The first enantiomerically pure [n]triangulanes and analogues: σ-[n]helicenes with remarkable features

Article abstract of DOI:10.1002/1521-3765(20020215)8:4<828::AID-CHEM828>3.0.CO;2-Y

(M)-(-)- and (P)-(+)-Trispiro-[2.0.0.2.1.1]nonanes [(M)- and (P)-3] as well as (M)-(-)- and (P)-(+)-tetraspiro[2.0.0.0.2.1.1.1]undecanes [(M)- and (P)-4]-enantiomerically pure unbranched [4]- and [5]triangulanes-have been prepared starting from racemic bi

Full text of DOI:10.1002/1521-3765(20020215)8:4<828::AID-CHEM828>3.0.CO;2-Y

FULL PAPER
The First Enantiomerically Pure [n]Triangulanes and Analogues:
s-[n]Helicenes with Remarkable Features**
Armin de Meijere,*[a] Alexander F. Khlebnikov,[c] Sergei I. Kozhushkov,[a]
Rafael R. Kostikov,[c] Peter R. Schreiner,[a, b] Alexander Wittkopp,[a, b]
Christopher Rinderspacher,[a, b] Henning Menzel,[d] Dmitrii S. Yufit,[e] and
Judith A. K. Howard[e]
Dedicated to Professor Lutz F. Tietze on the occasion of his 60th birthday
Abstract: (M)-(À)- and (P)-(‡)-Trispiro-
[2.0.0.2.1.1]nonanes [(M)- and (P)-3] as
well as (M)-(À)- and (P)-(‡)-tetraspiro-
[2.0.0.0.2.1.1.1]undecanes [(M)- and (P)-
4]-enantiomerically pure unbranched
[4]- and [5]triangulanes have been pre-
pared starting from racemic bicyclopro-
or anti-[(1SR,3RS)-4-methylenespiro-
pentyl]methanol (rac-18). This afforded
(S)-(À)- and (R)-(‡)-28 (starting from
rac-20), as well as enantiomerically pure
(M)-(À)- and (P)-(‡)-1,4-dimethylene-
spiropentanes [(M)- and (P)-23] starting
from rac-18. The methylenetriangulanes
(S)-(À)- and (R)-(‡)-28 were cyclopro-
panated furnishing (M)- and (P)-3. The
rhodium-catalyzed cycloaddition of eth-
yl diazoacetate onto (S)-(À)- and (R)-
(‡)-28 yielded four diastereomeric ethyl
trispiro[2.0.0.2.1.1]nonane-1-carboxyla-
tes in approximately equal proportions.
The enantiomerically pure esters
(1R,3S,4S)- and (1S,3R,4R)-30 were iso-
lated by careful distillation and then
transformed into [5]triangulanes (M)-
and (P)-4 using the same sequence of
reactions as applied for (M)- and (P)-3.
The structures of the key intermediates
(R)-12 and rac-31 were confirmed by
X-ray analyses. Although [4]- and [5]tri-
angulanes have no chromophore which
would lead to any significant absorption
above 200 nm, they have remarkably
high specific rotations even at 589 nm
with [a]2D0 ˆ À192.7 [(M)-3, c ˆ 1.18,
CHCl3)] or ‡373.0 [(P)-4, c ˆ 1.18,
CHCl3)]. This remarkable optical rota-
tation is in line with their helical ar-
rangement of s bonds, as confirmed by a
full valence space single excitation con-
figuration interaction treatment (SCI) in
conjunction with DFT computations at
the B3LYP/TZVP//B3LYP/6-31‡G(d,p)
level of theory which reproduce the
ORD very well. Thus, it is appropriate
to call the helically shaped unbranched
[n]triangulanes the ™s-[n]helicenes∫,
representing the s-bond analogues of
the aromatic [n]helicenes.
pylidenecarboxylic
[(1RS)-12]
and
exo-dispiro[2.0.2.1]heptane-1-carboxylic
[(1RS,3SR)-13] acids. The optical reso-
lutions of rac-12 and rac-13 furnished
enantiomerically pure acids (S)-(‡)-
12, (R)-(À)-12, (1R,3S)-(À)-13, and
(1S,3R)-(‡)-13. The ethyl ester (R)-25
of the acid (R)-(À)-12 was cyclopropa-
nated to give carboxylates (1R,3R)-26
and (1R,3S)-26. The ester (1R,3S)-26
and acids (1R,3S)-13 and (1S,3R)-13
were converted into enantiomerically
pure methylene[3]triangulanes (S)-(À)-
and (R)-(‡)-28. An alternative ap-
proach consisted of an enzymatic de-
racemization of endo-[(1SR,3SR)-di-
spiro[2.0.2.1]heptyl]methanol (rac-20)
Keywords: ab initio calculations ¥
chiral resolution ¥ cycloaddition ¥
small ring systems ¥ triangulanes
[a] Prof. Dr. A. de Meijere, Dr. S. I. Kozhushkov,
Prof. Dr. P. R. Schreiner, Dr. A. Wittkopp, Dipl.-Chem. C. Rinderspacher
Institut f¸r Organische Chemie
[d] Dr. H. Menzel
Institut f¸r Makromolekulare Chemie der Universit‰t Hannover
Am Kleinen Felde 30, 30167 Hannover (Germany)
der Georg-August-Universit‰t Gˆttingen
Tammannstrasse 2, 37077 Gˆttingen (Germany)
Fax : (‡49)551-399475
[e] Dr. D. S. Yufit, Prof. Dr. J. A. K. Howard
Department of Chemistry, University of Durham
Durham, South Rd., DH1 3LE (UK)
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[**] Preliminary communication: A. de Meijere, A. F. Khlebnikov, R. R.
Kostikov, S. I. Kozhushkov, P. R. Schreiner, A. Wittkopp, D. S. Yufit,
Angew. Chem. 1999, 111, 3682 3685; Angew. Chem. Int. Ed. 1999, 38,
3474 3477.
[b] Prof. Dr. P. R. Schreiner, Dr. A. Wittkopp,
Dipl.-Chem. C. Rinderspacher
Current address: Department of Chemistry
The University of Georgia, Athens, GA 30602-2556 (USA)
[c] Prof. Dr. A. F. Khlebnikov, Prof. Dr. R. R. Kostikov
St.-Petersburg State University, Chemical Department
Universitetskii Prosp. 2, Petrodvorets
198504, St.-Petersburg (Russia)
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828 842
however, are their potential rotatory powers in view of their
molecular helicity. We have therefore developed syntheses of
enantiomerically pure [4]- and [5]triangulanes as well as their
precursors, methylene- and dimethylene[n]triangulanes. Their
experimentally determined specific rotations are compared
with the best currently available computational results.
Introduction
Enantiomerically pure chiral compounds, which in the
ordinarily accessible UV/Vis spectral range (200 800 nm)
do not show any optical activity, may be termed crypto-
optically active.[1] As has been demonstrated by Wynberg
et al. some 35 years ago,[2] chiral hydrocarbons with four
different alkyl substituents at their centers of chirality, even in
neat form, do not exhibit any optical rotation and are thus
crypto-optically active. This essentially must have to do with
the conformational mobility in such acyclic hydrocarbons. In
contrast, unbranched [n]triangulanes 1 ([n]UT),[3] that is,
hydrocarbons which consist of spiro-annelated and thereby
mutually orthogonal cyclopropane rings only, are completely
rigid, and many of the higher [n]triangulanes 1 (n ꢀ4) are
chiral.[4]
Results
A feasible synthetic approach to a whole series of enantio-
merically pure [n]triangulanes appeared to be starting from
appropriately syn-1,3-disubstituted spiropentane derivatives.
However, it is difficult to prepare such compounds stereo-
selectively on a large scale.[7] Since intramolecular cyclo-
propanations of a remote double bond in alkenyl diazoacetate
catalyzed by a dirhodium tetrakis(carboxamidate) with chiral
ligands have been demonstrated to proceed with high
diastereoselectivities,[8] we examined this type of reaction
for (2-methylenecyclopropyl)methyl diazoacetate (10), pre-
pared from (2-methylenecyclopropyl)methanol (6) and N-
Boc-glycine (7) (Scheme 1), utilizing the [Rh2(5R-MEPY)4]
catalyst.[8] Unfortunately, this approach to the tricyclic lactone
11 turned out to be not more efficient than the previously
reported one:[9] the yield in the cyclization step was only 7%
of almost racemic 11 (ee ˆ 10%), the structure of which was
confirmed by X-ray crystallography (Figure 1).[10]
Other appropriate enantiomerically pure starting materials
for the preparation of (M)- or (P)-3 and 4 were obtained from
racemic bicyclopropylidenecarboxylic acid (rac-12), which is
easily available from the multifunctional C6-building block
bicyclopropylidene[11] by deprotonation and carboxylation,[12]
Achiral dispiro[2.0.2.1]heptane ([3]UT) 2 has two enantio-
topic positions: spiroannelation of a fourth cyclopropane ring
in either position a or b of 2 will lead to two enantiomeric
[4]UTs (M)- and (P)-3. They should not be crypto-optically
active due to their rigidity, although they are saturated
hydrocarbons and their spiro-carbon atoms, which are stereo-
genic centers, formally also contain four different alkyl
substituents only. To test this hypothesis, it ought to be
interesting to prepare and study enantiomerically pure (M)-
and (P)-[4]triangulanes [(M)-3 and (P)-3] the smallest chiral
[n]triangulanes,[4] and their higher analogues (M)- and (P)-
[5]triangulanes [(M)-4 and (P)-4] for comparison. Essentially,
the C2-symmetric molecules of (M)- and (P)-3 5 are sections
of a helix, and therefore the stereochemical descriptors for
helicenes[5] should best be applied for 3 and certain extended
unbranched triangulanes 1.[6] Racemic [4]triangulane rac-3
was first synthesized 28 years ago, yet in the meantime
improved syntheses as well as spectral, structural, and
thermochemical properties of rac-3 have been sufficiently
well documented.[3a,b] Racemic [5]triangulane rac-4 had
previously been prepared only as a mixture with meso-4.[4]
Among the most interesting features of these s-helicenes,
Figure 1. Structure of the tricyclic lactone 11 in the crystal.
Scheme 1. Attempted preparation of the tricyclic lactone 11 in enantio-
merically pure form by intramolecular cyclopropanation. a) DCC, DMAP,
CH2Cl2, 0 ! 258C, 3 h; b) 4 n HCl in Et2O, 0 ! 258C, 15 h; c) NaNO2, 5%
H2SO4, CH2Cl2/H2O, À58C, 0.5 h; d) Rh2(5R-MEPY)4 (0.3 mol%),
CH2Cl2, 408C, 13 h. DCC ˆ dicyclohexylcarbodiimde, DMAP ˆ 4-dimeth-
ylaminopyridine, MEPYˆ methyl 2-pyrrolidone-5(R)-carboxylate.
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A. de Meijere et al.
FULL PAPER
and from racemic exo-dispiro[2.0.2.1]heptane-1-carboxylic
acid (rac-13).[13] These two acids were optically resolved by
crystallization of suitable mixtures of diastereomeric salts.[14]
Among several tested enantiomerically pure bases such as
(‡)-2-amino-1-phenyl-1,3-propanediol, brucine, cinchoni-
dine, quinine, strychnine, and dehydroabietylamine, only the
latter gave readily crystallizing N and P[15] salts 14a, b and
15a, b with the acids rac-12 and rac-13, respectively. Two
crystallizations each from ethanol (for the purification of the
P salt 15b see Experimental Section), subsequent cleavage by
treatment with aqueous sodium hydroxide and then acidi-
fication with concentrated hydrochloric acid furnished enan-
tiomerically pure bicyclopropylidenecarboxylic acids (R)-(À)-
12 ([a]2D0 ˆ À183.7, c ˆ 1.0 in CHCl3, ee ꢀ98%), (S)-(‡)-12
([a]2D0 ˆ ‡183.2, c ˆ 1.0 in CHCl3, ee ꢀ98%), (1R,3S)-(À)-13
([a]2D0 ˆ À391.4, c ˆ 1.0 in CHCl3, ee ꢀ98%), and (1S,3R)-
(‡)-13 ([a]2D0 ˆ ‡361.9, cˆ 1.0 in CHCl3, ee ꢀ98%) (Scheme 2).
The absolute configuration of the acid (R)-12 was assigned
on the basis of the relative configuration of its (R)-a-
phenylethylamide (R,R)-17a as determined by an X-ray
crystal structure analysis (Scheme 2 and Figure 2). The amides
(R,R)-17a and (R,S)-17b were prepared from the racemic
acid rac-12 and (R)-(1-phenylethyl)amine (16) according to a
standard procedure,[16] separated by column chromatography
and assigned by comparison with authentic samples prepared
from the enantiomerically pure acids (R)-(À)-12 and (S)-(‡)-
12. This established the absolute configuration of (R,R)-17a.
As an indirect evidence for the relative configuration of the
diastereomeric amides 17a, b, their order of elution from
silica gel may be used. According to the rule established by
Helmchen et al.,[17] the first eluting amide 17b prepared from
the acid (‡)-12 and (R)-1-(phenylethyl)amine (16) should
have (S)-configuration and its antipode (À)-12 should have
(R)-configuration, in complete agreement with the assign-
Figure 2. X-ray structure of (R)-bicyclopropylidenecarboxylic acid (R)-N-
(1-phenylethyl)amide [(R,R)-17a].
ment from the crystal structure analysis. The absolute config-
urations of the acids (1R,3S)-13 and (1S,3R)-13 were estab-
lished by comparing the optical rotations of identical products
obtained after further transformations of the two acids 12 and
13 (see below).
In spite of its being successful for the preparation of (M)-
and (P)-3, the methodology starting from rac-12 and rac-13
appeared to be too elaborate for higher analogues in
enantiomerically pure form. Therefore, our recently devel-
oped access to enantiomerically pure (1S,3R)- and [(1R,3S)-4-
methylenespiropentyl]methanol [(1S,3R)-18 and (1R,3S)-18]
as well as racemic endo-(1S,3S)- and [(1R,3R)-dispiro[2.0.2.1]-
heptyl]methanol [(1S,3S)-20 and (1R,3R)-20] by means of an
enantioselective enzymatic acylation of the racemic alcohols
rac-18 and rac-20 catalyzed by Lipase PS (Pseudomonas sp.)
was considered (Scheme 3).[18] The acetates (1S,3R)-19 and
(1S,3S)-21 can be cleaved in a clean reaction by reduction with
LiAlH4 to give the corresponding alcohols (1S,3R)-18 and
(1S,3S)-20 in 95 and 99% yield, respectively,[18] and the
enantiomeric excess values of compounds prepared by this
route all exceeded 95%. The enantiomerically pure alcohols
(1R,3S)-18 and (1S,3R)-18 could be transformed to the
enantiomerically pure (M)-(À)- and (P)-(‡)-1,4-dimethylene-
spiropentanes (M)-23 and (P)-23 applying a sequence of
routine transformations already established in the prepara-
tion of racemic triangulanes.[3] First, (1R,3S)-18 and (1S,3R)-
18 were converted to the (bromomethyl)methylenespiropen-
tanes (1R,3S)-22 and (1S,3R)-22 by treatment with the
triphenylphosphane/bromine reagent in 78 and 79% yield,
respectively. Dehydrobromination of the latter with potassi-
um tert-butoxide gave the enantiomerically pure (M)-(À)- and
(P)-(‡)-1,4-dimethylenespiropentanes (M)-23 and (P)-23 in
48 and 50% yield, respectively, after gas chromatographic
separation in the last step, corresponding to 32 and 37%
overall yield from the racemic alcohol rac-18, with ee values of
96% for both, as determined by gas chromatography on a
chiral phase capillary column (see Experimental Section for
determinations of ee values and preparation of rac-23)
(Scheme 3).
Assuming that a successful diastereoselective cyclopropa-
nation of the central double bond in a suitable derivative of 12
would play a key role in any enantioselective synthesis of the
[4]- and [5]triangulanes 3 and 4, the acid (R)-12 was reduced
to the alcohol (R)-24,[19] since allyl and homoallyl alcohols are
known to be cyclopropanated diastereoselectively.[20] Un-
fortunately, however, the cyclopropanation of (R)-24 with the
Scheme 2. Optical resolution of racemic bicyclopropylidenecarboxylic
(rac-12) and exo-dispiro[2.0.2.1]heptane-1-carboxylic (rac-13) acids and
preparation of diastereomeric (R)-a-phenylethylamides (17a,b) of the
former. a) 1) aq. NaOH; 2) conc. HCl; 3) crystallization; b) Ph2P(O)Cl,
-
Et3N, EtOAc, À108C, 1 h.
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s-[n]Helicenes
828 842
Scheme 3. Enzymatic deracemization (kinetic resolution) of anti-
[(1SR,3RS)-4-methylenespiropentyl]methanol
(rac-18)
and
endo-
[(1SR,3SR)-dispiro[2.0.2.1]heptyl]methanol (rac-20) and preparation of
enantiomerically pure (M)-(À)- and (P)-(‡)-1,4-dimethylenespiropentanes
(M)-23 and (P)-23. a) Vinyl acetate, Lipase PS, Et2O, 20 8C, 12 h; b) Ph3P ¥
Br2, Py, CH2Cl2, À108C, 1.5 h, then 208C, 7 h; c) tBuOK, DMSO, 208C,
0.75 h, inverse addition of a solution of tBuOK in DMSO.
Scheme 4. Preparation of enantiomerically pure (1-dispiro[2.0.2.1]hep-
tyl)methanols 20 along different routes. a) LiAlH4, Et2O, 34 8C, 2 h;
b) CH2I2, Me3Al, CH2Cl2, 208C, 19 h; c) BF3 ¥ Et2O, EtOH, 788C, 2 h;
d) CH2I2, Zn, 1,2-dimethoxyethane, ultrasonication, 808C, 2 h; e) CH2N2,
Pd(OAc)2, Et2O, À58C.
CH2I2/Me3Al reagent[21] (Scheme 4) proceeded in low yield
(45%) and with poor stereoselectivity to give the alcohols
(1R,3R)-20 and (1R,3S)-20 in a ratio of 1.7:1, and even worse,
they could not be separated by chromatography. In a second
approach, the acid (R)-12 was first transformed into its ethyl
ester (R)-25,[12, 19a] following a standard procedure,[22] and then
(R)-25 was cyclopropanated with the Simmons Smith re-
agent (CH2I2/Zn).[20] The reaction was accelerated by ultra-
sonication[23] to give a mixture of ethyl endo-(1R,3R)- and exo-
(1R,3S)-(À)-1-(tert-butoxymethyl)dispiro[2.0.2.1]heptane
[(1R,3S)-29] was isolated and characterized (see Experimen-
tal Section). Although the methylene[3]triangulane 28 and
the tert-butyl ether 29 can easily be separated by an
appropriate choice of conditions for the ™bulb-to-bulb∫
distillation, probably, a sterically more demanding base
should be applied in this reaction to increase the yield of 28.
Better ee values were obtained in preparations of the
methylene[3]triangulanes 28 starting from the acid (R)-12,
while the ee values of alkenes prepared from the acid rac-13 or
alcohol rac-20 were similar in most cases.
Cyclopropanation of (S)-(À)-28a or (R)-(‡)-28b under the
conditions mentioned above furnished the enantiomerically
pure (M)-(À)- and (P)-(‡)-[4]triangulane (M)-(À)-3a and
(P)-(‡)-3b in 51 and 53% yield, respectively, after gas
chromatographic separation in the last step (Scheme 5),
corresponding to 7 and 19% overall yield from the racemic
acid rac-12 or the alcohol rac-20, respectively, with an ee of
ꢀ99% and ꢀ96%, respectively, as determined by gas
chromatography on a chiral phase capillary column.[25]
Attempted twofold cyclopropanation of the dimethylenespiro-
pentane (M)-(À)-23 furnished (M)-(À)-[4]triangulane (M)-
(À)-3b in only 14% yield, most probably because (M)-(À)-23
is unstable towards the palladium acetate catalyst.
(1R,3S)-[3]triangulane-1-carboxylates
(1R,3R)-26
and
(1R,3S)-26. These diastereomers were easily separated by
column chromatography and isolated in 28 and 41% yield,
respectively (Scheme 4). Thus, enantiomerically pure (1R,3S)-
26 was obtained in 19% yield from the racemic acid rac-12.
The enantiomerically pure ester (1R,3S)-26 was reduced to
the alcohol (1R,3S)-20a which was also prepared in 70% yield
by cyclopropanation of the alcohol (1R,3S)-18 with diazo-
methane under Pd(OAc)2 catalysis[24] (20b, the letters a, b, c
are used to distinguish identical compounds prepared from
different sources of enantiomerically pure materials). Reduc-
tion of the enantiomerically pure acids (1R,3S)- and (1S,3R)-
13 furnished (1R,3S)-20c and (1S,3R)-20a quantitatively. The
enantiomer (1S,3R)-20b was also synthesized in two steps
from the acetate (1S,3R)-19 in 95% overall yield (Scheme 4).
The enantiomerically pure alcohols 20 were transformed to
the enantiomerically pure (S)- or (R)-methylenedispiro-
[2.0.2.1]heptanes [(S)-(À)-28 or (R)-(‡)-28] in two steps.
First, treatment with the triphenylphosphane/bromine re-
agent furnished 1-(bromomethyl)-[3]triangulanes (1R,3S)-,
(1R,3R)-, (1S,3S)-, and (1S,3R)-27 in 77 99% yield
(Scheme 5). Dehydrobromination of the latter with potassium
tert-butoxide gave (S)-(À)-28 or (R)-(‡)-28 in 44 87% yield.
The dehydrobromination was complicated by a direct nucle-
ophilic substitution of bromine with tert-butoxide anion in
different proportions; in one preparation the corresponding
It should, in principle, be possible to prepare enantiomeri-
cally enriched or pure [5]- and [6]triangulanes [(M)-4 or (P)-4
and (M)-5 or (P)-5] from the same synthetic precursor as the
one used for (M)-3 and (P)-3, that is, methylene[3]triangulane
(S)-28 and (R)-28, since the position of the methylene group
predetermines any further extension of the helix. As the
meso-[5]triangulane (meso-4) is not optically active, the
alkene (S)-28d was transformed into a mixture of meso-4
1
and (M)-4 (ratio 1:5.2 according to the H NMR spectrum)
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A. de Meijere et al.
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the appropriate (1RS,3SR,4SR) relative configuration, as
confirmed by X-ray crystal structure analysis of the corre-
sponding acid (1RS,3SR,4SR)-31 (Scheme 6 and Figure 3).
Figure 3. Structure of the racemic (1RS,3SR,4SR)-trispiro[2.0.0.2.1.1]no-
nane-1-carboxylic acid [(1RS,3SR,4SR)-31] in the crystal.
Scheme 5. Preparation of enantiomerically pure (S)- and (R)-methylene-
dispiro[2.0.2.1]heptanes [(S)-(À)-28 and (R)-(‡)-28] as well as (M)- and
(P)-[4]triangulanes [(M)-(À)-3 and (P)-(‡)-3]. a) Ph3P ¥ Br2, Py, CH2Cl2,
À108C, 1.5 h, then 208C, 7 h; b) tBuOK, DMSO, 508C, 2 h; c) CH2N2,
Pd(OAc)2, Et2O, À58C.
With these results in hand, the synthesis of enantiomerically
pure esters (1R,3S,4S)-(À)-30 and (1S,3R,4R)-(‡)-30 could be
performed analogously starting from the enantiomerically
pure methylene[3]triangulanes (S)-(À)-28 and (R)-(‡)-28 in
27 and 19% isolated yield, respectively (Scheme 6). From
these esters the enantiomerically pure triangulanes (M)-4 and
(P)-4 could be prepared by a set of routine synthetic
transformations (Scheme 7) which were previously applied
for the [4]triangulanes (M)-3 and (P)-3. As in the analogous
sequence (Scheme 5), nucleophilic substitution of bromine
with tert-butoxide anion in the bromides (1R,3S,4S)- and
(1S,3R,4R)-33 essentially decreased the yield in the dehydro-
bromination step, leading to the formation of the tert-butyl
ethers (1R,3S,4S)- and (1S,3R,4R)-34 (19% yield in both
cases) (Scheme 7). Along this route, the enantiomerically
pure (M)-(À)- and (P)-(‡)-[5]triangulane (M)-(À)-4 and (P)-
(‡)-4 were prepared in 52 and 55% yield, respectively, after
gas chromatographic separation after the last step
(Scheme 7), corresponding to a 34 and 26% overall yield
from the esters 30, or 9 and 5% from (S)-28 and (R)-28,
respectively. The enantiomeric excess was ꢀ94% for both, as
determined by gas chromatography on a chiral phase capillary
column.[25] The racemic (PM)-4 for these determinations was
prepared similarly from the acid (1RS,3SR,4SR)-31 in 39%
overall yield (see Experimental Section).
using the established three-step procedure[4] in 29% overall
yield after gas chromatographic separation (Scheme 6). While
all attempts to isolate pure (M)-4 from this mixture were
unsuccessful, the mixture had a specific rotation of [a]D20
ˆ
À334.2 (c ˆ 1.5 in CHCl3), from which by correction for the
concentration of (M)-4 in the mixture, the value of [a]D20
ˆ
À381.2 (c ˆ 1.3 in CHCl3) for enantiomerically pure (M)-4 can
be derived.
The structures of (P)-(‡)-[5]triangulane (P)-(‡)-4 and rac-
4 were both examined by X-ray crystal structure analysis
(Figure 4). Naturally, the geometrical parameters of the
molecules (P)-4 and rac-4 are identical. The bond lengths
and angles in (P)-(‡)-4 and rac-4 are very close to those in [3]-
and [4]triangulanes[26] and correspond relatively well to the
general bond increment scheme which was previously devel-
oped for [n]triangulanes.[26] As it would be expected, there are
no strong intermolecular interactions in the crystals of (P)-4
and rac-4, and thus the terms ™columns∫ and ™layers∫ are used
for convenience only. The packing of the molecules in the two
crystals is almost identical in two directions (Figure 4). The
columns of the head-to-tail arranged molecules form layers
marked AA in Figure 4. However, whereas all the layers are
equivalent in the crystal of (P)-4, the ™left∫ and ™right∫ layers
alternate in the crystal of rac-4. The shortest intermolecular
Scheme 6. Elaboration of synthetic approaches to enantiomerically pure
(P)- and (M)-[5]triangulanes 4. a) CH3CHCl2, nBuLi, Et2O, À358C, 1 h;
b) tBuOK, DMSO, 508C, 2 h; c) CH2N2, Pd(OAc)2, Et2O, À58C;
d) N2CHCO2Et, [Rh(C7H15COO)2]2 (0.6 0.8 mol%), CH 2Cl2, 08C, 24 h;
e) KOH, EtOH/H2O, 78 8C, 4 h.
The addition of ethoxycarbonylcarbene, generated by
decomposition of ethyl diazoacetate in the presence of
dirhodium tetraoctanoate, to rac-28 was tested and found to
afford a mixture of four diastereomeric esters 30 (78% overall
yield) in a ratio of 26:15:26:33. The major diastereomer was
isolated in 25% yield by simply distilling off the other three
through a concentric tube column, and it turned out to possess
832
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s-[n]Helicenes
828 842
gulane (P)-(‡)-4: Upon cooling from room temperature to
À1008C this sample showed a sharp crystallization peak with
DG ˆ À3.01 kcalmolÀ1. The exact crystallization temperature
varied from sample to sample from À39 to À538C. Upon
heating the melting point was represented by a peak at 7.28C
with the same DG. This behavior with more than 45 degrees
difference of crystallization and melting temperature has been
reproduced in several cooling-heating cycles. However, after
having been heated to higher temperatures (1008C), (P)-(‡)-
4 changed its behavior although beside the melting peak
around 78C no more peaks were observed in the heating
curve. After having been heated to 1008C, the sample did not
show any crystallization peak upon cooling, but upon
subsequent heating from À100 to 308C it displayed the first
negative peak at À59.68C (DG ˆ 2.73 kcalmolÀ1) and then
melted at 8.88C with the same DG. So after having been
heated to 1008C, (P)-(‡)-4 does not show a crystallisation
upon cooling but only in the subsequent heating sequence. In
this respect the thermal behavior of (P)-(‡)-4 after having
been heated to 1008C is similiar to that of the racemate. In
spite of this, neither the NMR spectra nor the enantiomeric
purity of the sample (as determined by gas chromatography
on a chiral phase column) showed any change after having
been heated to 1008C.
The enantiomeric purities of all methylenetriangulanes and
triangulanes prepared were determined by gas chromatog-
Scheme 7. Preparation of enantiomerically pure (M)- and (P)-[5]triangu-
lanes (M)-(À)-4 and (P)-(‡)-4. a) LiAlH4, Et2O, 34 8C, 2 h; b) Ph3P ¥ Br2,
Py, CH2Cl2, À108C, 1.5 h, then 208C, 7 h; c) tBuOK, DMSO, 508C, 2 h;
d) CH2N2, Pd(OAc)2, Et2O, À58C.
contacts in the crystals of (P)-4 and
rac-4 are very similar. The shortest H ¥
¥¥ C contacts are H1 ¥¥¥ C6' contacts
between molecules in the columns
[2.92 and 2.98 ä for (P)-4 and rac-4,
respectively] and the shortest H ¥¥¥ H
contacts of 2.40 and 2.42 ä are be-
tween molecules in the ™A∫ layers.
The difference in the crystal pack-
ing of the molecules (P)-(‡)-4 and
rac-4 is reflected in an unusual behav-
ior of the two in the differential
scanning calorimetry (DSC). Thus,
upon cooling from room temperature
to À 1008C rac-[5]triangulane (rac-4)
does not show any transition, namely
no crystallization peak. However,
upon subsequent heating from À100
to 308C rac-4 displayed a broad crys-
tallization peak around À328C with
DG ˆ À1.82 kcalmolÀ1 and then melt-
ed at À148C (DG ˆ 1.84 kcalmolÀ1).
Figure 4. Structure of (P)-(‡)-[5]triangulane (P)-(‡)-4 in the crystal (bond lengths in ä, computed
values at B3LYP/6-31‡G** in parentheses), as well as packing of the molecules (P)-(‡)-4 and rac-4 in the
crystals (view along b axis), and arrangement of the layers in the crystals of (P)-4 (left) and rac-4 (right).
Even more interesting is the behavior
of the enantiomerically pure [5]trian-
Chem. Eur. J. 2002, 8, No. 4
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833

A. de Meijere et al.
FULL PAPER
Table 2. A comparison of the measured (in CHCl3) and DFT/SCI-
computed specific rotations of enantiomerically pure methylenetriangu-
lanes and triangulanes.
raphy using a chiral phase capillary column, and found to be
between 91% in one case and 94 99% in most cases
(Table 1). As different sources of enantiomerically pure
starting materials were used in the preparations, only the
results for the purest samples are summarized. The specific
rotations were determined in CHCl3 for all compounds.
Compound
l [nm]
[a]2D0
measured
computed[a]
(P)-(‡)-23
589
546
436
365
‡ 125.6
‡ 154.2
‡ 289.3
‡ 525.7
‡ 120.9
‡ 181.5
‡ 303.8
‡ 419.5
Table 1. Purities, enantiomeric excess values (ee) and specific rotations of
(M)-(À)-3
(S)-(À)-28
(3S,4S)-(À)-35
(P)-(‡)-4
589
546
436
365
À 192.7
À 229.7
À 400.2
À 648.2
À 219.2
À 266.3
À 487.0
À 840.1
À 385.8
À 451.6
À 824.9
À 1428.9
‡ 373.0
‡ 445.2
‡ 777.4
‡ 1264.0
À 217.9
À 264.0
À 407.8
À 576.7
À 261.6
À 313.7
À 500.8
À 749.0
À 318.6
À 461.8
À 934.3
À 1364.6
‡ 394.9
‡ 508.1
‡ 791.9
‡ 1080.3
all methylenetriangulanes and triangulanes prepared.
Entry
Compound
Purity (GC)
[%]
ee (GC)[a]
[%]
[a]2D0
/
c in CHCl3
1
2
3
4
5
6
7
8
9
(P)-(‡)-23
(M)-(À)-23
(S)-(À)-28
(R)-(‡)-28
(3S,4S)-(À)-35
(P)-(‡)-3
ꢀ 95
ꢀ 99
ꢀ 99
ꢀ 99
ꢀ 90
ꢀ 95
ꢀ 95
ꢀ 99
ꢀ 95
84[b]
ꢀ 96
ꢀ 96
ꢀ 94
ꢀ 91
ꢀ 94
ꢀ 96
ꢀ 99
ꢀ 94
ꢀ 94
ꢀ 95
‡ 125.6/1.1
À 123.6/1.2
À 219.2/1.1
‡ 213.2/1.1
À 385.8/1.1
‡ 187.5/1.0
À 192.7/1.2
‡ 373.0/1.0
À 334.2/1.2
À 381.2/1.3[c]
589
546
436
365
589
546
436
365
(M)-(À)-3
(P)-(‡)-4
(M)-(À)-4
(M)-(À)-4
589
546
436
365
10
[a] Chiral column with octakis(6-O-methyl-2,3-di-O-pentyl)-g-cyclodextrin
(50% in OV 1701 w/w) phase (Prof. W. A. Kˆnig, Universit‰t Hamburg).
[b] Containing 16% meso-4. [c] Extrapolated by correcting for the content
of achiral meso-4.
(M)-(À)-4
589
546
436
365
À 334.2
À 398.7
À 696.3
À 1033.1
À 394.9
À 508.1
À 791.9
À 1080.3
Discussion
[a] All computed values were shifted by a constant value to account for
effects of solvent/solute interactions, which currently cannot be taken into
account computationally (see Computational studies).
Although [4]- (3) and [5]triangulane (4) do not have a
chromophore which would lead to any significant absorption
above 200 nm, they have remarkably high specific rotations
even at 589 nm with [a]D20 ˆ ‡187.5 (c ˆ 1.0 in CHCl3) [(P)-
(‡)-3], À192.7 (c ˆ 1.2 in CHCl3) [(M)-(À)-3], ‡373.0 (c ˆ 1.0
in CHCl3) [(P)-(‡)-4], and À334.2 (c ˆ 1.2 in CHCl3) [(M)-
(À)-4]. Moreover, these specific rotations increase drastically
on going to shorter wavelengths; this indicates that these
compounds must have Cotton effects with large amplitudes in
the ORD below 200 nm. The same holds true for (P)-(‡)-
dimethylenespiropentane [(P)-(‡)-23] and (S)-(À)-1-methyl-
enedispiro[2.0.2.1]heptane [(S)-(À)-28c] (Table 2). The un-
usually large difference between the experimentally deter-
mined specific rotations for the [5]triangulanes (P)-(‡)-4 and
(M)-(À)-4 must be due to the lower purity of the latter (99 and
95%, respectively, see Table 1). The larger specific rotation of
(P)-(‡)-4 appears to be the more reliable value, since the
specific rotation for (M)-(À)-4 of [a]2D0 ˆ À381.2, which was
extrapolated from the value for the mixture of (M)-(À)-4 and
meso-4, matches that of (P)-(‡)-4 more closely.
This good agreement between experiment and theory for
the [4]- (3) and [5]triangulanes (4) as well as dimethylene-
spiropentane (23) and 1-methylenedispiro[2.0.2.1]-heptane
(28) not only provides confidence in the general applicability
of this computational approach to the simulation of ORD and
CD spectra,[33] but also confirms that the rotatory powers of 3
and 4 are an outflow of their helical arrangements of s bonds.
Thus [4]- and [5]triangulanes are true ™s-[n]helicenes∫, the
first s-bond analogues of the aromatic [n]helicenes which
have a helical arrangement of p skeletons and should
therefore better be termed p-[n]helicenes to distinguish them
from these newly established s-[n]helicenes. One important
difference has to be noted, though: While the p-[n]helicenes
have fully conjugated electronic systems, adjacent three-
membered rings in [n]triangulanes are orthogonal with
respect to each other. There is conjugative electronic inter-
action only between every other spirocyclopropane ring.[34]
On the other hand, the inherent helicity of the [n]triangulanes
is probably an essential contributor to the overall rotatory
power of the methylene[n-1]triangulanes, which are the
synthetic precursors of the [n]triangulanes. Thus, when
comparing the specific rotations of dimethylenespiropentane
(23), methylene[3]triangulane (28), [4]triangulane (3), meth-
ylene[4]triangulane (35), and [5]triangulane (4) (125.6, 219.2,
192.7, 385.8, and 373.08, respectively), it is noted that the big
increases occur on going from dimethylenespiropentane 23 to
methylene[3]triangulane 28 and [4]triangulane 3 as well as
from 3 to methylene[4]triangulane (35) and [5]triangulane (4),
For a better understanding of these remarkably high
rotatory strengths, density functional theory (DFT) compu-
tations were carried out at a reasonably high level of theory
31]
[B3LYP/6-31‡G(d,p)][27
applying a full valence space
single excitation configuration interaction treatment[32]
(DFT-SCI at B3LYP/TZVP). Indeed, the computed specific
rotations over the whole range of wavelengths are in very
good agreement with the experimental values and thus
confirm the strong Cotton effects in the ORD going along
with large ellipticities in the circular dichroism below 200 nm
(Table 2).
834
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Chem. Eur. J. 2002, 8, No. 4

s-[n]Helicenes
828 842
anti-rac-1-(tetrahydropyranyloxymethyl)-4-methylenespiropentane,[37] rac-
emic 1-methylenedispiro[2.0.2.1]heptane (rac-28),[38] racemic [4]triangu-
lane (rac-trispiro[2.0.0.2.1.1]nonane rac-3),[38] enantiomerically pure anti-
(4-methylenespiropentyl)methanols (1R,3S)- and (1S,3R)-18,[18] enantio-
merically pure endo-(dispiro[2.0.2.1]heptyl)methanols (1R,3R)- and
(1S,3S)-20,[18] (2-methylenecyclopropyl)methanol (6),[39] and (N-tert-butoxy-
carbonyl)glycine (7)[40] were prepared according to the previously pub-
lished procedures. The acid rac-12 was purified by column chromatography
on silica gel (eluent hexane/Et2O 3:2) followed by recrystallization from
hexane (rac-12: m.p. 109 110 8C). All operations in anhydrous solvents
were performed under argon in flame-dried glassware. Diethyl ether and
1,2-dimethoxyethane were dried by distillation from sodium/benzophe-
none, pyridine and DMSO from calcium hydride, CH2Cl2 from P2O5,
MeOH from magnesium dimethoxide. All other chemicals were used as
commercially available; Lipase PS (Pseudomonas sp.) was purchased from
Amano Pharmaceutical Co., Ltd. Organic extracts were dried over MgSO4.
NMR spectra were recorded on a Bruker AM 250 instrument (250 MHz for
1H and 62.9 MHz for 13C NMR). Multiplicities were determined by DEPT
(distortionless enhancement by polarization transfer) measurements.
Chemical shifts refer to dTMS ˆ 0.00 according to the chemical shifts of
residual CHCl3 signals. IR spectra were recorded on a Bruker IFS 66 FT-IR
as KBr pellets or oils between NaCl plates. Mass spectra were measured
with Finnigan MAT 95 (EI and HR-EI, at 70 eV, preselected ion peak
matching at R ꢁ 10000 to be within Æ2 ppm of the exact masses) and
Varian CH 5 (CI, at 70 eV) spectrometers. GC analyses were performed on
Siemens Sichromat 1-4. Preparative GC separations were performed on
Intersmat 130 and Varian Aerograph 920 instruments (20% SE 30 on
Chromosorb W-AW-DMCS, 1200 mm  8.2 mm column). Enantiomeric
while the specific rotations of methylene[n-1]triangulanes and
[n]triangulanes are all very close to each other.
As predicted by these computations,[35] the rotatory
strengths of the [5]triangulanes (M)-4 and (P)-4 turned out
to be about twice as large as those of the [4]triangulanes (M)-3
and (P)-3. It remains to be checked experimentally whether
this good agreement will also hold for the next higher
analogues, the [6]triangulanes (M)-5 and (P)-5 for which the
computed specific rotations at 589 nm ([a]2D0 ˆ 509.7) are only
29% larger than those of (M)-4 and (P)-4. Whether this is due
to the fact that the sum of all interplanar angles (SW) between
adjacent pairs of spiro-fused cyclopropane rings reaches 3608
in the [5]triangulanes (M)-4 and (P)-4, while it is 4508 in
[6]triangulanes (M)-5 and (P)-5, may only be speculated
about. The continuous change of interplanar angles can be
visualized by a ribbon connecting one methylene group each
of the two terminal cyclopropane rings in any [n]triangulane
with each of the methylene groups in the rings between them
(Figure 5). In (M)-4 and (P)-4, such a ribbon would complete
exactly one turn of a helix, while in the [6]triangulanes (M)-5
and (P)-5 it would simply go 908 beyond a full turn. The
original computational prediction that the rotatory power of
[5]triangulanes (M)-4 and (P)-4 should be about twice as large
as that of [4]triangulanes (M)-3 and (P)-3, has now actually
been proved (see Table 2). Apparently, it will be well worth to
prepare at least the next higher member in this series of s-
[n]helicenes, the [6]triangulanes (M)- and (P)-5 in enantio-
merically pure form. It will also be quite interesting to
investigate the Raman optical activities (ROA) of the whole
series of enantiomerically pure methylene[n-1]triangulanes
and [n]triangulanes, since the ROA of (M)-(À)-[4]triangulane
(M)-(À)-3 has been shown to disclose spectacular effects with
D values close to 0.5% in the 900 cmÀ1 region.[36]
excess values were determined using
a 25 m capillary column with
octakis(6-O-methyl-2,3-di-O-pentyl)-g-cyclodextrin (50% in OV 1701
w/w) phase (Prof. W. A. Kˆnig, Universit‰t Hamburg). Optical rotations
were measured on a Perkin Elmer 241 digital polarimeter in a 1 dm cell.
Melting points were determined on a B¸chi 510 capillary melting point
apparatus, values are uncorrected. TLC analyses were performed on
precoated sheets, 0.25 mm Sil G/UV254 (Macherey Nagel). Silica gel grade
60 (230 400 mesh) (Merck) was used for column chromatography.
DSC measurements: Differential scanning calorimetry of (P)-(‡)-4 and
rac-4 was performed on a Netzsch DSC 204/1/F instrument. The samples
were cooled down from room temperature to À1008C and then heated up
to 30 or 1008C, respectively, with a rate of 10 degrees per min. The
transition temperatures were determined as the peak maxima and the
transition enthalpy from the peak areas.
Crystal structure determinations: Suitable crystals of the compounds
(3SR,7SR)-11, (R,R)-17a, and (1RS,3SR,4SR)-31 were grown by slowly
concentrating their diluted solutions in hexane/Et2O mixtures. Crystals of
(P)-4 and rac-4 were grown in situ on the diffractometer in the capillary of
0.2 mm diameter. During cooling down the crystals of (R,R)-17a, peak-
Experimental Section
General aspects: Racemic bicyclopropylidenecarboxylic acid rac-12,[12]
racemic exo-dispiro[2.0.2.1]heptane-1-carboxylic acid rac-13,[13] racemic
Figure 5. The helicities of (M)-[4]triangulane (M)-3 and its higher analogues (M)-[5]- 4 and (M)-[6]triangulane 5.
Chem. Eur. J. 2002, 8, No. 4 ¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 0947-6539/02/0804-0835 $ 17.50+.50/0
835

A. de Meijere et al.
FULL PAPER
shape broadening occurred. The process was reversible and began at about
250 K. Therefore the X-ray experiment for (R,R)-17a was performed at
room temperature. The data were collected on an automated 4-circle
diffractometer Nonius CAD-4 [(R,R)-17a] and a Bruker SMART CCD 1 K
(other compounds) diffractometer (graphite monochromator, MoKa radi-
ation, w/2q scan for 17a, w scan for others). The structures were solved by
direct methods and refined by full-matrix least squares on F2. All non-
hydrogen atoms were refined anisotropically, all H atoms were located on
the difference Fourier maps and refined isotropically. H atoms of (R,R)-17a
were placed in calculated positions and refined as ™riding∫ atoms; the
absolute configuration was assigned on the basis of the known (R)-
configuration of 16, the Flack parameter for the reported configuration is
0(5) and for the inverted model 1(5). In all other structures H atoms were
located in the difference Fourier maps and refined isotropically. The
parameters of crystal data collections and structure refinements are
presented in Table 3.[10] Absolute configurations of all molecules could
not be determined reliably and were assigned on the basis of additional
chemical information. The lactone 11 forms so-called intergrowth crystals
which are highly unusual for molecular compounds. A detailed discussion
of the structural study of 11 will be published elsewhere.[41] Molecules in the
crystal of (R,R)-17a are connected by hydrogen bonds N-H ¥¥¥ O(1) [N ¥¥¥ O
2.807(8) ä] in the chains along the crystallographic b axis. Molecules of 31
in the crystal form centrosymmetrical dimers which is common for
carboxylic acids; molecules (P)-4 and rac-4 occupy special positions on
calcd (%) for C12H19NO4 (241.3): C 59.73, H 7.94, N 5.81; found C 59.68, H
7.77, N 5.74.
(2-Methylenecyclopropyl)methyl glycinate hydrochloride (9): The carba-
mate 8 (30.05 g, 124.5 mmol) was stirred with 4.5n HCl/Et2O solution
(100 mL) at 08C for 3 h. After additional stirring at ambient temperature
for 12 h, the precipitate was filtered off and dried in vacuo to give 9 (17.71 g,
80%) as a colorless powder. An analytical sample was recrystallized from
MeOH/Et2O 1:10. M.p. 90 92 8C; 1H NMR (D2O): d ˆ 5.44 (d, J ˆ 1.8 Hz,
ˆ
ˆ
1H; CH2), 5.40 (d, J ˆ 1.8 Hz, 1H; CH2), 4.09 (dd, J ˆ 7.3, 11.0 Hz, 1H;
CH2O), 3.94 (dd, J ˆ 8.3, 11.0 Hz, 1H; CH2O), 3.71 (s, 2H; CH2N), 1.80
1.70 (m, 1H; CH), 1.27 (t, J ˆ 8.8 Hz, 1H; CH2), 1.03 0.84 (m, 1H; CH 2);
13C NMR (D2O): d ˆ 107.2, 71.9, 42.5, 10.6 (CH2); 15.8 (CH); 170.6, 134.7
(C); elemental analysis calcd (%) for C7H12ClNO2 (177.6): C 47.33, H 6.82,
N 7.89; found C 47.11, H 6.76, N 7.95.
(3SR,7SR)-5-Oxatricyclo[5.1.0.01,3]octan-4-one [(3SR,7SR)-11]: CH2Cl2
(6.5 mL) was added to a solution of hydrochloride 9 (1.57 g, 8.85 mmol)
in H2O (2.2 mL). Under vigorous stirring, a solution of NaNO2 (0.74 g) in
H2O (2.2 mL) at À58C and then a solution of H2SO4 (43 mg) in H2O
(0.8 mL) at À88C were added dropwise. The organic phase was thoroughly
washed with NaHCO3 sat. solution (3 Â 5 mL), dried, and concentrated
under reduced pressure at 08C to give crude (2-methylenecyclopropyl)-
1
methyl diazoacetate (10) (1.18 g, 88%). H NMR: d ˆ 5.43 (d, J ˆ 1.8 Hz,
ˆ
ˆ
1H; CH2), 5.40 (d, J ˆ 1.8 Hz, 1H; CH2), 4.75 (brs, 1H; CH), 4.09 (dd,
J ˆ 6.5, 11.4 Hz, 1H; CH2O), 3.94 (dd, J ˆ 8.0, 11.4 Hz, 1H; CH2O), 1.85
1.70 (m, 1H; CH), 1.32 (tt, J ˆ 2.1, 9.0 Hz, 1H; CH2), 1.00 0.96 (m, 1H;
CH2); 13C NMR: d ˆ 105.0, 67.9, 8.6 (CH2); 46.0, 14.3 (CH); 166.7, 131.8 (C).
This compound was dissolved in CH2Cl2 (25 mL), and the resulting solution
was added to a solution of Rh2(5R-MEPY)4 (20 mg, 0.3 mol%) in CH2Cl2
(25 mL) at 408C during 8 h. After additional stirring at the same
temperature for 5 h, the mixture was concentrated at ambient pressure,
and the residue was distilled ™bulb-to-bulb∫ in vacuo (0.1 Torr) into a cold
trap (À788C). The content of the trap was purified by column chromatog-
raphy (20 g silica gel, 1 Â 20 cm column, pentane/Et2O 1:3) to give
(3SR,7SR)-11 (75 mg, 7%) as colorless crystals. Rf ˆ 0.30; m.p. 42 43 8C;
[a]2D0 ˆ À11.0 (c ˆ 3.22 in CHCl3); ee ˆ 10%; 1H NMR: d ˆ 4.68 (dd, J ˆ 6.5,
12.0 Hz, 1H; CH2O), 3.77 (dd, J ˆ 9.0, 12.0 Hz, 1H; CH2O), 1.83 (dd, J ˆ
2.8, 8.5 Hz, 1H; CH2), 1.75 (dd, J ˆ 4.0, 8.5 Hz, 1H; CH2), 1.67 (t, J ˆ
5.9 Hz, 1H; CH2), 1.56 1.47 (m, 2H; CH, CH 2), 1.33 (tt, J ˆ 1.0, 4.8 Hz,
1H; CH); 13C NMR: d ˆ 65.8, 16.6, 15.3 (CH2); 12.7, 11.6 (CH); 171.9, 18.1
(C).
À
the twofold axis passing through the C1 atom and the center of the C2 C2a
bond.
(2-Methylenecyclopropyl)methyl (N-tert-butoxycarbonyl)glycinate (8): A
solution of (N-tert-butoxycarbonyl)glycine (7) (27.142 g, 155 mmol) in
CH2Cl2 (50 mL) was added at 08C over a period of 20 min to a solution of
(2-methylenecyclopropyl)methanol (6) (13.795 g, 164 mmol), DMAP
(1.894 g, 15.5 mmol) and DCC (35.18 g, 170.5 mmol) in anhydrous CH2Cl2
(250 mL). After the reaction mixture was stirred for an additional 3 h at
ambient temperature, the precipitate was filtered off. The organic phase
was washed with aq. sat. NaHCO3 and brine (100 mL each), dried and
concentrated under reduced pressure. The residue was purified by column
chromatography (300 g silica gel, 6 Â 20 cm column, hexane/Et2O 1:1) to
give the carbamate 8 (30.693 g, 82%) as a colorless solid. Rf ˆ 0.42; m.p.
1
ˆ
42 44 8C (hexane); H NMR: d ˆ 5.37 (brs, 1H; CH2), 5.32 (brs, 1H;
ˆ
CH2), 5.14 (t, J ˆ 5.3 Hz, 1H; NH), 4.01 (dd, J ˆ 6.5, 11.2 Hz, 1H; CH2O),
3.93 (dd, J ˆ 8.3, 11.2 Hz, 1H; CH2O), 3.88 (d, J ˆ 5.3 Hz, 2H; CH2N),
1.85 1.70 (m, 1H; CH), 1.37 (s, 9H; 3CH 3), 1.35 1.15 (m, 1H; CH 2),
1.00 0.96 (m, 1H; CH 2); 13C NMR (D2O): d ˆ 28.3 (3CH3); 105.0, 67.7,
42.3, 8.7 (CH2); 14.0 (CH); 170.3, 155.6, 131.6, 79.7 (C); elemental analysis
Optical resolution of the acids rac-12 and rac-exo-13 with dehydroabietyl-
amine (General procedure GP 1): a) The pure racemic acid (20 mmol) was
Table 3. Crystal and data collection parameters for compounds (3SR,7SR)-11, (R,R)-17a, (1RS,3SR,4SR)-31, (P)-4, and rac-4.
(3SR,7SR)-11
(R,R)-17a
(1RS,3SR,4SR)-31
(P)-4
rac-4
formula
Mw
crystals
space group
a [ä]
b [ä]
c [ä]
b [8]
V [ä3]
Z
C7H8O2
124.13
orthorhombic
P212121
7.4346(8)
8.1758(9)
9.963(1)
96.00(3)
605.6(1)
4
C15H17NO
227.30
monoclinic
P21
10.623(2)
4.803(1)
13.283(3)
95.51(1)
674.0(2)
2
C10H12O2
164.20
monoclinic
P21/c
6.7097(4)
9.5859(5)
14.0695(8)
114.08(1)
900.75(9)
4
C11H14
146.22
monoclinic
C2
12.024(2)
5.3056(8)
7.609(1)
112.68(2)
443.2(1)
2
C11H14
146.22
monoclinic
C2/c
12.0052(8)
5.3146(3)
14.9813(9)
882.0(3)
4
F(000)
264
1.361
0.099
110.0(2)
50
244
1.120
0.070
298
352
1.211
0.083
100.0(2)
60.5
160
1.096
0.061
110.0(2)
59.4
320
1 [gcmÀ3
]
1.101
0.061
110.0(2)
29.9
m [mmÀ1
T [K]
Vmax [8]
]
25
refl. collected
refl. independent
Rint
4101
1066
0.121
0.0852
0.0486
1904
1631
0.073
0.141
10554
2501
0.055
0.1003
0.0375
2557
1139
0.022
0.1775
0.0695
4811
1200
0.020
0.1167
0.0392
wR2(F2)
R(F)
0.0524
no. parameters
refined
115
153
157
79
79
GOF
0.961
1.033
1.061
1.076
1.082
836
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0804-0836 $ 17.50+.50/0
Chem. Eur. J. 2002, 8, No. 4

s-[n]Helicenes
828 842
added with heating and stirring to a solution of pure dehydroabietylamine
(DAA, 1 equiv) in ethanol (20 mL). The solution was cooled to room
temperature and, after 24 h of resting, the crystalline N salt was separated
by filtration, washed with a minimal amount of ethanol and recrystallized
twice from EtOH (for 14a) or 75% aq. EtOH (for 15a, dissolved in hot
EtOH (6 mL), then water (2 mL) was added). The P salt was isolated as
indicated below.
M.p. 54 55 8C; [a]2D0 ˆ ‡361.9 (c ˆ 1.0 in CHCl3). Its 1H and 13C NMR
spectra were identical to those of (1R,3S)-13.
N-[(R)-1-Phenylethyl]-(R)-bicyclopropylidenecarboxamide (17a) and N-
[(R)-1-phenylethyl]-(S)-bicyclopropylidenecarboxamide (17b): A solution
of Et3N (0.303 g, 0.42 mL, 3.0 mmol) was added dropwise to a stirred
solution of the acid (1RS)-12 (0.373 g, 3.01 mmol) and diphenylphosphinic
chloride (0.712 g, 3.01 mmol) in anhydrous ethyl acetate (5 mL) at À108C.
After stirring for an additional 1 h at À108C, a solution of (R)-1-
phenylethylamine (16) (0.364 g, 3.01 mmol) in EtOAc (0.5 mL) was added
dropwise. The mixture was stirred at room temperature for 14 h and then
filtered. The filtrate was washed with 1n HCl (3 mL), 10% K2CO3 solution
(7 mL), and H2O (5 mL). The organic layer was dried and concentrated
under reduced pressure to give a mixture of 17a and 17b (0.682 g, ca.
100%). Their chromatographic separation (80 g silica gel, 20 Â 2 cm
column, hexane/Et2O 7:3) afforded 17b (1st eluted, 0.226 g, 66%) and
17a (2nd eluted, 0.226 g, 66%).
b) A suspension of the N or P salt (6 mmol) in a water/Et2O mixture (30 mL
of each) was cooled in an ice bath, and a solution of NaOH (0.3 g, 7.5 mmol)
in water (10 mL) was added dropwise with stirring. The mixture was stirred
until the salt had completely dissolved. The inorganic layer was washed
with diethyl ether (3 Â 30 mL) and acidified by addition of conc. HCl
solution (ca. 1 mL) to ca. pH 3 to give a colorless precipitate. The mixture
was extracted with diethyl ether (4 Â 30 mL), the combined ethereal
solutions were dried, concentrated under reduced pressure, and the residue
recrystallized from hexane (for 12) or from pentane at À268C (for 13)
yielding the enantiomerically pure free acid.
Compound 17a: M.p. 126 127 8C (from hexane/Et2O); [a]2D0 ˆ ‡6.5 (c ˆ
1.0 in CHCl3); IR (KBr): nÄ ˆ 3268, 1639 cmÀ1; 1H NMR: d ˆ 7.36 7.22 (m,
5H; Ph), 5.84 (brd, J ˆ 6.9 Hz, 1H; NH), 5.20 5.08 (m, 1H; CHN), 2.26
2.21 (m, 1H; CH), 1.84 1.79 (m, 1H; CH 2), 1.76 1.64 (m, 1H; CH 2), 1.48
(d, J ˆ 6.8 Hz, 3H; CH3), 1.28 1.15 (m, 4H; CH 2); 13C NMR: d ˆ 20.3
(CH3); 10.9, 3.5, 3.2 (CH2); 128.5, 126.0 (2CH); 127.1, 48.6, 21.8 (CH);
N Salt 14a and P salt 14b: From the racemic acid rac-12 (2.49 g, 20 mmol)
and DAA (5.72 g, 20 mmol) the N salt 14a (2.47 g, 60%) was obtained
according to GP 1a. The filtrate was concentrated under reduced pressure,
the solid residue was washed with a minimal amount of Et2O and dissolved
in EtOH (20 mL). This solution was diluted with water to a volume of ca.
100 mL under stirring and heating, and then carefully concentrated by
evaporation under reflux. The transparent solution was cooled to RT, and
after 24 h the crystalline P salt 14b was separated by filtration and
recrystallized from EtOH (14b: 3.09 g, 75%). 14a: m.p. 156 157 8C;
[a]2D0 ˆ À10.5 (c ˆ 1.0 in CHCl3). 14b: m.p. 158 160 8C; [a]2D0 ˆ ‡69.5 (c ˆ
1.0 in CHCl3).
‡
170.4, 143.4, 112.8, 111.2 (C); MS (EI): m/z (%): 227 (4) [M] , 226 (2) [M À
‡
‡
‡
H] , 212 (1) [M À CH3] , 184 (1), 123 (22), 105 (100) [C8H9] , 77 (19)
‡
[C6H5] ; MS (HR-EI): calcd for C15H17NO: 227.1310; found 227.1310).
Compound 17b: M.p. 155 156 8C (from hexane/Et2O); [a]2D0 ˆ ‡128.5
(c ˆ 1.0 in CHCl3); IR (KBr): nÄ ˆ 3268, 1636 cmÀ1; 1H NMR: d ˆ 7.38 7.23
(m, 5H; Ph), 5.83 (brd, J ˆ 6.9 Hz, 1H; NH), 5.19 5.07 (m, 1H; CHN),
2.25 2.18 (m, 1H; CH), 1.84 1.70 (m, 1H; CH 2), 1.70 1.64 (m, 1H; CH 2),
1.46 (d, J ˆ 6.9 Hz, 3H; CH3), 1.43 1.16 (m, 4H; CH 2); 13C NMR: d ˆ 20.4
(CH3); 11.5, 3.5, 3.3 (CH2); 128.6, 126.1 (2CH); 127.2, 48.6, 21.7 (CH);
N Salt 15a and P salt 15b: From the racemic exo-acid rac-13 (11.08 g,
80.2 mmol) and DAA (38.17 g of 60% purity, 80.2 mmol), the N salt 15a
(8.04 g, 47%) was obtained according to GP 1a; m.p. 158 159 8C; [a]D20
ˆ
‡
170.5, 143.3, 112.8, 111.1 (C); MS (EI): m/z (%): 227 (1) [M] , 226 (1) [M À
À75.6 (c ˆ 0.8 in CHCl3). The combined mother liquors were concentrated,
and the residue was distributed between Et2O (200 mL) and aq. NaOH (6 g
NaOH in 200 mL of H2O). The water layer was extracted with diethyl ether
(3 Â 100 mL), acidified with conc. HCl (ca. 4 mL) to pH 3, and then
extracted with Et2O (4 Â 100 mL) and pentane (100 mL). The combined
organic solutions were dried, filtered and concentrated under reduced
pressure to give the crude acid (1S,3R)-13 (9.0 g, ca. 65.1 mmol), which was
treated with DAA (18.6 g, 65.1 mmol, pure) in hot ethanol (40 mL). Et2O
(20 mL) was added to the resulting solution, and the mixture was kept at
‡28C for 12 h. The precipitate was separated, washed with Et2O and dried
in vacuo to give the P salt (9.73 g, 23 mmol) with m.p. 138 141 8C. This salt
was dissolved in boiling CH2Cl2 (60 mL), and then methylene chloride was
replaced with Et2O (ca. 120 mL). After cooling, the precipitate was filtered
off and dried in vacuo affording the pure P salt 15b (8.00 g, 47%) with m.p.
145 147 8C; [a]2D0 ˆ ‡139.6 (c ˆ 1.0 in CHCl3).
‡
‡
‡
H] , 212 (1) [M À CH3] , 198 (1), 184 (2), 123 (19), 105 (100) [C8H9] , 77
‡
(15) [C6H5] ; MS (HR-EI): calcd for C15H17NO: 227.1310; found 227.1310).
Ethyl (R)-bicyclopropylidenecarboxylate [(R)-25]: The acid (R)-12 (4.00 g,
32.2 mmol) was treated with BF3 ¥ Et2O (3.2 mL) in anhydrous EtOH
(40 mL) (788C, 2 h) to give ester (R)-25 (4.73 g, 97%) according to the
protocol of Kadaba;[22] b.p. 52 54 8C (3 Torr); [a]2D0 ˆ À142.5 (c ˆ 1.9 in
1
CHCl3). The H and 13C NMR spectra of (R)-25 were identical with those
reported for rac-25.[19a]
Ethyl exo-(1R,3R)- and endo-(1R,3S)-dispiro[2.0.2.1]heptane-1-carboxy-
late [(1R,3R)-26 and (1R,3S)-26]: A mixture of ester (R)-25 (4.56 g,
30 mmol), Zn (mossy) (17.6 g, 269 mmol), and anhydrous 1,2-dimethoxy-
ethane (40 mL) in a round-bottomed flask was immersed in an ultrasonic
cleaning bath, and the mixture was irradiated with ultrasound while being
heated to 608C, and diiodomethane (64.3 g, 19.4 mL, 240 mmol) was added
dropwise. After having been irradiated at 808C for another 2 h, the mixture
was cooled to RT, diluted with pentane (100 mL), poured into sat. aqueous
NH4Cl solution, and extracted with pentane (4 Â 50 mL). The combined
organic layers were washed with water, dried, and concentrated under
reduced pressure. The residual oil was distilled under reduced pressure to
give a 2:3 mixture (3.70 g, 74%) of (1R,3R)- and (1R,3S)-26. B.p. 64 678C
(3 Torr). The pure isomers were obtained by column chromatography
[300 g silica gel, 5 Â 30 cm column, hexane/Et2O 100:1, the (1R,3R)-isomer
was eluted first] and then distilled ™bulb-to-bulb∫ in vacuo.
(R)-(À)-Bicylopropylidenecarboxylic acid [(R)-12]: From the salt 14a
(2.47 g, 6.04 mmol), the acid (R)-(À)-12 (0.584 g, 78%) was obtained
according to GP 1b; m.p. 1108C; [a]2D0 ˆ À183.7 (c ˆ 1.0 in CHCl3); ee
‡
ꢀ98%; IR (KBr): nÄ ˆ 1724 cmÀ1; MS (EI): m/z (%): 124 (2) [M] , 123 (22)
‡
‡
‡
[M À H] , 96 (16) [M À C2H4] , 95 (44) [M À H À C2H4] , 84 (32), 79 (100)
‡
[M À CO2H] , 77 (65), 67 (25), 51 (43); MS (HR-EI): calcd for C7H8O2:
124.0524; found 124.0524).
(S)-(‡)-Bicylopropylidenecarboxylic acid [(S)-12]: From the salt 14b
(3.09 g, 7.55 mmol), the acid (S)-(‡)-12 (0.79 g, 84%) was obtained
according to GP 1b; m.p. 1108C; [a]2D0 ˆ ‡183.2 (c ˆ 1.0 in CHCl3); ee
(1R,3R)-26: Yield: 1.38 g (28%); [a]2D0 ˆ À63.8 (c ˆ 1.3 in CHCl3).
1
ꢀ98%. The H and 13C NMR spectra of (R)- and (S)-12 were identical to
(1R,3S)-26: Yield: 2.03 g (41%); [a]2D0 ˆ À266.0 (c ˆ 1.15 in CHCl3). The
1H and 13C NMR spectra of (1R,3R)- and (1R,3S)-26 were identical to those
reported for rac-endo- and rac-exo-26.[13a,b]
those reported for rac-12.[12]
(1R,3S)-(À)- and (1S,3R)-(‡)-Dispiro[2.0.2.1]heptane-1-carboxylic acids
[(1R,3S)- and (1S,3R)-13]: (1R,3S)-13: From the N salt 15a (41.0 g,
96.8 mmol), the acid (1R,3S-)13 (9.50 g, 71%) was obtained according to
GP 1b after two recrystallizations; m.p. 578C; [a]2D0 ˆ À391.4 (c ˆ 1.0 in
CHCl3); 1H NMR: d ˆ 11.2 (brs, 1H; OH), 1.79 (dd, J ˆ 4.3, 7.6 Hz, 1H;
CH), 1.63 (t, J ˆ 4.2 Hz, 1H; CH2), 1.38 (d, J ˆ 4.6 Hz, 1H; CH2), 1.34 (d,
J ˆ 4.6 Hz, 1H; CH2), 1.29 (dd, J ˆ 4.1, 7.6 Hz, 1H; CH2), 0.92 0.84 (m,
2H; CH2), 0.70 0.64 (m, 2H; CH 2); 13C NMR: d ˆ 15.3, 12.2, 5.8, 5.7
(CH2); 19.9 (CH); 180.9, 25.3, 15.0 (C).
Preparation of triangulanylmethanols
General procedure GP 2: A solution of the respective ester or acid
(40 mmol) in anhydrous diethyl ether (30 mL) was added dropwise to a
suspension of the specified amount of LiAlH4 in Et2O (100 mL) at a rate
maintaining a gentle reflux. After 2 h of heating under reflux, quenching
the reaction with Na2SO4 sat. solution and filtration, the precipitate was
additionally extracted overnight with Et2O in a Soxhlet apparatus. The
combined organic solutions were dried and concentrated under reduced
pressure. The residue was pure enough to be used without further
purification.
(1S,3R)-13: From the P salt 15b (8.00 g, 18.9 mmol), the acid (1S,3R-)13
(2.20 g, 84%) was obtained according to GP 1b after two recrystallizations.
Chem. Eur. J. 2002, 8, No. 4
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0804-0837 $ 17.50+.50/0
837

A. de Meijere et al.
FULL PAPER
(R)-(À)-Bicyclopropylidenylmethanol [(R)-24]: From LiAlH4 (0.95 g,
25 mmol) and acid (R)-12 (2.72 g, 21.9 mmol), alcohol (R)-24 (1.84 g,
76%) was obtained according to GP 2; [a]2D0 ˆ À13.3 (c ˆ 0.95 in CHCl3).
The 1H and 13C NMR spectra of the alcohol (R)-24 were identical to those
reported for the racemic compound.[19a]
18.1, 7.3 (CH2); 23.3 (CH); 134.4, 19.1 (C); MS (CI): m/z (%): 209/207 (40/
‡
‡
41) [M‡NH3‡NH4] , 192/190 (100/98) [M‡NH4] , 175/173 (26/24)
‡
‡
[M‡H] , 127 (31), 125 (75), 110 (79) [M À HBr‡NH4] , 108 (100).
Preparation of the bromides
General procedure GP 3: Bromine (1.05 equiv) was added at À30 to
À158C over a period of 10 min to a solution of triphenylphosphane
(1.05 equiv) in anhydrous dichloromethane (50 mL). After an additional
15 min of stirring, a mixture of the respective alcohol (35 mmol) and
anhydrous pyridine (1 equiv) in CH2Cl2 (15 mL) was added dropwise at
À308C. The mixture was stirred for 1.5 h at À108C, and then at ambient
temperature for an additional 7 h. After evaporation of the solvent,
pentane (100 mL) was added, the mixture was stirred for 7 h, and then
filtered. The precipitate was thoroughly washed with pentane (3 Â 50 mL),
and the combined pentane extracts were filtered through silica gel (0.5 cm
layer). The filtrate was concentrated under reduced pressure (ca. 200 Torr),
and the residue was distilled ™bulb-to-bulb∫ in vacuo (0.1 Torr) into a cold
trap (À788C).
(1R,3S)-(À)-(Dispiro[2.0.2.1]hept-1-yl)methanol [(1R,3S)-20]: a) From
LiAlH4 (0.5 g, 13.2 mmol) and ester (1R,3S)-26 (1.95 g, 11.7 mmol), alcohol
(1R,3S)-20a (1.24 g, 85%) was obtained according to GP 2 as an oil. [a]D20
ˆ
À104.3 (c ˆ 1.2 in CHCl3); 1H NMR: d ˆ 3.61 (dd, J ˆ 6.4, 11.1 Hz, 1H;
CH2O), 3.47 (dd, J ˆ 7.3, 11.1 Hz, 1H; CH2O), 2.73 (s, 1H; OH), 1.26 1.18
(m, 1H; CH), 1.15 (d, J ˆ 4.1 Hz, 1H; CH2), 1.05 (d, J ˆ 4.1 Hz, 1H; CH2),
0.80 0.75 (m, 3H; CH 2), 0.66 (t, J ˆ 4.4 Hz, 1H; CH2), 0.58 0.49 (m, 2H;
CH2); 13C NMR: d ˆ 65.94, 10.41, 9.99, 5.34, 5.24 (CH2); 18.77 (CH); 13.59
‡
‡
(2C); MS (EI): m/z (%): 124 (0.8) [M] , 123 (2) [M À H] , 109 (12), 105
(18), 95 (38), 91 (100), 79 (86), 77 (47), 67 (50), 53 (42).
b) From LiAlH4 (13.70 g, 361 mmol) and the acid (1R,3S)-13 [18.40 g,
133.2 mmol; with [a]2D0 ˆ À380.1 (c ˆ 1.0 in CHCl3) and m.p. 568C], alcohol
(1R,3S)-20c (16.50 g, 100%) was obtained according to GP 2. [a]D20
À112.5 (c ˆ 1.2 in CHCl3).
ˆ
(1R,3S)-(À)-1-(Bromomethyl)-4-methylenespiropentane
[(1R,3S)-22]:
From the alcohol (1R,3S)-18 (2.40 g, 21.8 mmol), Ph3P (5.99 g, 22.8 mmol),
Br2 (3.65 g, 1.18 mL, 22.8 mmol), and pyridine (1.72 g, 1.76 mL, 21.7 mmol),
bromide (1R,3S)-22 (2.93 g, 78%) was obtained according to GP 3 after
additional purification by column chromatography (20 g silica gel, 2.2 Â
15 cm column, pentane) followed by distillation under reduced pressure.
Rf ˆ 0.58; b.p. 58 61 8C (23 mbar); [a]2D0 ˆ À305.6 (c ˆ 1.0 in CHCl3). The
1H and 13C NMR spectra of the product were identical to those of rac-22.
(1S,3R)-(‡)-(Dispiro[2.0.2.1]hept-1-yl)methanol [(1S,3R)-20]: a) From
LiAlH4 (16.0 g, 421.6 mmol) and acid (1S,3R)-13 [21.60 g, 156.3 mmol;
with [a]2D0 ˆ ‡357.0 (c ˆ 1.3 in CHCl3) and m.p. 54 56 8C], alcohol (1S,3R)-
20a (19.1 g, 98%) was obtained according to GP 2 as an oil. [a]2D0 ˆ ‡106.5
(c ˆ 1.3 in CHCl3). The 1H and 13C NMR spectra of the product were
identical to those of the (1R,3S)-20.
b) From LiAlH4 (0.83 g, 21.9 mmol) and the acetate (1S,3R)-21 (2.94 g,
17.7 mmol), alcohol (1S,3R)-20b (2.09 g, 95%) was obtained according to
GP 1. [a]2D0 ˆ ‡108.3 (c ˆ 1.2 in CHCl3); MS (CI): m/z (%): 159 (20)
(1S,3R)-(‡)-1-(Bromomethyl)-4-methylenespiropentane
[(1S,3R)-22]:
From the alcohol (1S,3R)-18 (1.42 g, 12.89 mmol), Ph3P (3.55 g,
13.53 mmol), Br2 (2.16 g, 0.70 mL, 13.53 mmol), and pyridine (1.02 g,
1.04 mL, 12.89 mmol), bromide (1S,3R)-22 (1.77 g, 79%) was obtained
according to GP 3. [a]D20 ˆ ‡305.2 (c ˆ 1.6 in CHCl3). The 1H and 13C NMR
spectra of the product were identical to those of rac-22.
‡
‡
‡
[M‡NH3‡NH4] , 142 (71) [M‡NH4] , 124 (39) [M À H2O‡NH4] , 107
‡
(100) [M À OH] .
(1RS,3SR,4SR)-(Trispiro[2.0.0.2.1.1]non-1-yl)methanol (rac-32): From
LiAlH4 (504 mg, 13.28 mmol) and the acid rac-31 (1.45 g, 8.83 mmol),
alcohol rac-32 (1.32 g, ꢂ100%) was obtained according to GP 2 as an oil.
1H NMR: d ˆ 3.68 (dd, J ˆ 6.4, 11.0 Hz, 1H; CH2O), 3.56 (dd, J ˆ 7.2,
11.0 Hz, 1H; CH2O), 2.06 (s, 1H; OH), 1.35 1.25 (m, 1H; CH), 1.21 (d, J ˆ
3.4 Hz, 2H; CH2), 0.97 (d, J ˆ 3.7 Hz, 1H; CH2), 0.95 0.89 (m, 2H; CH 2),
0.84 0.78 (m, 1H; CH 2), 0.71 0.64 (m, 3H; CH 2), 0.58 (t, J ˆ 4.4 Hz, 1H;
CH2); 13C NMR: d ˆ 66.2, 12.2, 9.6, 8.8, 4.7, 4.0 (CH2); 18.4 (CH); 18.8, 18.0,
(1S,3S)-(‡)-1-(Bromomethyl)dispiro[2.0.2.1]heptane [(1S,3S-27]: From
the alcohol (1S,3S)-20 (8.68 g, 69.91 mmol), Ph3P (19.25 g, 73.4 mmol),
Br2 (11.73 g, 3.78 mL, 73.4 mmol), and pyridine (5.53 g, 5.65 mL,
69.91 mmol), bromide (1S,3S)-27 (10.05 g, 77%) was obtained according
to GP 3 as an oil. [a]2D0 ˆ ‡20.0 (c ˆ 1.0 in CHCl3); 1H NMR: d ˆ 3.39 (dd,
J ˆ 6.8, 10 Hz, 1H; CH2Br), 3.16 (dd, J ˆ 8.3, 10 Hz, 1H; CH2Br), 1.82
(dddd, J ˆ 4.5, 6.8, 7.8, 8.3 Hz, 1H; CH), 1.27 1.19 (m, 2H; CH 2), 1.13 (d,
J ˆ 3.8 Hz, 1H; CH2), 0.96 0.79 (m, 3H; CH 2), 0.67 0.57 (m, 2H; CH 2);
13C NMR: d ˆ 37.4, 13.8, 13.4, 5.3, 5.1 (CH2); 22.1 (CH); 13.8, 12.8 (C); MS
‡
14.1 (C); MS (CI): m/z (%): 185 (29) [M‡NH3‡NH4] , 168 (100)
‡
‡
‡
[M‡NH4] , 150 (18) [M] , 133 (69) [M À OH] , 125 (35), 108 (30), 105
‡
‡
(25).
(EI): m/z (%): 188/186 (1/1) [M] , 187/185 (10/10) [M À H] , 105 (39) [M À
‡
(1S,3R,4R)-(‡)-(Trispiro[2.0.0.2.1.1]non-1-yl)methanol [(1S,3R,4R)-32]:
From LiAlH4 (2.0 g, 52.7 mmol) and ester (1S,3R,4R)-30 (4.40 g,
22.9 mmol), alcohol (1S,3R,4R)-32 (3.07 g, 89%) was obtained according
to GP 2. [a]2D0 ˆ ‡226.6 (c ˆ 1.0 in CHCl3). The 1H and 13C NMR spectra of
the product were identical to those of rac-32.
BrÀ 2H] , 91 (100), 79 (100), 77 (42), 67 (20), 65 (22), 53 (20); MS (HR-
EI): calcd for C8H11Br: 188.0024; found: 188.00309.
(1R,3R)-(À)-1-(Bromomethyl)dispiro[2.0.2.1]heptane [(1R,3R)-27]: From
the alcohol (1R,3R)-20 (11.89 g, 95.76 mmol), Ph3P (26.37 g, 100.55 mmol),
Br2 (16.07 g, 5.18 mL, 100.55 mmol), and pyridine (7.58 g, 7.75 mL,
95.76 mmol), bromide (1R,3R)-27 (15.44 g, 86%) was obtained according
to GP 3. [a]2D0 ˆ À18.0 (c ˆ 1.0 in CHCl3). The 1H and 13C NMR spectra of
the product were identical to those of (1S,3S)-27.
(1R,3S,4S)-(À)-(Trispiro[2.0.0.2.1.1]non-1-yl)methanol
[(1R,3S,4S)-32]:
From LiAlH4 (2.0 g, 52.7 mmol) and ester (1R,3S,4S)-30 (4.40 g,
22.9 mmol), the alcohol (1R,3S,4S)-32 (3.16 g, 92%) was obtained accord-
ing to GP 2. [a]2D0 ˆ À211.16 (c ˆ 1.1 in CHCl3). The 1H and 13C NMR
spectra of the product were identical to those of rac-32.
(1R,3S)-(À)-1-(Bromomethyl)dispiro[2.0.2.1]heptane [(1R,3S)-27]: a) From
the alcohol (1R,3S)-20a (1.14 g, 9.18 mmol, prepared from ester (1R,3S)-
26), Ph3P (2.53 g, 9.65 mmol), Br2 (1.56 g, 0.5 mL, 9.76 mmol), and pyridine
(0.78 mL), bromide (1R,3S)-27a (1.35 g, 79%) was obtained according to
rac-1-(Bromomethyl)-4-methylenespiropentane
(rac-22):
Bromine
(7.497 g, 2.42 mL, 46.91 mmol) was added at À30 to À158C over a period
of 10 min to a solution of triphenylphosphane (12.304 g, 46.91 mmol) in
anhydrous dichloromethane (100 mL). After an additional 15 min of
stirring, a solution of racemic anti-(1RS,3SR)-1-(tetrahydropyranyloxy-
methyl)-4-methylenespiropentane[37] (9.21 g, 47.4 mmol) in CH2Cl2 (25 mL)
was added dropwise at 08C over a period of 0.5 h. The mixture was stirred
for an additional 2 h at ambient temperature, washed with brine (4 Â
100 mL), dried, and concentrated under reduced pressure at 08C. Pentane
(100 mL) was added, the mixture was stirred for an additional 2 h, and then
filtered. The precipitate was thoroughly washed with pentane (3 Â 50 mL),
and the combined pentane extracts were concentrated under reduced
pressure (ca. 200 Torr). The residue was purified by column chromatog-
1
GP 3. [a]2D0 ˆ À110.6 (c ˆ 1.5 in CHCl3); H NMR: d ˆ 3.47 (d, J ˆ 7.6 Hz,
2H; CH2Br), 1.46 (dq, J ˆ 4.4, 7.5 Hz, 1H; CH), 1.33 (d, J ˆ 3.8 Hz, 1H;
CH2), 1.12 (d, J ˆ 3.8 Hz, 1H; CH2), 1.03 (dd, J ˆ 4.7, 7.6 Hz, 1H; CH2),
0.89 0.76 (m, 3H; CH 2), 0.68 0.62 (m, 2H; CH 2); 13C NMR: d ˆ 5.4
(2CH2); 38.4, 14.2, 10.1 (CH2); 19.5 (CH); 23.3, 14.4 (C).
b) From alcohol (1R,3S)-20b (1.08 g, 8.7 mmol), Ph3P (2.40 g, 9.16 mmol),
Br2 (1.46 g, 0.27 mL, 9.14 mmol), and pyridine (712 mg, 0.73 mL,
9.0 mmol), bromide (1R,3S)-27b (1.32 g, 81%) was obtained according to
GP 3. [a]2D0 ˆ À105.1 (c ˆ 1.2 in CHCl3).
c) From alcohol (1R,3S)-20c (16.30 g, 131.3 mmol), Ph3P (34.40 g,
131.1 mmol), Br2 (21.25 g, 6.85 mL, 133 mmol), and pyridine (10.39 g,
10.62 mL, 131.3 mmol), bromide (1R,3S)-27c (24.30 g, 99%) was obtained
according to GP 3. [a]2D0 ˆ À106.8 (c ˆ 1.1 in CHCl3).
raphy (50 g silica gel, 3 Â 20 cm column, pentane) to give rac-22 (7.42 g,
1
ˆ
91%) as a slightly yellow oil. Rf ˆ 0.58; H NMR: d ˆ 5.30 (brs, 1H; CH2),
ˆ
5.18 (t, J ˆ 2.1 Hz, 1H; CH2), 3.50 (dd, J ˆ 7.1, 10 Hz, 1H; CH2Br), 3.44
(dd, J ˆ 7.8, 10 Hz, 1H; CH2Br), 1.92 1.79 (m, 1H; CH), 1.54 (dd, J ˆ 0.5,
7.0 Hz, 1H; CH2), 1.41 (dd, J ˆ 4.8, 7.8 Hz, 1H; CH2), 1.34 (dd, J ˆ 2.1,
7.0 Hz, 1H; CH2), 1.10 (t, J ˆ 4.8 Hz, 1H; CH2); 13C NMR: d ˆ 99.5, 36.9,
(1S,3R)-(‡)-1-(Bromomethyl)dispiro[2.0.2.1]heptane
[(1S,3R)-27]:
a) From alcohol (1S,3R)-20a (19.0 g, 153 mmol), Ph3P (40.20 g,
153.3 mmol), Br2 (24.82 g, 8.0 mL, 155.3 mmol), and pyridine (12.1 g,
838
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0804-0838 $ 17.50+.50/0
Chem. Eur. J. 2002, 8, No. 4

s-[n]Helicenes
828 842
12.4 mL, 153 mmol), bromide (1S,3R)-27a (28.0 g, 98%) was obtained
according to GP 3. [a]D20 ˆ ‡108.5 (c ˆ 1.2 in CHCl3). The 1H and 13C NMR
spectra of the product were identical to those of (1R,3S)-27.
impurities (according to the 1H NMR spectrum), but was used in the next
step without further purification.
b) Bromide (1R,3S)-27c (24.30 g, 129.9 mmol) was treated with tBuOK
(18.50 g, 164.9 mmol) according to GP 4a. After workup 2, ™bulb-to-bulb∫
distillation furnished the alkene (S)-28c (a solution in pentane, ca. 6.0 g
according to the 1H NMR spectrum, 44%) (bath temperature 20 40 8C)
and (1R,3S)-(À)-1-(tert-butoxymethyl)dispiro[2.0.2.1]heptane [(1R,3S)-29]
(3.70 g, 16%) (bath temperature 50 80 8C). Analytical samples were
b) From alcohol (1S,3R)-20b (2.761 g, 22.23 mmol), Ph3P (6.12 g,
23.34 mmol), Br2 (3.73 g, 1.20 mL, 23.34 mmol), and pyridine (1.76 g,
1.8 mL, 22.23 mmol), bromide (1S,3R)-27b (2.58 g, 62%) was obtained
according to GP 3. [a]2D0 ˆ ‡106.4 (c ˆ 1.8 in CHCl3).
(1RS,3SR,4SR)-1-(Bromomethyl)trispiro[2.0.0.2.1.1]nonane
(rac-33):
purified by preparative GC. (S)-28c: [a]2D0 ˆ À219.2 (c ˆ 1.1 in CHCl3); ee
From alcohol rac-32 (1.33 g, 8.85 mmol), Ph3P (2.44 g, 9.30 mmol), Br2
1
ˆ
ˆ
ꢀ94%; H NMR: d ˆ 5.28 (brs, 1H; CH2), 5.20 (t, J ˆ 2.4 Hz, 1H; CH2),
1.59 (d, J ˆ 3.5 Hz, 1H; CH2), 1.47 (d, J ˆ 3.5 Hz, 1H; CH2), 1.42 (t, J ˆ
1.7 Hz, 1H; CH2), 1.24 (d, J ˆ 7.7 Hz, 1H; CH2), 0.93 0.68 (m, 4H; CH 2);
the 13C NMR spectrum of the product was identical to that reported for the
racemic compound.[34] (1R,3S)-29: [a]D20 ˆ À124.3 (c ˆ 1.3 in CHCl3);
1H NMR: d ˆ 3.47 (dd, J ˆ 5.7, 9.4 Hz, 1H; CH2O), 3.13 (dd, J ˆ 8.0,
9.4 Hz, 1H; CH2O), 1.21 1.18 (m, 1H; CH), 1.16 (s, 9H; 3CH 3), 1.13 (d,
J ˆ 4.9 Hz, 1H; CH2), 1.03 (d, J ˆ 3.4 Hz, 1H; CH2), 0.84 (d, J ˆ 4.4 Hz, 1H;
CH2), 0.83 0.76 (m, 2H; CH 2), 0.64 (t, J ˆ 4.4 Hz, 1H; CH2), 0.59 (dd, J ˆ
4.6, 6.1 Hz, 2H; CH2); 13C NMR: d ˆ 27.6 (3CH3); 65.3, 10.9, 10.4, 5.4, 5.3
(CH2); 16.9 (CH); 72.3, 18.7, 13.7 (C); elemental analysis calcd (%) for
C12H20O (180.28): C 79.94, H 11.18; found C 80.01, H 11.30.
(1.49 g, 0.48 mL, 9.34 mmol), and pyridine (699 mg, 0.72 mL, 8.84 mmol),
1
bromide rac-33 (1.64 g, 87%) was obtained according to GP 3. H NMR:
d ˆ 3.47 (d, J ˆ 7.5 Hz, 2H; CH2Br), 1.51 (tdd, J ˆ 4.3, 7.5, 7.8 Hz, 1H; CH),
1.37 (d, J ˆ 4.0 Hz, 1H; CH2), 1.26 (d, J ˆ 4.0 Hz, 1H; CH2), 1.12 (dd, J ˆ
4.5, 7.6 Hz, 1H; CH2), 1.04 (d, J ˆ 4.0 Hz, 1H; CH2), 0.97 (d, J ˆ 4.0 Hz, 1H;
CH2), 0.87 0.80 (m, 1H; CH 2), 0.73 (dd, J ˆ 2.9, 5.4 Hz, 1H; CH2), 0.70
0.62 (m, 3H; CH2); 13C NMR: d ˆ 38.3, 13.1, 12.2, 9.1, 4.8, 4.2 (CH2); 19.1
‡
(CH); 23.1, 18.8, 14.2 (C); MS (CI): m/z (%): 232/230 (8/10) [M‡NH4] ,
‡
‡
215/213 (14/16) [M‡H] , 150 (18) [M À HBr‡NH4] , 135 (38), 133 (100)
‡
[M À Br] .
(1R,3S,4S)-(À)-1-(Bromomethyl)trispiro[2.0.0.2.1.1]nonane [(1R,3S,4S)-
33]: From alcohol (1R,3S,4S)-32 (3.05 g, 20.3 mmol), Ph3P (5.34 g,
20.4 mmol), Br2 (3.29 g, 1.06 mL, 20.6 mmol), and pyridine (1.61 g,
1.64 mL, 20.3 mmol), bromide (1R,3S,4S)-33 (3.93 g, 91%) was obtained
according to GP 3. [a]D20 ˆ À193.2 (c ˆ 1.1 in CHCl3). The 1H and 13C NMR
spectra of the product were identical to those of rac-33.
c) From bromide (1S,3S)-27 (9.92 g, 53 mmol) and tBuOK (8.88 g,
79.1 mmol), the alkene (S)-28d (3.55 g, 63%) was obtained according
to GP 4b after workup 2 (bath temperature 408C). An analytical sample
was purified by preparative GC; [a]2D0 ˆ À218.5 (c ˆ 1.2 in CHCl3);
ee ꢀ94%.
(3R)-(‡)-1-Methylenedispiro[2.0.2.1]heptane [(R)-28]: a) From bromide
(1S,3R)-27a (28.0 g, 150 mmol) and tBuOK (25.0 g, 223 mmol), the
methylenetriangulane (R)-28a (13.60 g, 85%) was obtained according to
GP 4b after workup 1. An analytical sample was purified by preparative
GC. [a]2D0 ˆ ‡213.2 (c ˆ 1.1 in CHCl3); ee ꢀ91%. 1H and 13C NMR spectra
of the product were identical to those of (S)-28.
(1S,3R,4R)-(‡)-1-(Bromomethyl)trispiro[2.0.0.2.1.1]nonane [(1S,3R,4R)-
33]: From alcohol (1S,3R,4R)-32 (2.90 g, 19.3 mmol), Ph3P (5.08 g,
19.4 mmol), Br2 (3.13 g, 1.01 mL, 19.6 mmol), and pyridine (1.53 g,
1.56 mL, 19.3 mmol), bromide (1S,3R,4R)-33 (3.88 g, 94%) was obtained
according to GP 3. [a]D20 ˆ ‡208.2 (c ˆ 1.5 in CHCl3). The 1H and 13C NMR
spectra of the product were identical to those of rac-33.
Preparation of the methylenetriangulanes
b) From bromide (1S,3R)-27b (700 mg, 3.74 mmol) and tBuOK (600 mg,
5.35 mmol), the methylenetriangulane (R)-28b (a solution in pentane, ca.
320 mg according to the 1H NMR spectrum, 81%) was obtained according
to GP 4b.
General procedure GP 4: A solution of potassium tert-butoxide (tBuOK)
(1.12 g, 10 mmol) in anhydrous DMSO (25 mL) was added over a period of
30 min to a solution of the respective bromide (9 mmol) in anhydrous
DMSO (10 mL) kept at 208C, and the reaction mixture was stirred at 208C
for 15 min (GP 4a) or a solution of the bromide (7 mmol) in anhydrous
DMSO (10 mL) was added over a period of 1 h dropwise to a solution of
tBuOK (1.12 g, 10 mmol) in anhydrous DMSO (15 mL) kept at 508C, and
the reaction mixture was stirred at 508C for 1 h (GP 4b). The volatile
materials were distilled ™bulb-to-bulb∫ under reduced pressure (0.01 Torr)
into a cold (À788C) trap at a temperature of 35 to 408C inside the
distillation flask, then the product was washed thoroughly with ice-cold
water and dried (workup 1) or the mixture was poured into ice-cold water
and extracted with pentane (3 Â 5 mL) (workup 2). The combined pentane
solutions were dried and carefully concentrated under ambient pressure.
The residue was distilled ™bulb-to-bulb∫ under reduced pressure (0.2 Torr)
at the bath temperatures indicated below into a cold (À788C) trap.
c) From bromide (1R,3R)-27 (15.44 g, 82.5 mmol) and tBuOK (13.82 g,
123.1 mmol), the methylenetriangulane (R)-28c (a solution in pentane, ca.
6.82 g according to the 1H NMR spectrum, 78%) was obtained according to
GP 4b after workup 2 (bath temperature 408C). An analytical sample was
purified by preparative GC. [a]2D0 ˆ ‡166.3 (c ˆ 1.0 in CHCl3); ee ꢀ79%.
(3RS,4RS)-1-Methylenetrispiro[2.0.0.2.1.1]nonane [(3RS,4RS)-35]: Bro-
mide (1RS,3SR,4SR)-33 (1.64 g, 7.70 mmol) was treated with tBuOK
(1.13 g, 10 mmol) according to GP 4b. After workup 2, ™bulb-to-bulb∫
distillation furnished the alkene (3RS,4RS)-35 (a solution in pentane, ca.
670 mg according to the 1H NMR spectrum, 67%) (bath temperature 20
608C) and (1RS,3SR,4SR)-1-(tert-butoxymethyl)trispiro[2.0.0.2.1.1]nonane
[(1RS,3SR,4SR)-34] (318 mg, 20%) (bath temperature 60 100 8C). The
analytical samples were purified by preparative GC [(3SR,4SR)-35] or
column chromatography [(1RS,3SR,4SR)-34, 20 g silica gel, 20 Â 2 cm
column, hexane/Et2O 10:1].
rac-1,4-Dimethylenespiropentane [(MP)-23]: From bromide rac-22 (3.47 g,
20 mmol) and tBuOK (2.50 g, 22.3 mmol), diene (MP)-23 (940 mg, 51%)
was obtained according to GP 4a after workup 2 (bath temperature 308C)
and purification by preparative GC. The 1H and 13C NMR spectra of the
product were identical to the reported ones.[37]
1
ˆ
ˆ
(3SR,4SR)-35: H NMR: d ˆ 5.30 (brs, 1H; CH2), 5.23 (m, 1H; CH2),
1.50 (d, J ˆ 3.7 Hz, 1H; CH2), 1.43 (d, J ˆ 3.7 Hz, 1H; CH2), 1.33 1.32 (m,
2H; CH2), 1.26 (d, J ˆ 3.9 Hz, 1H; CH2), 1.10 (d, J ˆ 3.9 Hz, 1H; CH2),
0.88 0.69 (m, 4H; 2CH 2); 13C NMR: d ˆ 99.0, 15.9, 12.5, 8.3, 4.7, 4.0 (CH2);
135.8, 22.5, 16.5, 14.3 (C).
(M)-(À)-1,4-Dimethylenespiropentane [(M)-23]: From bromide (1R,3S)-
22 (2.85 g, 16.47 mmol) and tBuOK (2.05 g, 18.27 mmol), diene (M)-23
(726 mg, 48%) was obtained according to GP 4a after workup 2 (bath
temperature 308C) and purification by preparative GC. [a]2D0 ˆ À123.6
(c ˆ 1.2 in CHCl3); ee ꢀ96%. The 1H and 13C NMR spectra of the product
were identical to those of rac-23.
1
[(1RS,3SR,4SR)-34: Rf ˆ 0.45; H NMR: d ˆ 3.49 (dd, J ˆ 5.8, 9.5 Hz, 1H;
CH2O), 3.15 (t, J ˆ 9.5 Hz, 1H; CH2O), 1.21 1.15 (m, 3H; CH ‡CH2), 1.18
(s, 9H; 3CH3), 1.01 (d, J ˆ 3.7 Hz, 1H; CH2), 0.93 (dd, J ˆ 4.4, 7.7 Hz, 1H;
CH2), 0.88 (d, J ˆ 3.7 Hz, 1H; CH2), 0.81 0.76 (m, 1H; CH 2), 0.68 (t, J ˆ
6.2 Hz, 2H; CH2), 0.62 (dd, J ˆ 7.7, 10 Hz, 1H; CH2), 0.53 (t, J ˆ 4.4 Hz, 1H;
CH2); 13C NMR: d ˆ 27.6 (3CH3); 65.4, 12.3, 9.7, 9.5, 4.7, 4.1 (CH2); 16.5
(CH); 72.4, 18.7, 18.1, 14.1 (C); elemental analysis calcd (%) for C14H22O
(206.32): C 81.49, H 10.75; found C 81.41, H 10.90.
(P)-(‡)-1,4-Dimethylenespiropentane [(P)-23]: From bromide (1S,3R)-22
(1.73 g, 10.0 mmol) and tBuOK (1.36 g, 12.12 mmol), diene (P)-23 (462 mg,
50%) was obtained according to GP 4a after workup 2 (bath temperature
308C) and purification by preparative GC. [a]2D0 ˆ ‡117.3 (c ˆ 1.0 in
CHCl3); ee ꢀ96%. The 1H and 13C NMR spectra of the product were
identical to those of rac-23.
(3R,4R)-(‡)-1-Methylenetrispiro[2.0.0.2.1.1]nonane [(3R,4R)-35]: From
bromide (1S,3R,4R)-33 (3.80 g, 17.8 mmol) and tBuOK (3.50 g, 31.2 mmol),
alkene (3R,4R)-35 (a solution in pentane, ca. 1.35 g according to the
1H NMR spectrum, 57%) and (1S,3R,4R)-(‡)-1-(tert-butoxymethyl)tri-
spiro[2.0.0.2.1.1]nonane [(1S,3R,4R)-34] (680 mg, 19%) were obtained
according to GP 4b. (3R,4R)-35: [a]2D0 ˆ ‡506.2 (c ˆ 1.0 in CHCl3).
(3S)-(À)-1-Methylenedispiro[2.0.2.1]heptane [(S)-28]: a) From bromide
(1R,3S)-27a (1.25 g, 6.7 mmol) and tBuOK (1.12 g, 10 mmol), methylene-
triangulane (S)-28a (618 mg, 87%) was obtained according to GP 4b after
workup 1; [a]2D0 ˆ À191.2 (c ˆ 1.0 in CHCl3). This alkene contained ca. 10%
Chem. Eur. J. 2002, 8, No. 4
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0804-0839 $ 17.50+.50/0
839

A. de Meijere et al.
FULL PAPER
(1S,3R,4R)-34: [a]D20 ˆ ‡214.3 (c ˆ 1.2 in CHCl3). Their 1H and 13C NMR
lane (4.71 mmol) and Pd(OAc)2 (60 mg) in diethyl ether (15 mL). The
reaction mixture was filtered through a 3 cm pad of Celite and carefully
concentrated at ambient pressure. The residue was distilled ™bulb-to-bulb∫
under reduced pressure (0.01 Torr) into a cold (À788C) trap, if not
otherwise specified. The content of the trap was purified by preparative
GC.
spectra were identical to those of the racemic compounds.
(3S,4S)-(À)-1-Methylenetrispiro[2.0.0.2.1.1]nonane [(3S,4S)-35]: From
bromide (1R,3S,4S)-33 (3.80 g, 17.8 mmol) and tBuOK (3.50 g, 31.2 mmol),
alkene (3S,4S)-35 (a solution in pentane, ca. 1.81 g according to the
1H NMR spectrum, 77%) and (1R,3S,4S)-(À)-1-(tert-butoxymethyl)trispi-
ro[2.0.0.2.1.1]nonane [(1R,3S,4S)-34] (680 mg, 19%) were obtained accord-
ing to GP 4b. (3S,4S)-35: [a]2D0 ˆ À385.8 (c ˆ 1.1 in CHCl3). (1S,3S,4R)-34:
[a]2D0 ˆ À205.0 (c ˆ 1.1 in CHCl3). Their 1H and 13C NMR spectra were
identical to those of the racemic compounds.
(1R,3S)-(À)-(Dispiro[2.0.2.1]hept-1-yl)methanol [(1R,3S)-20a]: From the
(methylenespiropentyl)methanol (1R,3S)-18 (1.37 g, 12.43 mmol), alcohol
(1R,3S)-20b (1.08 g, 70%) was obtained according to GP 6 after purifica-
tion of the crude product by column chromatography (25 g silica gel, 1.5 Â
20 cm column, hexane/Et2O 1:1); Rf ˆ 0.42; [a]2D0 ˆ À110.4 (c ˆ 1.2 in
CHCl3).
Preparation of diastereomers and enantiomers of ethyl trispiro[2.0.0.2.1.1]-
nonane-1-carboxylates 30
(1S,3R)-(Dispiro[2.0.2.1]hept-1-yl)methyl acetate [(1S,3R)-21]: From ace-
tate (1S,3R)-19 (2.69 g, 17.7 mmol), crude acetate (1S,3R)-21 (2.94 g) was
obtained in quantitative yield according to GP 6 after ™bulb-to-bulb∫
General procedure GP 5: Ethyl diazoacetate (125 mmol) was added
dropwise to a stirred solution of the corresponding methylenedispirohep-
tane (85 mmol) and dirhodium tetraoctanoate (0.6 0.8 mol%) in anhy-
drous methylene chloride (120 mL) at 08C. The first half was added at a
rate of 1 mL per h, the second half at 0.5 mL per h. After 30 min of
additional stirring at ambient temperature, the mixture was filtered
through a short pad of silica gel, and the solvent was removed. The residue
was ™bulb-to-bulb∫ distilled in vacuo (0.01 Torr, bath temperature
<1108C) into a cooled trap (À788C). The content of the trap, consisting
of a mixture of four cycloadducts (ratio ca. 26:15:26:33) and diethyl
butenedioates, was very carefully distilled using a concentric tube (Fischer
Spaltrohr HMS 500) column at 1 Torr during one week, slowly increasing
the bath temperature from 71 to 1018C and the mantle temperature from
20 to 458C. The collected fractions had boiling points ranging from 41.1 to
65.18C; their compositions were monitored by 1H NMR spectroscopy. The
residue consisted of the practically pure (1RS,3SR,4SR)-diastereomer
which was additionally purified by ™bulb-to-bulb∫ distillation.
1
distillation. H NMR: d ˆ 4.09 (dd, J ˆ 6.4, 11.1 Hz, 1H; CH2O), 3.95 (dd,
J ˆ 7.3, 11.1 Hz, 1H; CH2O), 2.05 (s, 3H; CH3), 1.31 1.18 (m, 1H; CH),
1.15 (d, J ˆ 4.1 Hz, 1H; CH2), 1.05 (d, J ˆ 4.1 Hz, 1H; CH2), 0.80 0.75 (m,
3H; CH2), 0.66 (t, J ˆ 4.4 Hz, 1H; CH2), 0.58 0.49 (m, 2H; CH 2);
13C NMR: d ˆ 15.2 (CH3); 68.2, 10.6, 10.5, 5.4, 5.3 (CH2); 21.0 (CH); 171.2,
19.0, 13.7 (C).
(M)-(À)-Trispiro[2.0.0.2.1.1]nonane [(M)-3]: a) From alkene (S)-28a
(0.50 g, 4.71 mmol), [4]triangulane (M)-3a (0.287 g, 51%) was obtained
according to GP 6. [a]2D0 ˆ À192.7 (c ˆ 1.2 in CHCl3); ee ꢀ99%. The 1H and
13C NMR spectra of (M)-3a were identical to those reported for the
racemic compound.[38]
b) From the diene (M)-23 (200 mg, 2.17 mmol), the [4]triangulane (M)-3b
(38 mg, 14%) was obtained after purification by preparative GC; [a]D20
À190.1 (c ˆ 1.3 in CHCl3).
ˆ
Ethyl (1RS,3SR,4SR)-trispiro[2.0.0.2.1.1]nonane-1-carboxylate [(1RS,3SR,
4SR)-30]: From alkene (3RS)-28 (11.10 g, 104.6 mmol), ethyl diazoacetate
(18.0 g, 16.6 mL, 157.8 mmol), and dirhodium tetraoctanoate (0.5 g,
0.6 mol%), ester (1RS,3SR,4SR)-30 (5.11 g, 25%) was obtained according
(P)-(‡)-Trispiro[2.0.0.2.1.1]nonane [(P)-3]: a) From the alkene (R)-28b
(280 mg, 2.64 mmol), [4]triangulane (P)-3b (167 mg, 53%) was obtained
according to GP 6. [a]2D0 ˆ ‡187.5 (c ˆ 1.0 in CHCl3); ee ꢀ96%. The 1H and
13C NMR spectra of (P)-3 were identical to those reported for the racemic
compound.[38]
1
to GP 5. H NMR: d ˆ 4.12 (m, 2H; CH2O), 1.81 (dd, J ˆ 4.4, 7.6 Hz, 1H;
CH), 1.44 (d, J ˆ 4.1 Hz, 1H; CH2), 1.29 1.18 (m, 4H; CH 2), 1.24 (t, J ˆ
1.1 Hz, 3H; CH3), 1.05 (d, J ˆ 4.0 Hz, 1H; CH2), 0.85 0.80 (m, 1H, CH 2),
0.75 0.62 (m, 3H, CH 2); 13C NMR: d ˆ 14.3 (CH3), 60.2, 13.3, 12.5, 11.1,
4.9, 4.3 (CH2), 19.3 (CH), 173.6, 23.9, 19.3, 14.4 (C).
b) From the alkene (R)-28c (590 mg, 5.56 mmol), [4]triangulane (P)-3c
(351 mg, 53%) was obtained according to GP 6. [a]2D0 ˆ ‡148.5 (c ˆ 1.7 in
CHCl3); ee ꢀ79%.
Ethyl (1R,3S,4S)-(À)-trispiro[2.0.0.2.1.1]nonane-1-carboxylate [(1R,3S,
4S)-30]: From alkene (3S)-28 [9.00 g, a mixture of (3S)-28c (6.00 g) and
(3S)-28d (3.00 g), 84.79 mmol], ethyl diazoacetate (14.11 g, 13.0 mL,
123.6 mmol), and dirhodium tetraoctanoate (0.50 g, 0.80 mol%), ester
rac-Tetraspiro[2.0.0.0.2.1.1.1]undecane (rac-4): From the racemic alkene
rac-35 (335 mg, 2.54 mmol), racemic [5]triangulane rac-4 (249 mg, 67%)
was obtained according to GP 6. 1H NMR: d ˆ 1.12 [d, J ˆ 3.7 Hz, 2H;
9(11)-CH2], 1.09 [d, J ˆ 3.7 Hz, 2H; 9(11)-CH2], 1.06 (s, 2H; 10-CH2),
0.88 0.65 (m, 8H; 4CH 2); 13C NMR: d ˆ 10.9, 4.7, 4.3 (2CH2); 11.2 (CH2);
18.6, 13.6 (2C).[4]
(1R,3S,4S)-30 (4.40 g, 27%) was obtained according to GP 5. [a]D20
ˆ
À288.4 (c ˆ 1.2 in CHCl3). The 1H and 13C NMR spectra of the product
were identical to those of (1RS,3SR,4SR)-30.
(P)-(‡)-Tetraspiro[2.0.0.0.2.1.1.1]undecane [(P)-4]: From the alkene
(3R,4R)-35 (900 mg, 6.8 mmol), [5]triangulane (P)-4 (543 mg, 55%) was
obtained according to GP 6. [a]2D0 ˆ ‡373.0 (c ˆ 1.0 in CHCl3), ee ꢀ94%.
The 1H and 13C NMR spectra of (P)-4 were identical to those of the racemic
compound.
Ethyl (1S,3R,4R)-(‡)-trispiro[2.0.0.2.1.1]nonane-1-carboxylate [(1S,3R,
4R)-30]: From the alkene (3R)-28a (13.20 g, 124.3 mmol), ethyl diazoace-
tate (21.70 g, 20.0 mL, 190 mmol), and dirhodium tetraoctanoate (0.60 g,
0.60 mol%), ester (1S,3R,4R)-30 (4.53 g, 19%) was obtained according to
GP 5; [a]2D0 ˆ ‡226.6 (c ˆ 1.0 in CHCl3).
(M)-(À)-Tetraspiro[2.0.0.0.2.1.1.1]undecane [(M)-4]: a) From alkene
(3S,4S)-35 (480 mg, 3.63 mmol), [5]triangulane (M)-4 (274 mg, 52%) was
obtained according to GP 6. [a]2D0 ˆ À334.2 (c ˆ 1.2 in CHCl3); ee ꢀ94%.
The 1H and 13C NMR spectra of (M)-4 were identical to those of the
racemic compound.
(1RS,3SR,4SR)-Trispiro[2.0.0.2.1.1]nonane-1-carboxylic acid [(1RS,3SR,
4SR)-31]: A mixture of ester (1RS,3SR,4SR)-30 (2.80 g, 14.6 mmol) and a
solution of KOH (1.32 g, 23.5 mmol) in water (2 mL) and ethanol (20 mL)
was heated under reflux for 4 h and then concentrated on a rotatory
evaporator. The residue was diluted with water (20 mL), extracted with
Et2O (2 Â 25 mL), acidified with 10% HCl to pH 3 under ice-cooling, then
extracted with Et2O (3 Â 40 mL) and pentane (2 Â 40 mL). The combined
extracts were dried (MgSO4) and concentrated under reduced pressure to
give the acid (1RS,3SR,4SR)-31 (2.39 g, 100%). M.p. 89 91 8C (aq. EtOH);
1H NMR: d ˆ 10.05 (s, 1H; OH), 1.85 (dd, J ˆ 4.1, 7.4 Hz, 1H; CH), 1.54 (t,
J ˆ 4.1 Hz, 1H; CH2), 1.39 (d, J ˆ 4.7 Hz, 1H; CH2), 1.37 (dd, J ˆ 4.1, 7.4 Hz,
1H; CH2), 1.31 (d, J ˆ 4.1 Hz, 1H; CH2), 1.23 (d, J ˆ 4.7 Hz, 1H; CH2), 1.08
(d, J ˆ 4.1 Hz, 1H; CH2), 0.89 0.83 (m, 1H; CH 2), 0.78 0.75 (m, 1H;
CH2), 0.73 0.68 (m, 2H, CH 2); 13C NMR: d ˆ 14.3, 12.5, 11.3, 4.9, 4.4
(CH2); 19.4 (CH); 180.5, 25.0, 19.5, 14.5 (C). Attempted optical resolution
of this acid with DAA was unsuccessful.
b) nBuLi (10 mmol, 3.92 mL of a 2.55m solution in hexane) was added at
À358C over 1 h to a stirred solution of the alkene (S)-28d (261 mg,
2.46 mmol) and 1,1-dichloroethane (987 mg, 0.83 mL, 10 mmol) in anhy-
drous Et2O. The reaction mixture was allowed to warm to ambient
temperature and then poured onto ice. The organic phase was separated,
dried, filtered through a 3 cm pad of silica gel and concentrated under
reduced pressure. The residue (657 mg) was treated with tBuOK (873 mg,
7.78 mmol) according to GP 4a, workup 2 (408C bath temperature). The
obtained pentane solution, after careful concentration, was subjected to
cyclopropanation according to GP 6 with
a diazomethane solution
prepared from 6.0 g N-methyl-N-nitroso urea. Purification by preparative
GC furnished a non-separable mixture (103 mg, 29% over three steps) of
(M)-4 and meso-4 and in a ratio of 5.2:1 (according to the 1H NMR
spectrum[4]) with an optical rotation of [a]D20 ˆ À319.8 (c ˆ 1.5 in CHCl3).
Correction for the content of achiral meso-4 led to the derived value of
[a]2D0 ˆ À381.2 (c ˆ 1.3 in CHCl3); ee ꢀ95%.
Preparation of triangulanes and substituted triangulanes
General procedure GP 6: A solution of diazomethane [prepared from
6.00 g (58 mmol) of N-methyl-N-nitrosourea] in Et2O (60 mL) was added
dropwise at À5 to ‡38C to a solution of the respective methylenetriangu-
840
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0804-0840 $ 17.50+.50/0
Chem. Eur. J. 2002, 8, No. 4

s-[n]Helicenes
828 842
Computational studies: Geometries were optimized utilizing the GAUS-
would be (S)-3. See: IUPACTentative Rules for the Nomenclature in
Organic Chemistry. Section E. Fundamental Stereochemistry in J. Org.
Chem. 1970, 35, 2849 2867.
SIAN 98[27] program package within the framework of density functional
theory (DFT) employing the non-local gradient-corrected exchange-
30]
correlation functional of Becke, Lee, Yang, and Parr (B3LYP)[28
in
[7] H.-P. Guan, M. B. Ksebati, Y.-C. Cheng, J. C. Drach, E. R. Kern, J.
Zemlicka, J. Org. Chem. 2000, 65, 1280 1290.
conjunction with the 6-31‡G(d,p) basis set.[31] The singlet singlet excita-
tion energies and rotatory strengths of the lowest lying states were obtained
from a full valence space single excitation configuration interaction
treatment (SCI).[32] The CI calculations were carried out with the
TURBOMOLE[42] program system at the B3LYP level utilizing a TZVP
basis set.[43, 44] The resulting circular dichroism after a Kronig Kramers
transformation[45] gave the specific rotations in the ORD at the recorded
wavelengths (Table 2). As the calculated data are for the gas phase,
whereas the experimental ones are obtained for solutions, significant
deviations are to be expected. Any correction for this, of course, requires
that the solvent does not interact specifically, e.g., through hydrogen
bonding, with the solute, and that the latter only experiences an averaged
solvent field effect which currently cannot be accounted for in the
computations. As the computed compounds are pure hydrocarbons, the
optical rotations of which were measured in chloroform, a correction by
shifting the calculated plane dispersion curve by a constant value of 100 nm
appears to be justified. Regardless, curvatures of the computed and
experimental ORD traces agree remarkably well which emphasizes the
quality of the theoretical approach used here.[32]
[8] a) M. P. Doyle, W. W. Winchester, J. A. A. Hoorn, V. Lynch, S. H.
Simonsen, R. Ghosh, J. Am. Chem. Soc. 1993, 115, 9968 9978;
b) M. P. Doyle, C. S. Peterson, M. N. Protopopova, A. B. Marnett,
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8826 8837; c) M. P. Doyle, S. B. Davies, W. Hu, Org. Lett. 2000, 2,
1145 1147.
[9] K. B. Wiberg, J. R. Snoonian, J. Org. Chem. 1998, 63, 1390 1401.
[10] Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-163580 (11), CCDC-112810 [(R,R)-17a], CCDC-163581
[(1RS,3SR,4SR)-31], CCDC-163582 [(P)-4], and CCDC-163583
(rac-4). Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
(‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
[11] a) A. de Meijere, S. I. Kozhushkov, T. Spaeth, N. S. Zefirov, J. Org.
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diazoacetate, chromatographic separation of endo- and exo-cyclo-
adducts followed by hydrolysis: a) P. E. Eaton, K. A. Lukin, J. Am.
Chem. Soc. 1993, 115, 11370 11375; b) A. de Meijere, S. I. Kozhush-
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starting material, methylenespiropentane, can now be prepared on a
large scale by flash vacuum pyrolysis of bicyclopropylidene: c) A.
de Meijere, S. I. Kozhushkov, D. Faber, V. Bagutskii, R. Boese, T.
Haumann, R. Walsh, Eur. J. Org. Chem. 2001, 3607 3614. The authors
are grateful to Dipl.-Chem. V. Bagutskii for his donation of a sample
of methylenespiropentane.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie, and EPSRC (UK). R.R.K. and A.W. are
indebted to the German Academic Exchange Service (DAAD) for
Research Fellowships. A.W. also thanks the Nieders‰chsische Graduier-
tenfˆrderung for a scholarship and Dr. M. Prall for his assistance. We are
grateful to the companies BASF AG, Bayer AG, Chemetall GmbH,
Degussa AG, and H¸ls AG for generous gifts of chemicals. We thank Dr. K.
Miyazawa, Chisso Petrochemical Corporation, and Prof. M. P. Doyle,
University of Arizona, for the donation of Lipase PS and Rh2(5R-MEPY)4,
respectively. We are grateful to Prof. H. Butenschˆn, TU Hannover, for his
kind help in providing the DSC measurements, and Mrs. E. Pfeil,
Universit‰t Gˆttingen, for measurements of optical rotations. We are
particularly indebted to Dr. B. Knieriem, Universit‰t Gˆttingen, for his
careful proofreading of the final manuscript.
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other spiroannelated cyclopropane rings as substituents, (M)-3
according to the IUPAC rules may also be termed (R)-3, and (P)-3
Chem. Eur. J. 2002, 8, No. 4
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0804-0841 $ 17.50+.50/0
841

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[33] Planar chiral and arylaliphatic helical molecules have previously been
successively treated in the same way. See also: S. Grimme, J. Harren,
Received: June 26, 2001 [F3373]
842
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