Stereochemistry of contiguous cyclopropane formation from cascade cyclization of a skipped dienyl homoallyl triflate

Article abstract of DOI:10.1039/b412811g

Solvolysis of asymmetric homoallylic triflates bearing a terminal stannyl substituent gives disubstituted cyclopropanes and bicyclopropanes bearing differentiated termini in high enantiopurity.

Full text of DOI:10.1039/b412811g

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Stereochemistry of contiguous cyclopropane formation from cascade
cyclization of a skipped dienyl homoallyl triflate
Christopher M. Lincoln, James D. White* and Alexandre F. T. Yokochi
Department of Chemistry, Oregon State University, Corvallis, Oregon, 97331-4003, USA.
E-mail: james.white@orst.edu; Fax: 541-737-2660; Tel: 541-737-2173
Received (in Cambridge, UK) 20th August 2004, Accepted 29th September 2004
First published as an Advance Article on the web 28th October 2004
Solvolysis of asymmetric homoallylic triflates bearing
a
primary hydroxyl group gave 4 which was reduced with Red-Al to
a trans-allylic alcohol. The derived allylic chloride 5 underwent
displacement with lithio tri-n-butylstannane,5 and subsequent
cleavage of the silyl ether afforded 6. Exposure of 6 to triflic
anhydride in base at low temperature resulted in rapid solvolysis of
the transient homoallylic triflate to produce a mixture of two
cyclopropanes in quantitative yield. These cyclopropanes were
readily identified by 1H NMR as trans- and cis-vinylcyclopropanes
7 and 8, formed in the ratio 7.6 : 1 respectively. HPLC analysis on a
stationary chiral phase showed 7 and 8 to be enantiomerically pure.
In order to study the effect of double bond geometry on the
homoallyl-to-cyclopropylcarbinyl cyclization, the cis-isomer of 6
was synthesized from (R)-(1)-dimethyl malate (9), as shown in
Scheme 2. Selective reduction of this diester,6 masking of the
resultant primary alcohol as its trityl ether, and protection of the
remaining secondary alcohol led to 10. This ester was converted to
the corresponding aldehyde which was condensed with phospho-
nate 117 to give cis-a,b-unsaturated ester 12. Transformation of 12
to allylic chloride 13 and displacement with lithio tri-n-butyl-
stannane5 furnished cis-homoallylic alcohol 14. Treatment of 14
with triflic anhydride under conditions similar to those used for 6
yielded trans-cyclopropane 7 as virtually the sole product (7 : 8 w
36 : 1). A rationale for the improved stereoselectivity seen in the
cyclization of 14 as compared with 6 must await further study.
The efficient cyclization of homoallylic alcohol 14 to cyclopro-
pane 7 suggested an extension to a system containing a skipped
diene, where a second contiguous cyclopropane could be formed in
a cascade process. For this purpose, we prepared cis-3-(tri-n-
butylstannyl)-2-propenol (15)8 from propargyl alcohol and coupled
this stannane in a Stille reaction with trans-allylic chloride 5
(Scheme 3). Conversion of the resulting alcohol to allylic chloride
16 was followed by displacement with lithio tri-n-butylstannane5
and cleavage of the silyl ether to yield alcohol 17. Treatment of 17
with triflic anhydride in collidine resulted in the quantitative
formation of three enantiomerically pure, stereoisomeric bicyclo-
propanes in the ratio 3.7 : 1 : 1.
terminal stannyl substituent gives disubstituted cyclopropanes
and bicyclopropanes bearing differentiated termini in high
enantiopurity.
The rearrangement of a homoallyl cation to a cyclopropylcarbinyl
cation is thought to play a role in the biogenesis of a variety of
cyclopropane-containing natural products,1 a hypothesis which
previously led us to design successful biomimetic syntheses of
eicosanoids such as the constanolactones.2 The strategy underlying
this approach to cyclopropane synthesis can be applied more
broadly and would be particularly valuable if it could be extended
to a set of contiguous cyclopropanes such as that present in the
fungal metabolite FR-900848.3
We have examined the rearrangement of homoallylic systems
bearing a leaving group (triflate) at one terminus and a cation-
stabilizing metal (tin) at the other to clarify the role of double bond
geometry in the cyclization process as well as elucidate the absolute
stereochemistry associated with this reaction. Related studies in a
racemic series bearing a terminal silicon substituent have been
published by Taylor.4
We first studied the reactivity of an enantiopure trans-
homoallylic triflate bearing a tri-n-butylstannyl residue at the
distal terminus. Synthesis of the requisite homoallylic alcohol began
from (S)-(2)-glycidol (1) which was protected as its trityl ether
before conversion to alkynol 2 with lithiated alkyne 3 (Scheme 1).
Protection of the secondary alcohol followed by unmasking of the
Scheme 2 Reagents and conditions: i, BH3?SMe2, NaBH4 (cat), THF, 88%;
ii, Ph3CCl, Et3N, CH2Cl2, 64%; iii, TBSCl, imidazole, DMF, 92%; iv,
Scheme 1 Reagents and conditions: i, Ph3CCl, Et3N, CH2Cl2, 92%; ii,
LiCMCCH2OTBS (3), THF, BF3?OEt2, 278 uC, 93%; iii, TBSCl,
imidazole, DMF; iv, TBAF, THF, 80% from 2; v, Red-Al, Et2O; vi,
MsCl, LiCl, collidine, DMF, 0 uC A rt, 83% from 4; vii, LiSnBu3, THF,
278 uC, 93%; viii, TBAF, THF, 79%; ix, Tf2O, collidine, CH2Cl2, Et3N,
288 uC, 99%.
˚
DIBALH, CH2Cl2, 0 uC, 94%; v, TPAP (cat), NMO, 4 A mol. sieves,
CH2Cl2, 78%; vi, (CF3CH2O)2P(O)CH2CO2Me (11), KHMDS, 18-crown-
6, THF, 89%; vii, DIBALH, CH2Cl2, 0 uC, 76%; viii, MsCl, LiCl, collidine,
DMF, 0 uC A rt, 99%; ix, LiSnBu3, THF, 278 uC, 93%; x, TBAF, THF,
collidine, 0 uC A rt, 63%; xi, Tf2O, collidine, CH2Cl2, Et3N, 278 uC, 91%.
2 8 4 6
C h e m . C o m m u n . , 2 0 0 4 , 2 8 4 6 – 2 8 4 7
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

View Online
Scheme 5 Reagents and conditions: i, TBDPSCl, imidazole, DMAP,
CH2Cl2, 93%; ii, DIBALH, CH2Cl2, 220 uC, 61%; iii, TPAP (cat),
˚
NMO, 4 A mol. sieves, CH2Cl2; iv, NaClO2, KH2PO4, H2O2, MeCN–
H2O; v, DCC, BrCCl3, 2-mercaptopyridine-N-oxide, hn, 0 uC, 52% from
24; vi, t-BuLi, CuI.PBu3, O2, 278 uC, 75% (ref. 3c).
Scheme 3 Reagents and conditions: i, LiAlH4, THF; Bu3SnOTf, 0 uC A rt,
83%; ii, 5, PdCl2(MeCN)2, NMP; iii, MsCl, LiCl, collidine, DMF, 0 uC A
rt; iv, LiSnBu3, THF, 278 uC, 78% from 15; v, TBAF, THF, Et3N, 72%;
vi, Tf2O, collidine, CH2Cl2, Et3N, 278 uC, 99%.
(Scheme 5). Oxidation of 24 to the corresponding carboxylic acid
and brominative decarboxylation under photolytic conditions
afforded the bromobicyclopropane 25. Falck has shown that
copper catalyzed homocoupling of 25 yields a quatercyclopropane
26 which has been elaborated to FR-900848.3c
In summary, we have shown there is a pathway in the solvolytic
displacement of homoallylic triflates which can be used in a cascade
process to generate the trans,syn,trans configuration of
a
contiguous bicyclopropane. The method produces differentiated
terminal functional groups, a feature which lends itself to the
synthesis of polycyclopropane motifs in natural products such as
FR-900848.
Financial support was provided by the National Science
Foundation (0413994-CHE).
Notes and references
{ Crystal data for 22 (C19H32O4, M ~ 324.45): T ~ 100 K, monoclinic,
Scheme 4 Reagents and conditions: i, K2OsO4?H2O, NaIO4, THF–H2O; ii,
NaBH4, THF–H2O; iii, (2)-menthyl chloroformate, MeCN, pyridine; iv,
H2, Pd(OH)2/C, EtOH, 45% (four steps); v, 3,5-dinitrobenzoyl chloride,
pyridine, CH2Cl2; vi, C6H5CO2Na, MeOH–H2O, 8% (five steps).
˚
unit cell dimensions a ~ 9.2830(7), b ~ 5.5489(5), c ~ 18.4252(14) A, b ~
3
90.844(6)u, V ~ 948.99(13) A , P21 (#4), Z ~ 2, m ~ 0.621 mm21. Rigaku/
˚
MSC Rapid, CuKa radiation: 6021 reflections measured in the range
4.76 v h/u v 59.99, of which 2220 unique (Rint ~ 0.0895). Final
refinement of 219 parameters against this data set including 8 additional
restraints yielded R1 ~ 0.0818 (all data), wR2 ~ 0.1972 (all data). For 23
(C26H34N2O9, M ~ 518.55): T ~ 100 K, orthorhombic, unit cell
In order to determine the configuration of the major isomer 18,
the mixture produced from 17 was oxidized with potassium osmate
and sodium periodate and the resultant aldehydes were reduced to
primary alcohols 20 and 21 (Scheme 4). These alcohols were
reacted with (2)-menthyl chloroformate and the trityl group was
removed by hydrogenolysis to give a mixture from which the major
stereoisomer was separated by chromatography and crystallized.
This compound was shown by X-ray crystallographic analysis{ to
possess the relative configuration of trans,syn,trans-bicyclopropane
22, the absolute configuration being defined by the configuration of
(2)-menthol.
One of the two minor stereoisomers was found to have the
trans,anti,cis configuration of 21 by its transformation to the 3,5-
dinitrobenzoate derivative 23 which also yielded to X-ray crystal-
lographic analysis.{ The bicyclopropanes from which 22 and 23
originate are therefore 18 and 19, respectively, and our results
confirm that in each case inversion took place at the hydroxyl-
bearing carbon of 17 as the first cyclopropane was formed.
Formation of the second cyclopropane, if it is in concert with the
first, should lead to 18, but the presence of 19 suggests the cascade
process is partially interrupted at a monocyclopropylcarbinyl
cation with consequent loss of stereocontrol in the second
cyclization event. The third stereoisomeric bicyclopropane from
17 was also obtained in pure form as its 3,5-dinitrobenzoate and
has been tentatively identified as the trans,syn,cis isomer.
˚
dimensions a ~ 7.5080(3), b ~ 8.6340(3), c ~ 40.4790(15) A, V ~
2624.01(17) A , P212121 (#19), Z ~ 4, m ~ 0.834 mm21. Rigaku/MSC
3
˚
Rapid, CuKa radiation: 27905 reflections measured in the range
2.18 v h/u v 71.31, of which 3925 unique (Rint ~ 0.015). Final
refinement of 337 parameters against this data set yielded R1 ~ 0.0483 (all
data), wR2 ~ 0.1190 (all data). CCDC 249269–242970. See http://
www.rsc.org/suppdata/cc/b4/b412811g/ for crystallographic data in .cif or
other electronic format.
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C h e m . C o m m u n . , 2 0 0 4 , 2 8 4 6 – 2 8 4 7
2 8 4 7