Alkenenitrile transmissive olefination: Synthesis of the putative lignan "morinol I"

Article abstract of DOI:10.1002/ejoc.201101235

Grignard reagents trigger an addition-elimination with α′- hydroxy acrylonitriles to selectively generate Z-alkenenitriles. The modular assembly of Z-alkenenitriles from a Grignard reagent, acrylonitrile, and an aldehyde is ideal forstereoselectively synthesizing alkenes, as illustrated in the synthesis of the putative lignan morinol I.

Full text of DOI:10.1002/ejoc.201101235

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101235
Alkenenitrile Transmissive Olefination: Synthesis of the Putative Lignan
“Morinol I”
Fraser F. Fleming,*[a] Wang Liu,[b] Lihua Yao,[a] Bhaskar Pitta,[a] Matthew Purzycki,[a] and
P. C. Ravikumar[c]
Keywords: Nitriles / Rearrangement / Olefination / Allylic compounds
Grignard reagents trigger an addition–elimination with αЈ-
nard reagent, acrylonitrile, and an aldehyde is ideal for
hydroxy acrylonitriles to selectively generate Z-alkeneni- stereoselectively synthesizing alkenes, as illustrated in the
triles. The modular assembly of Z-alkenenitriles from a Grig-
synthesis of the putative lignan morinol I.
and pharmaceuticals.[8] Generally, only one E/Z stereoiso-
mer is bioactive, or at least significantly more active, under-
scoring the need for rapid, modular, stereoselective synthe-
ses of alkenenitriles.[9]
Introduction
Six-electron transition structures undergird many ex-
tremely powerful synthetic methods.[1] Diels–Alder cycload-
ditions, electrocyclic reactions, and [3,3] sigmatropic re-
arrangements all proceed through privileged six-electron,
six-atom transition structures. A remarkable diversity of
atom substitutions are tolerated within the six-membered
ring; Cope, Claisen, and aza-Cope reactions incorporate
carbon, oxygen, and nitrogen ring atoms, respectively.
Equally powerful are heteroatom–metal combinations pro-
ceeding through six-membered Zimmerman–Traxler transi-
tion structures that efficiently and stereoselectively allow al-
dol condensations, allylations, and intramolecular hydride
reductions.[2]
Scheme 1. Transmissive olefination route to Z-alkenenitriles.
Harnessing the facility of six-electron reactions to drive
the formal displacement of hydroxide is rare – only high-
valent titanium and cerium promote the elimination.[3] Typ-
Results and Discussion
Exploratory forays focused on a magnesium oxide driven
ically, allylic alcohols require activation prior to displace- rearrangement because of the strength of the Mg=O
ment because hydroxide is a poor leaving group.[4] Concep- bond,[10] the prevalence of commercial Grignard reagents,
tually, hydroxide ejection from hydroxyalkenenitrile 1 and ready access to activated allylic alcohols through
(Scheme 1) could be promoted through a concerted, six- Baylis–Hillman condensations.[11] After some optimization
electron, anionic rearrangement (2 Ǟ 3) and by forming a of temperature and stoichiometry, the addition of an excess
particularly stable metal oxide. Preferential rearrangement amount of iPrMgCl to hydroxyalkenenitrile 1a was found
through conformer 2ЈЈ would assemble α-substituted Z-alk- to readily afford Z-alkenenitrile 3a as a single dia-
enenitrile 3, whose stereoselective synthesis is challeng- stereomer[12] (Table 1, Entry 1).
ing.[4a,5] The value of alkenenitriles lies in their versatility
The transmissive olefination smoothly generates an array
as synthetic intermediates[6] and as potent pharmacophores of Z-alkenenitriles 3 from the corresponding hydroxy-
embedded within numerous bioactive natural products[7] alkenenitriles 1 (Table 1). The extremely compact nitrile
group resists nucleophilic attack by the proximal Grignard
reagent, instead channeling a stereoselective[12] alkyl ad-
[a] Department of Chemistry and Biochemistry, Duquesne
University,
dition–elimination to alkenenitrile 3. For example, addition
of BuMgCl to nitrile 1a forms perfumery agent 3c as a sin-
gle stereoisomer (Table 1, Entry 3).[13] Sterically de-
manding, secondary, and tertiary Grignard reagents add
with efficacies comparable to those of primary Grignard
reagents (Table 1, Entries 2 and 3 vs. 1, 4, and 5). Similarly,
no significant difference in efficiency is observed between
Pittsburgh, PA 15282-1530, USA
Fax: +1-412-396-5683
E-mail: flemingf@duq.edu
[b] Department of Chemistry, Ohio State University,
Ohio, USA
[c] School of Basic Sciences, Indian Institute of Technology,
Mandi, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101235.
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F. F. Fleming, W. Liu, L. Yao, B. Pitta, M. Purzycki, P. C. Ravikumar
SHORT COMMUNICATION
Table 1. αЈ-Hydroxy alkenenitrile transmissive olefination.[a]
electron-rich and electron-deficient aryl hydroxynitriles
(Table 1, compare Entries 3, 10, and 11). Although acet-
ylenic Grignard reagents do not engage in the rearrange-
ment, vinylmagnesium halides effectively generate skipped
dienes without detectable olefin isomerization (Table 1, En-
tries 6 and 9).
Modest oxygenation within the Grignard reagent is toler-
ated (Table 1, Entry 7), although attempts to use (1,3-di-
oxan-2-ylethyl)magnesium bromide were unsuccessful. The
transmissive olefination with (3-methoxyphenethyl)magne-
sium bromide employed one equivalent of iPrMgBr as a
sacrificial base (Table 1, Entry 7), reducing the amount of
the Grignard reagent required for alkyl transfer to two
equivalents. Using this procedure, alkenenitrile 3g was pre-
pared in 62% yield.
A carbinol substituent capable of stabilizing charge is re-
quired for the rearrangement.[14] Presumably the sp2 center
promotes the rearrangement by aligning a p orbital with
the C–O bond undergoing cleavage. In addition to benzylic
alcohols (Table 1, Entries 1–11), cinnamyl alcohol 1d read-
ily affords conjugated dienenitriles[9,15] 3l–n (Table 1, En-
tries 12–14).
The addition–elimination requires 3.5 equiv. of Grignard
reagent suggesting rearrangement via the more nucleophilic
magnesiate 4 (Scheme 2) rather than an alkylmagnesium
alkoxide (cf. 2, M = Mg; Scheme 1).[16] Consistent with the
intermediacy of a magnesiate, no rearrangement is observed
on treating 1a with one equivalent of dibutylmagnesium.
Magnesium cations appear essential, as the sequential ad-
dition of one equivalent of RMgX followed by an excess
amount of RLi affords only trace amounts of alkenenitrile
3. Formation of Z-alkenenitrile 3 is consistent with a con-
certed,[17] exocyclic intramolecular rearrangement through
magnesiate 4ЈЈ in which the sterically miniscule nitrile
group[18] eclipses the carbinol substituent R1. The model
also accounts for the higher selectivity of aryl over alkenyl
substituents R1 assuming that the latter orients[14] to posi-
tion a proton toward the eclipsing inside substituent (H* in
4Ј and CN in 4ЈЈ).
Scheme 2. Transmissive olefination mechanism.
Rapid access to Z-alkenenitriles stimulated applying the
transmissive olefination to the synthesis of the neolignan
morinol I. Isolated during a bioactivity guided isolation of
the Chinese medicinal herb Morina chinensis,[19] morinol I
possesses a skipped diene unique among this class of neolig-
nan metabolites (6a, Scheme 3).[20] Vinylmagnesium bro-
mide initiated transmissive olefination with veratraldehyde-
derived nitrile 1b effectively provided requisite Z-dieneni-
trile 3o as a single stereoisomer.[11b] Subsequent exposure
of 3o to 3,4-dimethoxyboronic acid in the presence of
[a] An excess amount of the Grignard reagent was added to hy-
droxynitrile 1 at 0 °C and after 50 min saturated, aqueous NH4Cl
was added.
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Alkenenitrile Transmissive Olefination
Pd(OAc)2 and Ag2CO3 affords dienenitrile 5 with full con-
trol over the olefin stereochemistry (Scheme 3). Conven-
tional iBu2AlH reduction of nitrile 5,[21] hydrolysis, and al-
dehyde reduction afforded an 8:1 ratio of E/Z enal dia-
stereomers that were reduced to target alcohol (7Z,7ЈE)-6a
and diastereomer (7E,7ЈE)-6b. Neither alcohol (7Z,7ЈE)-6a
nor C7–C8 E-diastereomer (7E,7ЈE)-6b exhibit spectro-
Experimental Section
General Transmissive Olefination Procedure: An ethereal solution
of the Grignard reagent (3.5 equiv.) was slowly added to a stirred
0 °C, THF solution of 1. After 50 min, the mixture was quenched
with 0.1 m HCl solution, and then the resulting mixture was stirred
vigorously for 5 min. The crude product was extracted with diethyl
ether, dried (MgSO4), concentrated, and purified by radial
scopic data matching the reported spectral listing of the chromatography to afford analytically pure material.
natural product. Unfortunately, samples and copies of the
Supporting Information (see footnote on the first page of this arti-
spectroscopic data exhibited by the natural lignin are not
available to resolve the ambiguous HMBC and NOE data
that are inconsistent with the skipped diene structure pro-
posed for morinol I.[22] Although the precise structure of
morinol I is elusive, the five-step synthesis of the putative
structure of morinol I demonstrates the ability of the trans-
missive olefination strategy to rapidly assemble this type of
molecular scaffold.
cle): Experimental procedures, spectroscopic and analytical data,
and copies of the NMR spectra for all new compounds.
Acknowledgments
Financial support from the National Institutes of Health
(2R15AI051352-03) and in part from the National Science Founda-
tion CHE (0808996; NMR: 0614785, X-ray: 024872, HRMS:
0421252) is gratefully acknowledged.
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Conclusions
The transmissive olefination of hydroxy alkenenitriles ef-
ficiently and stereoselectively assembles Z-alkenenitriles
from three readily available components: an aldehyde,
acrylonitrile, and a Grignard reagent. The strategy directly
employs Baylis–Hillman alcohols without prior hydroxyl
activation by harnessing a unique elimination of magne-
sium oxide. Simply adding excess Grignard reagent to an
αЈ-hydroxyalkenenitrile triggers a transmissive olefination
to efficiently provide a diverse array of Z-alkenenitriles. The
versatility of the transmissive olefination is illustrated in the
rapid synthesis of the structure proposed for the lignan mo-
rinol I.
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SHORT COMMUNICATION
[12] 1H NMR spectroscopic analysis of the crude reaction mixture
failed to identify any of the E-alkenenitrile with aryl carbinols
1a–c.
[13] S.-I. Guan, G.-h. Zhou, Wuhan Huagong Xueyuan Xuebao
2005, 27, 5–7.
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synthesis as the best avenue for determining the correct struc-
ture. Full details of the transmissive olefination approach to
morinol I alkene diastereomers and structural isomers will be
published in a separate account.
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[17] The rearrangement could potentially proceed through a non-
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is typically low with alkenes not having β-substituents, whereas
Received: August 23, 2011
Published Online: October 28, 2011
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Eur. J. Org. Chem. 2011, 6843–6846