would furnish multi-component adduct 4.
Vinylepoxides comprise an interesting class of electro-
philes, as they possess more than one nucleofugal site;
therefore, nucleophilic addition can proceed either in an
SN2 or SN2’ fashion.[8] In the case at hand, selective SN2’
addition is necessary for the subsequent 1,4-Brook rearrange-
ment. Furthermore, as a new double bond is generated upon
[*] Dr. M. Z. Chen, Dr. O. Gutierrez, Dr. A. B. Smith III
Department of Chemistry, University of Pennsylvania
231 S. 34thStreet, Philadelphia, PA 19104 (USA)
E-mail: smithab@sas.upenn.edu
[**] Financial support was provided by the NIH (CA-19033 and GM-
87605), XSEDE (TG-CHE 120052), and an NCI postdoctoral
fellowship (1F32CA171736) to M.Z.C. We also thank Dr. R. Kohli
and Dr. P. Carroll at the University of Pennsylvania for assistance in
obtaining high-resolution mass spectra and X-ray crystallography,
respectively.
Supporting information for this article, including a general proce-
dure for the through-bond/through-space ARC reaction and char-
acterization of all new compounds, is available on the WWW under
http://dx.doi.org/10.1002/anie.201309270.
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SN2’ addition, issues concerning the E/Z selectivity must also
be addressed and resolved.
the solvent, ambient reaction temperature, and a reaction
time of two hours. Premature Brook rearrangement was
observed when the reaction was carried out in THF or for an
extended time in Et2O. Performing the reaction at 08C led to
low conversion. Exploiting the optimized conditions, lithia-
tion of TBS-dithiane (8) with nBuLi in Et2O followed by
addition to 7 furnished exclusively the SN2’ addition product 9
in 80% yield, albeit with a modest level of E/Z selectivity
[E/Z=2.5:1; Figure 4a, Eq. (1)]. Lithium dibutyl cuprate (10;
generated in situ from nBuLi and CuI) proved to be a better
nucleophile, as the SN2’ addition proceeded readily at 08C
with equally high efficiency and chemoselectivity to furnish
adduct 11 in 93% yield, again as a 2.5:1 mixture of the
E/Z isomers [Figure 4a, Eq. (2)].
To explore the proposed through-bond/through-space
ARC, we first constructed trans-disubstituted vinylepoxide 7
(Figure 3) as a bifunctional linchpin. Condensation of acro-
lein with malonic acid, followed by reduction with LiAlH4,
furnished 2,4-pentadiene-1-ol (5).[9] Tungstic acid catalyzed
chemoselective epoxidation of the internal alkene,[10] fol-
lowed by an Appel reaction[11] with CBr4, led to bromovinyl-
epoxide 6,[2b] which upon treatment with lithiated TMS-
dithiane underwent a highly chemoselective substitution
reaction to furnish vinylepoxide 7. The structure of 7 was
confirmed by X-ray crystallography.
Having achieved a highly selective SN2’ addition to
vinylepoxide 7, we next examined the combination of
through-bond and through-space ARC in a single flask
(Figure 4b). After addition of an external nucleophile to 7
under the aforementioned reaction conditions, HMPA was
added to the resulting alkoxide at À408C to trigger a 1,4-
Brook rearrangement to generate a new dithiane anion,
which was trapped with allyl bromide. Subsequent removal of
the TMS group using HCl (1.0n) furnished the three-
component adduct. Both lithiated TBS-dithiane and lithium
dibutyl cuprate readily participated in through-bond/through-
space ARC to yield the three-component adducts 12 and 13,
each as a 2.5:1 mixture of the E/Z isomers in 55% and 70%
yield, respectively [Figure 4b, Eqs. (3) and (4)]. It is note-
worthy that the E and Z isomers undergo Brook rearrange-
ment and subsequent alkylation with equal efficiency.
Figure 3. Synthesis of trans-disubstituted vinylepoxide linchpin 7.
With linchpin 7 in hand, the initial through-bond ARC by
SN2’ addition was explored. We previously demonstrated that
the reaction of vinylepoxides with sterically hindered 2-
substituted 1,3-dithiane anions proceeds predominantly in an
SN2’ fashion.[12] Organocuprates are also known to undergo
selective SN2’ addition with vinylepoxides.[13] Therefore,
lithiated dithianes and organocuprates were chosen as the
initiating nucleophiles (Figure 4a). With lithiated TBS-
dithiane, the optimal reaction conditions include Et2O as
To define the origin of the modest E/Z selectivity of the
SN2’ addition to 7, transition-state models were proposed
based on the stereoelectronic requirement[8] that necessitates
a nearly coplanar arrangement of the alkene and the epoxide
to permit effective interaction between the p orbital and the
À
breaking C O bond (Figure 5a). Because of the lack of
Figure 5. Transition-state models to rationalize E/Z selectivity.
significant steric interactions between the s-trans (14) and
s-cis (15) conformers, SN2’ addition results in a mixture of
E/Z isomers. However, the possibility of greatly improved
E/Z selectivity in the case of cis-disubstituted and trans-
trisubstituted vinylepoxides can be seen in Figure 5b and c.
The presence of a destabilizing steric interaction in the s-cis
conformers (17 and 19) would be expected to strongly
disfavor these conformers, thus favoring the formation of
the E alkene by SN2’ addition to the s-trans conformers (16
Figure 4. Through-bond/through-space ARC with linchpin 7. TBS=tert-
butyldimethylsilyl.
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Table 1: Through-bond/through-space ARC with linchpin 22.[a]
and 18). To explore this scenario, we turned to cis-disubsti-
tuted and trans-trisubstituted vinylepoxide linchpins.
The synthesis of cis-disubstituted vinylepoxide 22 is
depicted in Figure 6. Mono-protection of (Z)-2-butene-1,4-
diol with TBSCl, followed by epoxidation with meta-chloro-
Entry
NuLi
Yield [%]
E/Z[b]
Product
1
2
80
67
ꢀ20:1
ꢀ20:1
(E)-12, R=allyl
23, R=prenyl
3
71
ꢀ20:1
Figure 6. Synthesis of cis-disubstituted vinylepoxide linchpin 22.
peroxybenzoic acid (m-CPBA) furnished epoxy alcohol 20.
Parikh–Doering oxidation[14] of the alcohol, followed by
Wittig reaction with Ph3PMeBr[15] and removal of the TBS
group then led to vinylepoxy alcohol 21. Appel halogena-
tion[11] with CBr4 and chemoselective substitution with
lithiated TMS-dithiane completed the synthesis of 22, the
structure of which was confirmed by X-ray crystallography.
With linchpin 22 in hand, we first explored the through-
bond ARC by SN2’ addition (Figure 7). As expected, addition
of lithiated TBS-dithiane to 22 at ambient temperature
proceeded with excellent chemo- and stereoselectivity to
furnish adduct (E)-9 exclusively in 67% yield [Figure 7,
Eq. (1)]. Likewise, SN2’ addition of Bu2CuLi to 22 afforded
adduct (E)-11 in 90% yield with an E/Z ratio of ꢀ 20:1
[Figure 7, Eq. (2)].
4
5
85
56
ꢀ20:1
ꢀ20:1
24, R=allyl
25, R=Bn
6
7
57
47
ꢀ20:1
ꢀ20:1
26, R=Et
27, R=iPr
[a] Reaction conditions: i) 22, RLi, Et2O, RT, 2 h or 22, R2CuLi, 08C, 1 h;
ii) electrophile, HMPA, Et2O, À408C to RT, 1 h; then RT, 3 h; iii) 1.0n HCl
(aq). [b] The E/Z ratio was determined by 1H NMR analysis of the crude
product mixture. Bn=benzyl.
Lithiated alkyl dithianes also proved to be competent
nucleophiles (entries 6 and 7). Both ethyl and isopropyl di-
thianes participated in the through-bond/through-space ARC
with 22 to deliver three-component adducts 26 and 27 in 57%
and 47% yield, respectively. In all cases, excellent chemo-
selectivity and
E/Z selectivity (E/Z ꢀ 20:1) were observed.
We next constructed trans-trisubstituted vinylepoxide 30
for through-bond/through-space ARC (Figure 8). Wittig
reaction of (carbethoxyethylidene)triphenylphosphorane
with acrolein,[16] followed by reduction with LiAlH4 and
chemoselective epoxidation catalyzed by tungstic acid,[10]
furnished dienol 28. Appel reaction[11] with CBr4 and chemo-
selective substitution with lithiated TMS-dithiane, in this case
Figure 7. Through-bond ARC by SN2’ addition to linchpin 22.
We next examined the combined through-bond and
through-space ARC with linchpin 22. Both lithiated TBS-
dithiane and Bu2CuLi underwent sequential SN2’ addition to
22, 1,4-Brook rearrangement, and alkylation with high
efficiency and excellent selectivity (Table 1, entries 1–3).
Lithiated TMS-dithiane, which has previously been shown
to undergo exclusive SN2 addition with vinylepoxides in THF/
HMPA,[12] reacted with 22 in a strictly SN2’ fashion in Et2O to
deliver adducts 24 and 25 in 85% and 56% yield, respectively
(entries 4 and 5), demonstrating that a subtle change in
solvent and additive can completely reverse the chemo-
selectivity of the nucleophilic addition to vinylepoxides.
Figure 8. Synthesis of trans-trisubstituted vinylepoxide linchpin 30.
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requiring catalytic amounts of tetrabutylammonium iodide
(TBAI) because of steric encumbrance, completed the syn-
thesis of vinylepoxide 30, the structure of which was con-
firmed by X-ray crystallography.
The results for through-bond/through-space ARC with
linchpin 30 are illustrated in Figure 9. As expected, initial SN2’
[1] a) A. B. Smith III, C. M. Adams, Acc. Chem. Res. 2004, 37, 365 –
377; b) A. B. Smith III, W. M. Wuest, Chem. Commun. 2008,
5883 – 5895.
[2] a) A. B. Smith III, A. M. Boldi, J. Am. Chem. Soc. 1997, 119,
6925 – 6926; b) A. B. Smith III, S. M. Pitram, A. M. Boldi, M. J.
Gaunt, C. Sfouggatakis, W. H. Moser, J. Am. Chem. Soc. 2003,
125, 14435 – 14445; c) A. B. Smith, M. Xian, W.-S. Kim, D.-S.
Kim, J. Am. Chem. Soc. 2006, 128, 12368 – 12369; d) A. B.
Smith III, M. Xian, J. Am. Chem. Soc. 2006, 128, 66 – 67.
[3] a) A. B. Smith III, V. A. Doughty, Q. Lin, L. Zhuang, M. D.
McBriar, A. M. Boldi, W. H. Moser, N. Murase, K. Nakayama,
M. Sobukawa, Angew. Chem. 2001, 113, 197 – 201; Angew. Chem.
Int. Ed. 2001, 40, 191 – 195; b) A. B. Smith, Q. Lin, V. A.
Doughty, L. Zhuang, M. D. McBriar, J. K. Kerns, C. S. Brook,
N. Murase, K. Nakayama, Angew. Chem. 2001, 113, 202 – 205;
Angew. Chem. Int. Ed. 2001, 40, 196 – 199.
[4] A. B. Smith III, M. A. Foley, S. Dong, A. Orbin, J. Org. Chem.
2009, 74, 5987 – 6001.
[5] A. B. Smith III, H. Smits, D.-S. Kim, Tetrahedron 2010, 66, 6597 –
6605.
[6] a) A. B. Smith III, D.-S. Kim, Org. Lett. 2004, 6, 1493 – 1495;
b) A. B. Smith III, D.-S. Kim, Org. Lett. 2005, 7, 3247 – 3250;
c) A. B. Smith III, D.-S. Kim, J. Org. Chem. 2006, 71, 2547 – 2557.
[7] B. Melillo, A. B. Smith III, Org. Lett. 2013, 15, 2282 – 2285.
[8] “Vinylepoxides in Organic Synthesis”: B. Olofsson, P. Somfai in
Aziridines and Epoxides in Organic Synthesis (Ed.: A. K.
Yudin), VCH, Weinheim, 2006, pp. 315 – 343.
[9] X.-Z. Jiao, P. Xie, L.-S. Zu, X.-T. Liang, J. Asian Nat. Prod. Res.
2003, 5, 165 – 169.
[10] D. Prat, R. Lett, Tetrahedron Lett. 1986, 27, 707 – 710.
[11] R. Appel, Angew. Chem. 1975, 87, 863 – 874; Angew. Chem. Int.
Ed. Engl. 1975, 14, 801 – 811.
Figure 9. Through-bond/through-space ARC with linchpin 30. Reaction
conditions: a) i) 8, nBuLi, Et2O, RT, 5 min; ii) 30, Et2O, RT, 2 h. b) i) 8,
nBuLi, Et2O, RT, 5 min; ii) 30, Et2O, RT, 2 h; iii) allyl bromide, HMPA,
TBAI (2.5 mol%), RT, 5 h; iv) HCl (2.0n), 36 h.
addition of lithiated TBS-dithiane to 30 proceeded with
excellent E selectivity. However, owing to a premature Brook
rearrangement, a 1:1 mixture of the pre-Brook (31) and post-
Brook (32) products was isolated in a combined yield of 83%
[Figure 9, Eq. (1)]. Multiple attempts to suppress the prema-
ture Brook rearrangement were unsuccessful in this case.
Pleasingly, single-flask through-bond/through-space ARC
with 30 did proceed to deliver the desired product 33, albeit
in only 35% yield [Figure 9, Eq. (2)].[17]
[12] A. B. Smith III, S. M. Pitram, M. J. Gaunt, S. A. Kozmin, J. Am.
Chem. Soc. 2002, 124, 14516 – 14517.
In summary, we have achieved the design, synthesis, and
validation of three vinylepoxide linchpins (7, 22, and 30) for
through-bond/through-space ARC.[18] These vinylepoxides
represent the first examples of a new class of bifunctional
linchpins that employ both through-bond and through-space
modes of negative charge migration to facilitate the synthesis
of three-component adducts.
[13] a) J. A. Marshall, Chem. Rev. 1989, 89, 1503 – 1511; b) R. J.
Anderson, J. Am. Chem. Soc. 1970, 92, 4978 – 4979; c) A.
Alexakis, G. Cahiez, J. F. Normant, Tetrahedron Lett. 1978, 19,
2027 – 2030; d) C. Cahiez, A. Alexakis, J. F. Normant, Synthesis
1978, 528 – 530; e) S. Araki, Y. Butsugan, Chem. Lett. 1980, 185 –
186.
[14] J. R. Parikh, W. v. E. Doering, J. Am. Chem. Soc. 1967, 89, 5505 –
5507.
[15] G. Wittig, U. Schçllkopf, Chem. Ber. 1954, 87, 1318 – 1330.
[16] E. Piers, G. L. Jung, E. H. Ruediger, Can. J. Chem. 1987, 65,
670 – 682.
Received: October 23, 2013
Published online: December 16, 2013
[17] This reaction proceeded to deliver the TMS-protected three-
component adduct in ca. 52% yield. However, the desired
product was inseparable from the quenched Brook intermediate.
[18] Transition-state energy calculations using B3LYP density func-
tional theory were performed for three vinylepoxides (7, 22, and
30). See the Supporting Information for full computational
details.
Keywords: anion relay chemistry · Brook rearrangement ·
nucleophilic addition · through-bond interactions ·
through-space interactions
.
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