Stereoselective preparation of six diastereomeric quatercyclopropanes from bicyclopropylidene and some derivatives

Article abstract of DOI:10.1002/chem.200600799

Diastereomeric meso- and d,l-bis(bicyclopropylidenyl) (5) were obtained upon oxidation with oxygen of a higher-order cuprate generated from lithiobicyclopropylidene (4) in 50 and 31 % yield, respectively. Their perdeuterated analogues meso-[D₁₄]- and d,l-[D₁₄]-5 were obtained along the same route from perdeuterated bicyclopropylidene [D ₈]-3 (synthesized in six steps in 7.4% overall yield from [D8]-THF) in 20.5% yield each. Dehalogenative coupling of 1,1-dibromo-2- cyclopropylcyclopropane (6) gave a mixture of all possible stereoisomers of 1,5-dicyclopropylbicyclopropylidene 16 in 69% yield, from which (Z)-cis-16 was separated by preparative gas chromatography (26% yield). The crystal structure of meso-5 looks like a super-position of the crystal structures of two outer bicyclopropylidene units (3) and one inner s-rrans-bicyclopropyl unit, whereas the two outer cyclopropyl moieties adopt a gauche orientation with respect to the cyclopropane rings at the inner bicyclopropylidene units in (Z)-cis-16. Birch reduction with lithium in liquid ammonia of meso-5 and d,l-5 gave two pairs of diastereomeric quatercyclopropanes trans,trans-(R*,S*, R*, S*)-17/cis,trans-(R*,S*,R*,R*)-18 and trans,trans-(R*,S*,S*,R*)-19/cis,trans-(R*, S*,S*,S*)-20 in 97 and 76% yield, respectively, in a ratio 9:1 for every pair. The latter diastereomer was also obtained as the sole product by Birch reduction of (Z)-cis-16 in 96% yield. Under the same conditions, tetradecadeuterio analogues trans,trans-[D₁₄]-(R*S*, R*,S*)-17/cis,trans-[D₁₄]-(R*, S*,R*, R*)-18 (8:1) and trans,trans[D₁₄]-(R*,S*,S*, R*)-19/cis,trans-[D₁₄](R*,S*,S*,S*)-20 (12:1) were prepared from mwo-[D₁₄]-5 and d,l-[D₁₄]-5 in 37 and 63 % yield, respectively. Reduction of meso-5 with diimine gave the cis,cisquatercyclopropane (S*,S*,R*,R*)-21 as the main product (58% yield) along with the cis,trans-diastereomer (S*,S*, R*,S*)-18 (29% yield). Thus, five of the six possible diastereomeric quatercyclopropanes were obtained from meso-5, d,l-5, and (Z)-cis-16. The X-ray crystal structure analyses of transjrans-(R*,S*,R*,S*)- 17 and cis,cis(S*,S*,R*,R*)-21 revealed for the both an unusual conformation in which the central bicyclopropyl unit adopts an s-fran.s-(antiperiplanar) orientation with φ=180.0°, and the two terminal bicyclopropyl moieties adopt a synclinal conformation with φ = 49.8 and 72.0°, respectively. In solution the vicinal coupling constants 〈³J_H,H〉 in trans,trans(R*,R*, R*,S*)-[D₁₄]-17, trans,trans(R*,S*,S*, R*)-[D₁₄]-19, trans,trans(R*,S*,R*,R*)- [D₁₄]-18 and trans,cis(R*,S*,S*,S*)-[D ₁₄]-20 were found to be 4.1, 4.7, 5.9 and 5.9 Hz, respectively. This indicates a predominance of the all-gauche conformer in (R*,S*, R*,S*)-17 and a decreasing fraction of it in this sequence of the other diastereomers.

Full text of DOI:10.1002/chem.200600799

FULL PAPER
DOI: 10.1002/chem.200600799
Stereoselective Preparation of Six Diastereomeric Quatercyclopropanes from
Bicyclopropylidene and Some Derivatives
Malte von Seebach,[a] Sergei I. Kozhushkov,[a] Heiko Schill,[a] Daniel Frank,[a]
Roland Boese,*[b] Jordi Benet-Buchholz,[b] Dmitry S. Yufit,[c] and Armin de Meijere*[a]
Dedicated to the memory of Dr. Burkhardt Knieriem
Abstract: Diastereomeric meso- and
d,l-bis(bicyclopropylidenyl) (5) were
obtained upon oxidation with oxygen
of a higher-order cuprate generated
from lithiobicyclopropylidene (4) in 50
and 31% yield, respectively. Their per-
deuterated analogues meso-[D14]- and
d,l-[D14]-5 were obtained along the
same route from perdeuterated bicyclo-
propylidene [D8]-3 (synthesized in six
steps in 7.4% overall yield from [D8]-
THF) in 20.5% yield each. Dehaloge-
native coupling of 1,1-dibromo-2-cyclo-
propylcyclopropane (6) gave a mixture
of all possible stereoisomers of 1,5-di-
cyclopropylbicyclopropylidene 16 in
69% yield, from which (Z)-cis-16 was
separated by preparative gas chroma-
tography (26% yield). The crystal
structure of meso-5 looks like a super-
position of the crystal structures of two
outer bicyclopropylidene units (3) and
one inner s-trans-bicyclopropyl unit,
whereas the two outer cyclopropyl
moieties adopt a gauche orientation
with respect to the cyclopropane rings
at the inner bicyclopropylidene units in
(Z)-cis-16. Birch reduction with lithium
in liquid ammonia of meso-5 and d,l-5
gave two pairs of diastereomeric qua-
tercyclopropanes trans,trans-(R*,S*,R*,
S*)-17/cis,trans-(R*,S*,R*,R*)-18 and
trans,trans-(R*,S*,S*,R*)-19/cis,trans-
(R*,S*,S*,S*)-20 in 97 and 76% yield,
respectively, in a ratio 9:1 for every
pair. The latter diastereomer was also
obtained as the sole product by Birch
reduction of (Z)-cis-16 in 96% yield.
Under the same conditions, tetradeca-
deuterio analogues trans,trans-[D14]-
(R*,S*,R*,S*)-17/cis,trans-[D14]-(R*,
S*,R*,R*)-18 (8:1) and trans,trans-
[D14]-(R*,S*,S*,R*)-19/cis,trans-[D14]-
(R*,S*,S*,S*)-20 (12:1) were prepared
from meso-[D14]-5 and d,l-[D14]-5 in 37
and 63% yield, respectively. Reduction
of meso-5 with diimine gave the cis,cis-
quatercyclopropane (S*,S*,R*,R*)-21
as the main product (58% yield) along
with
the
cis,trans-diastereomer
(S*,S*,R*,S*)-18 (29% yield). Thus,
five of the six possible diastereomeric
quatercyclopropanes were obtained
from meso-5, d,l-5, and (Z)-cis-16. The
X-ray crystal structure analyses of
trans,trans-(R*,S*,R*,S*)-17 and cis,cis-
(S*,S*,R*,R*)-21 revealed for the both
an unusual conformation in which the
central bicyclopropyl unit adopts an s-
trans-(antiperiplanar) orientation with
f=180.08, and the two terminal bicy-
clopropyl moieties adopt a synclinal
conformation with f=49.8 and 72.08,
respectively. In solution the vicinal cou-
3
pling constants h JH,Hi in trans,trans-
(R*,S*,R*,S*)-[D14]-17,
(R*,S*,S*,R*)-[D14]-19,
trans,trans-
trans,cis-
(R*,S*,R*,R*)-[D14]-18 and trans,cis-
(R*,S*,S*,S*)-[D14]-20 were found to
be 4.1, 4.7, 5.9 and 5.9 Hz, respectively.
This indicates a predominance of the
all-gauche conformer in (R*,S*,R*,S*)-
17 and a decreasing fraction of it in
this sequence of the other diastereom-
ers.
Keywords: bicyclopropylidenes
·
À
C C coupling · conformation analy-
sis · lithiation · small-ring systems
Introduction
[a] Dr. M. von Seebach, Dr. S. I. Kozhushkov, Dr. H. Schill, D. Frank,
Prof. Dr. A. de Meijere
Institut für Organische und Biomolekulare Chemie
der Georg-August-Universität Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax : (+49)551-399-475
Remarkably, nature not only produces a large variety of bio-
logically active and structurally interesting compounds with
single cyclopropyl moieties,[1–3] but also brings forward prod-
ucts which contain fatty acid residues with four and even
five consecutive cyclopropane rings.[4]
One example is the antifungal nucleoside FR-900848 1,
which was isolated as a natural product from Streptoverticil-
lum fervens in 1990,[5] the other is U-106305 2, a cholesteryl
ester transfer protein inhibitor from the fermentation broth
of Streptomyces sp. UC 11136.[6] In both compounds the con-
secutive oligocyclopropane moieties are all-trans-configured.
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[b] Prof. Dr. R. Boese, Dr. J. Benet-Buchholz
Institut für Anorganische Chemie, Universität Essen
Universitätsstrasse 3–5, 45117 Essen (Germany)
Fax : (+49)201-183-2535
E-mail: boese@structchem.uni-essen.de
[c] Dr. D. S. Yufit
Department of Chemistry, University of Durham
Durham, South Rd., DH1 3LE (UK)
Chem. Eur. J. 2007, 13, 167 – 177
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167

Scheme 1. Retrosynthetic considerations concerning quatercyclopropanes
8 to be prepared from bicyclopropylidene (3) and dibromobicyclopropyl
6.
It comes as no surprise that several synthetically oriented
groups around the world have invested a considerable
amount of work into the development of feasible syntheses
of these two compounds.[7–10] The total synthesis of FR-
900848 1[11,12] and U-106305 2[12,13] was achieved in 1996 by
Barrett et al., and the key step for the stereoselective assem-
bly of the quatercyclopropane moiety was the enantioselec-
tive Simmons–Smith-type cyclopropanation of 2-butene-1,4-
diol as developed by Charette et al.[14] The higher acyclic
and even cyclic syn-all-trans-oligocyclopropyl-1,n-dimetha-
nol derivatives have been prepared not only as precursors to
the natural products 1 and 2 but also out of interest in their
conformational behavior.[15] Having gained some experience
with the conformational analysis of bicyclopropyl early
on,[16,17] we were intrigued by the conformational features of
the quater- and quinquecyclopropane units in 1 and 2. We
therefore set out to prepare as many as possible of the six
diastereomers of unsubstituted quatercyclopropane as
model compounds and study their structural and conforma-
tional properties. In view of the fact that the tetrasubstituted
alkene bicyclopropylidene (3),[18] which already contains two
cyclopropyl groups with a stereoselectively reducible double
bond between them, can easily be deprotonated with n-bu-
tyllithium in tetrahydrofuran at 08C,[19] we anticipated it to
be a feasible building block for the construction of stereo-
isomeric quatercyclopropanes.
The oxidative coupling of two lithiobicyclopropylidene
molecules (4) was indeed accomplished under different con-
ditions (Scheme 2). For instance, transmetallation of 4 with
anhydrous magnesium bromide solution, followed by treat-
ment with cupric chloride at À788C (cf. ref. [22]) afforded a
1.6:1 mixture of meso- and d,l-bis(bicyclopropylidenyl) (5)
in 44% yield (Scheme 2). A similar result was achieved
upon oxidation with oxygen of a higher-order cuprate[20a]
generated from lithiobicyclopropylidene (4) and cuprous cy-
anide adopting a published procedure,[23] upon which the
Results and Discussion
The concept was to subject lithiobicyclopropylidene (4),
formed upon deprotonation of (3) with n-butyllithium
almost quantitatively,[19] to some sort of homocoupling, if
necessary via some other organometallic intermediate de-
rived from 4, adopting one of the established procedures,[20]
and thus convert it into a bis(bicyclopropylidenyl) (5), which
would contain the four cyclopropane rings necessary for the
target compounds (Scheme 1). Alternatively, another bicy-
clopropylidene derivative 7 with four cyclopropyl groups
should be accessible by the highly efficient dimerization of
bromocoppercyclopropylidenoids[21] generated from dibro-
mocyclopropanes, in this case 2,2-dibromobicyclopropyl 6,
by treatment with n-butyllithium in tetrahydrofuran in the
presence of cupric chloride. The resulting bicyclopropyli-
dene 7 just as the bis(bicyclopropylidenyl) (5), by trans- or
cis-stereoselective reduction of the double bonds would
yield various diastereomeric quatercyclopropanes 8.
Scheme 2. Preparation of the diastereomeric bis(bicyclopropylidenyl)s
meso-5 and d,l-5 as well as meso-10 and d,l-10 under various conditions
and as cupric chloride-assisted dehalogenative dimerization of 1,1-dibro-
mo-2-cyclopropylcyclopropane (6). a) nBuLi, THF, 08C, 1 h; b) MgBr2,
Et2O, À78!208C, 1 h, then CuCl2, À78!208C, 2.5 h; c) CuCN, À100!
À408C, 0.5 h, then O2, À788C, 0.5 h; d) [CuIBu3P]4, À788C, 1 h, then O2,
À788C, 1 h; e) N2CHCO2Et, [Rh
G
12.5 h; f) EtMgBr, Ti
A
208C, 24h; h) tBuOK, DMSO, 208C, 24h; i) CHBr 3, KOH (pellets),
TEBACl, CH2Cl2, 20–258C, 2 h; j) CuCl2, THF, À1008C, slow addition of
nBuLi over 1 h, then À100!208C, 2 h.
168
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Chem. Eur. J. 2007, 13, 167 – 177

Quatercyclopropanes
FULL PAPER
bisspirocyclopropanated bicyclopropylidene 9[24] gave a mix-
ture of the corresponding dehydrodimers meso- and d,l-10
in 21% yield. The higher-order cuprate generated from lith-
iobicyclopropylidene (4) and tetrakis[iodo(tri-n-butylphos-
G
phine)copper(i)] [CuIBu3P]4 could be oxidatively dimerized
to give a 1.6:1 mixture of meso-5 and d,l-5 in 81% yield
(Scheme 2). An attempted alternative approach to bis(bicy-
clopropylidenyl) of type 5 utilizing the Kulinkovich reac-
tion[25] turned out unfruitful. Although the twofold reductive
cyclopropanation of the diester 12 prepared from butadiene
(11) by twofold cyclopropanation with ethyl diazoacetate,
worked perfectly well, and the conversion of the biscyclo-
propanol 13 to the dibromide 14 also gave a reasonable
yield (60%), the twofold dehydrobromination of 14 yielded
only 1.7% of a mixture of meso-5 and d,l-5 (Scheme 2).
The tetraspirocyclopropanated bis(bicyclopropylidenyl)s
meso-10 and d,l-10 can be separated by simple column chro-
matography on silica gel (see Experimental Section). As
meso-5 crystallized well from its 20% ethereal solution at
À208C, it could be separated from the d,l-diastereomer and
purified very easily, while the purification of the d,l-diaster-
eomer d,l-5 with this method was a little more tedious. Al-
ternatively, the bis(bicyclopropylidenyl)s meso-5 and d,l-5
were separated quite well by column chromatography on
silica gel impregnated with 5% of silver nitrate,[26] however,
some material was lost due to partial decomposition. Deha-
logenative coupling of the known 1,1-dibromo-2-cyclopro-
pylcyclopropane (6)[27] under modified conditions[28] based
on those of Neuenschwander et al.[21] gave a mixture of all
four possible diastereomers (Scheme 2) in 69% yield, from
which only (Z)-cis-16 could be separated and isolated in
pure form by preparative gas chromatography (26% yield).
While the meso-diastereomer meso-5 with s-trans orienta-
tion of the two bicyclopropylidenyl groups possesses Ci sym-
metry, d,l-5 has C2 symmetry. Since three diastereomers of
16 could not be isolated in pure form, their structures could
not be unequivocally assigned on the basis of the NMR
spectra of the mixture. Only the single isolated diastereomer
was assigned the (Z)-cis-configuration as determined by an
X-ray crystal structure analysis (Figure 1). A crystal struc-
ture analysis was also performed for meso-5 (Figure 1).
In the crystal, the hydrocarbon meso-5 adopts a Ci-sym-
metrical conformation with an s-trans-orientation of the cen-
tral bicyclopropyl unit (antiperiplanar conformation with
f=180 and 179.48 in the two independent molecules, re-
spectively). The parent bicyclopropyl also has such a confor-
mation in the crystal,[30] whereas in the gas phase[17,31] and in
the liquid[16,32] the synclinal (gauche) conformer predomi-
nates. From a structural point of view, meso-5 is essentially a
linked combination of the structures of bicyclopropylidene
(3)[18b] and of bicyclopropyl.[30a] Thus, the structures of both
bicyclopropylidene units in meso-5 are actually undistorted
in comparison with the parent bicyclopropylidene (3),[18b]
and the bond length h between the two bicyclopropylidenes
in meso-5 [1.494(1) Š] is essentially the same as the central
bond length in bicyclopropyl [1.4924(4) Š], as measured at
100 K.[30a] Apparently, no additional electronic interactions
Figure 1. Structures of meso-bis(bicyclopropylidenyl) (meso-5, top left),
1,5-dicyclopropylbicyclopropylidene [(Z)-cis-16, top right)] and fractions
of their molecular packing (bottom) in the crystals.[29] Bond lengths [Š]
(mean values based on assumed Ci symmetry for meso-5 and Cs symme-
try for (Z)-cis-16). meso-5: a=1.5332(12), b=1.4617(12), c=1.4657(12),
d=1.3045(12), e=1.4689(12), f=1.4664(12), g=1.5371(12), h=
1.4938(12). (Z)-cis-16: A=1.303(2), B=1.477(3), C=1.479(3), D=
1.546(3), E=1.494(3), F=1.503(3), G=1.504(3), H=1.500(2).
in comparison with those existing in bicyclopropyl can be at-
tributed to meso-5 on the basis of its X-ray crystal structural
data. For (Z)-cis-16 the situation is different. As in meso-5,
the distance E between the cyclopropyl and bicyclopropyli-
dene moieties [1.494(3) Š], the bond lengths within the ter-
minal cyclopropanes and that of the double bond are very
close to those found in bicyclopropyl and in bicyclopropyli-
dene (3), respectively. However, the distal (with respect to
the double bond) bond D in the bicyclopropylidene frag-
ment of (Z)-cis-16 is slightly longer [1.546(3) Š, measured
at 230 K] than the corresponding one in bicyclopropylidene
(3) [1.534(2) Š, measured at 245 K], and the proximal
bonds
B and C are slightly longer too [1.478(3) vs
1.467(1) Š]. These structural changes cannot easily be ex-
plained by an electronic influence of the terminal cyclopro-
pane rings (cf. [33]). Only one of the two terminal cyclo-
propyl groups adopts an s-trans- (antiperiplanar) conforma-
tion with f=178.88 with respect to the adjacent three-mem-
bered ring of the bicyclopropylidene core, while the other
ring adopts a gauche (synclinal) orientation with f=47.58.
As was mentioned above, such differences in conformation
have remarkably little effect on the geometrical parameters
of the molecule.
Birch reduction of meso-bis(bicyclopropylidenyl) (meso-5)
with lithium in liquid ammonia proceeds diastereoselectively
and in almost quantitative yield to give the two diastereo-
meric quatercyclopropanes trans,trans-(R*,S*,R*,S*)-17 and
cis,trans-(R*,S*,R*,R*)-18 in a ratio of 9:1 (Scheme 3). On
the other hand, reduction of meso-5 with diimine, in situ
generated from 2-nitrobenzenesulfonyl hydrazide,[34] gave
Chem. Eur. J. 2007, 13, 167 – 177
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169

A. de Meijere, R. Boese et al.
Scheme 4. Preparation of meso- (meso-[D14]-5) and d,l- (d,l-[D14]-5) per-
deuteriobis(bicyclopropylidenyl)s as well as their Birch reduction. a)
Scheme 3. Reduction of bis(bicyclopropylidenyl)s meso-5 and d,l-5, as
well as of (Z)-cis-16 under various conditions. a) Li, liq. NH3, À788C,
1.5 h, then MeOH, À78!208C; b) 2-nitrobenzenesulfonyl hydrazide
(8.7 equiv), MeOH, 208C, 5 h; c) H2, Pd/BaSO4 (2 mol%), MeOH, 208C,
16–44 h.
Ca
3 h, then EtOH, 20!788C, 1.5 h at 788C; c) EtONa, EtOH, 20!788C,
1 h at 788C, then aq. 10m H2SO4, 08C; d) C2D5MgBr, Ti(OiPr)4, Et2O,
A
AHCTREUNG
208C, 1 h, then aq. 10% H2SO4, 08C, 1 h; e) Ph3P·Br2, Py, CH2Cl2, À15!
208C, 48 h; f) tBuOK, DMSO, 208C, 48 h; g) nBuLi, THF, 208C, 1 h,
then CuCN, À100!À408C, 0.5 h, then O2, À788C, 0.5 h; h) Li, liq. NH3,
À788C 1.5 h, then MeOH, À78!208C.
the cis,cis-quatercyclopropane (S*,S*,R*,R*)-21 as the main
product (58% yield, isolated by preparative gas chromatog-
raphy) along with the cis,trans-diastereomer (R*,S*,R*,R*)-
18 (29% yield). Thus, as three of the six possible diastereo-
meric quatercyclopropanes were obtained from meso-5, the
other three ought to be accessible analogously from d,l-bis-
(bicyclopropylidenyl) (d,l-5). Indeed, Birch reduction of the
latter was accomplished with the same diastereoselectivity
(9:1) to give the quatercyclopropanes trans,trans-
(R*,S*,S*,R*)-19 and cis,trans-(R*,S*,S*,S*)-20, however, in
lower isolated yield (76%). The minor component of this
mixture—the quatercyclopropane cis,trans-(R*,S*,S*,S*)-
20—was also obtained as the sole product by Birch reduc-
tion of (Z)-cis-2,2’-dicyclopropylbicyclopropylidene (Z)-cis-
16 in 96% yield (Scheme 3).
cyclopropanation with perdeuterated ethylmagnesium bro-
mide (prepared in two steps from commercially available
[D5]-ethanol, see Experimental Section) followed by conver-
sion to the bromide and subsequent dehydrobromination ac-
cording to an established protocol[24a,b] furnished perdeuter-
iobicyclopropylidene [D8]-3 in 49% yield over three steps
(Scheme 4).[37] Finally, [D8]-3 was converted into a 1:1 mix-
ture of meso-[D14]-5 and d,l-[D14]-5 which were separated by
column chromatography on silica gel impregnated with 5%
of silver nitrate.
Under the same conditions as applied for the Birch reduc-
tion of the diastereomeric bis(bicyclopropylidenyl)s, the per-
deuterated analogues meso-[D14]-5 and d,l-[D14]-5 gave the
With the purpose to separate and more easily determine
the vicinal H,H-coupling constants between cyclopropyl
groups in quatercyclopropanes, the perdeuteriobis(bicyclo-
propylidenyl)s meso-[D14]- and d,l-[D14]-5 were also pre-
pared, applying the procedure c discussed above (see
Scheme 2), from perdeuteriobicyclopropylidene [D8]-3. The
latter was obtained from perdeuterated g-butyrolactone
(prepared from perdeuteriotetrahydrofuran) according to an
established protocol[24a,b] (Scheme 4). Thus, [D8]-THF ([D8]-
23) was oxidized to [D6]-g-butyrolactone ([D6]-24) in 63%
yield adopting a published procedure.[35] This was converted
by a known method[36] into ethyl [D4]-cyclopropanecarboxy-
late ([D4]-26) in two steps in 40% overall yield. Reductive
tetradecadeuterated
quatercyclopropanes
trans,trans-
(R*,S*,R*,S*)-[D14]-17 and cis,trans-(R*,S*,R*,R*)-[D14]-18
(8:1) in 37% yield as well as trans,trans-(R*,S*,S*,R*)-[D14]-
19 and cis,trans-(R*,S*,S*,S*)-[D14]-20 (12:1) in 63% yield
(Scheme 4).
In the trans,trans-quatercyclopropane (R*,S*,R*,S*)-17, as
disclosed by X-ray crystal structure analysis at 150 K, the
bonds a, c, d and g are virtually of the same lengths as the
corresponding bonds in unsubstituted cyclopropane,[30a]
while the bonds b, e and f are slightly longer. The bonds be-
tween the cyclopropane moieties d [1.496(2) Š] and h
[1.491(3) Š] are essentially the same as the corresponding
one in bicyclopropyl [1.4924(4) Š].[30a] In contrast to this, in
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Chem. Eur. J. 2007, 13, 167 – 177

Quatercyclopropanes
FULL PAPER
the cis,cis-quatercyclopropane (S*,S*,R*,R*)-21, as disclosed
by X-ray crystal structure analysis at 113 K, the bonds B, F
and G are also of the same lengths as the bonds in unsubsti-
tuted cyclopropane,[30a] however, the bonds A, C and E are
slightly shorter. Moreover, the bonds between the cyclopro-
pane moieties D [1.481(2) Š] and H [1.480(3) Š] are defi-
nitely shorter than the corresponding one in bicyclopropyl
[1.4924(4) Š].[30a] This indicates a change in hybridization of
the involved carbon atoms in (S*,S*,R*,R*)-21, but the
reason for this change compared to bicyclopropyl is not
clear.
found to be equal to 4.1 Hz. This corroborates that at least
for the outer bicyclopropyl units in this meso-quatercyclo-
propane the proportion of the gauche conformers is even
more prevalent than in parent bicyclopropyl. On going from
trans,trans-(R*,S*,R*,S*)-[D14]-17
via
trans,trans-
(R*,S*,S*,R*)-[D14]-19 and trans,cis-(R*,S*,R*,R*)-[D14]-18
to trans,cis-(R*,S*,S*,S*)-[D14]-20 the predominance of this
3
conformer decreases, as seen from the corresponding h JH,H
i
values which were equal to 4.1, 4.7, 5.9 and 5.9 Hz, respec-
tively. However, in contrast to the case of bicyclopropyl,[16]
these values practically do not change, at least not systemat-
ically, on raising or lowering temperature, but an up-field
shift of the 1H signals was observed upon decreasing the
temperature.
In the crystal, both the trans,trans-quatercyclopropane
(R*,S*,R*,S*)-17
and
the
cis,cis-quatercyclopropane
(S*,S*,R*,R*)-21 adopt a remarkable conformation in which
the two central cyclopropyl groups are in an s-trans (anti-
periplanar) orientation with f=180.08 just as in crystalline
bicyclopropyl,[30a] and the two terminal cyclopropyl groups
each are in gauche (synclinal) orientations with respect to
their nearest neighbors with f=49.8 and 72.08, respectively
(Figure 2). These conformations must result from energetic
In order to gage the reasons for the different conforma-
tional preferences of the diastereomeric quatercyclopro-
panes 17–22 in the solid states and in solutions, their geome-
tries were optimized at the B3LYP/6-31G(d) level of theory
starting with the geometry of the lowest energy conformer
in each case, as obtained by MMFF force field calcula-
tions.[39] In all but one case, the s-trans conformation of each
two adjacent cyclopropane rings with a maximum deviation
of ꢀ6.58 came out to be energetically preferred. Only for
the trans,cis-isomer 18 was a gauche orientation of the two
central cyclopropanes with a torsional angle of f=828 pre-
dicted to be more stable. The energies of the meso-trans,-
trans 17 and the d,l-trans,trans isomer 19 were found to be
very similar and the lowest among those of all diastereomers
(Table 1). To check whether the predicted preference for the
Table 1. Computed energy differences (DE in kcalmolÀ1 relative to the
energy of the all-s-trans conformer of 19) for six diastereomeric quatercy-
clopropanes 17–22 for geometries optimized from two different starting
geometries and at different levels of theory.
Figure 2. Structures of quatercyclopropanes trans,trans-(R*,S*,R*,S*)-17
(top) and cis,cis- (S*,S*,R*,R*)-21 (bottom) in the crystal.[29] Bond
lengths [Š] in (R*,S*,R*,S*)-17 (mean values based on assumed Ci sym-
metry): a=1.498(3), b=1.505(2), c=1.500(3), d=1.496(2), e=1.504(3),
f=1.507(2), g=1.502(2), h=1.491(3). Bond lengths [Š] in (S*,S*,R*,R*)-
21 (mean values based on assumed Ci symmetry): A=1.480(2), B=
1.493(2), C=1.488(2), D=1.481(2), E=1.487(2), F=1.499(2), G=
1.496(2), H=1.480(3).
Compound
B3LYP/6-31G(d)
MP2(fc)/6-31G(d)//
B3LYP/6-31G(d)
all-s-trans all-gauche g,g,t[a] all-s-trans all-gauche g,g,t[a]
17
18
19
20
21
22
0.0
0.3
5.7
0.5
4.0
7.3
7.6
0.1
À0.6[b]
0.0
0.6
1.9
À2.1
2.3
1.0[b]
0.0
1.4
3.1
À1.1
À1.9
1.3
2.6
2.5
1.1
0.6
compromises between intramolecular van der Waals interac-
tions between hydrogen atoms or simply from crystal pack-
ing effects. It is noteworthy that such a conformation has
never been observed in the solid state for either of the
quater- or quinquecyclopropane derivatives along the routes
to FR-900848 (1) (all-gauche conformation[10b,12]) and to U-
106305 (2) (gauche/trans/gauche/gauche conformation[13c]), or
the macrocyclic compounds containing a quinquecyclopro-
pane fragment (predominating trans/trans/gauche/trans con-
formation[15a]).
3.8
4.4
1.6
[a] gauche,gauche,s-trans conformer. [b] s-trans,gauche,s-trans conformer.
s-trans conformations were artefacts produced by the
MMFF force field,[40,41] all-gauche conformations with f=
488 were used as starting geometries for the optimization at
the same level of theory. For all six diastereomers 17–22, the
all-gauche conformations were calculated to be of higher
energy than the corresponding optimized all-s-trans con-
former. Many of the torsional angles f increased during op-
timization to values of 55–608 and even up to 848.
In solution, the synclinal conformation of bicyclopropyl is
known to be more stable than the antiperiplanar one by
150–160 calmolÀ1,[16b,38] as derived from, for example, the
temperature dependence of the vicinal spin-spin coupling
Since this is in sharp contrast to the experimental results
3
3
constant h JH,Hi in 2,2,3,3,2’,2’,3’,3’-octadeuteriobicyclopropyl
on the basis of vicinal coupling constants h JH,Hi, single
(4.42 Hz at +70 decreasing to 4.21 at À658C).[16] At 258C in
point energies for all optimized structures were also comput-
ed at the MP2(fc)/6-31G(d) level of theory.[42] By this
3
CD2Cl2 the value of h JH,Hi for (R*,S*,R*,S*)-[D14]-17 was
Chem. Eur. J. 2007, 13, 167 – 177
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
171

A. de Meijere, R. Boese et al.
Celite (0.5 cm) and silica gel (1 cm), then concentrated under reduced
method, at least for the meso-trans,trans-17 and the d,l-
trans,trans-19, the all-gauche conformers were predicted to
be the more stable ones. The larger value of this differences
(about 2 kcalmolÀ1) compared with the expected value (ca.
0.5 kcalmolÀ1 for three gauche conformations) supports the
higher prevalence of the gauche conformations in 17 and 19
as predicted by the NMR experiments. The larger energy
difference for the two conformations of 18 than that for 20
was reproduced at this level of theory as well, still being in
disagreement with the observed coupling constants. Since
pressure. Distillation under reduced pressure furnished dibromide
6
(101.6 g, 82%) as a colorless liquid with b.p. 77–788C (20 mbar) [lit.:[27]
yield 51%, b.p. 768C (14Torr)]. Its NMR spectra were identical to the
reported ones.[27]
Preparation of bis(bicyclopropylidenyl)s meso-5, d,l-5, meso-10 and d,l-
10
General procedure GP 1: nBuLi (15 mmol as a solution in hexane) and
the respective hydrocarbon 3 or 9 (15 mmol) were mixed in anhydrous
THF (40 mL) at À788C. After having been stirred at 08C for 1 h, the sol-
ution was cooled to À1008C, and CuCN (7.5 mmol) or [CuIBu3P]4
(1.88 mmol) was added in one portion. The mixture was allowed to warm
to À408C over a period of 15 min, and stirred at this temperature for an
additional 15 min until a clear solution had formed. After this, the reac-
tion mixture was recooled to À788C, and a slow stream of oxygen was
passed through the mixture with stirring for 0.5 h. The mixture was al-
lowed to warm to 08C, diluted with pentane (40 mL) and poured into
ice-cold water. The organic phase was washed with sat. aq. NH4Cl solu-
tion and brine (50 mL each), dried and carefully concentrated under re-
duced pressure at 08C. The product was purified as indicated below.
3
the larger h JH,Hi values measured for 18 and 20 suggested a
higher s-trans conformer contribution, the geometry of the
respective gauche,gauche,s-trans conformations were opti-
mized, and the energies calculated as before. Indeed, these
conformations were predicted to be more favorable than the
all-gauche conformation at the MP2(fc)/6-31G(d)//B3LYP/6-
31G(d) level of theory. For 18, this conformation corre-
sponds to the lowest-energy conformer found.
meso-Bis(bicyclopropylidenyl) (meso-5) and d,l-bis(bicyclopropylidenyl)
(d,l-5): a) Column chromatography (Rf =0.57, 30 g silica gel, 3.5”12 cm
column, hexane) of the residue (825 mg) obtained from bicyclopropyli-
dene (3) (1.03 g, 1.20 mL, 12.8 mmol), nBuLi (13.0 mmol, 7.9 mL of a
1.64m solution in hexane) and CuCN (560 mg, 6.25 mmol) in THF
(50 mL) according to GP 1 gave a 1.6:1 mixture of meso-5 and d,l-5
(375 mg, 37%) as a wax.
Experimental Section
General aspects: Bicyclopropylidene (3),[24b] 7-cyclopropylidenedispiro-
b) Column chromatography (Rf =0.57, 30 g silica gel, 3.5”12 cm column,
hexane) of the residue (1.34g) obtained from bicyclopropylidene ( 3)
(504mg, 0.59 mL, 6.29 mmol), nBuLi (6.30 mmol, 3.84mL of a 1.64 m sol-
ution in hexane) and [CuIBu3P]4 (1.235 g, 786 mmol) in THF (50 mL) ac-
cording to GP 1 gave a 1.6:1 mixture of meso-5 and d,l-5 (404 mg, 81%)
as a wax. This was taken up with diethyl ether (2.3 mL), and the resulting
solution was allowed to stand at À208C over two days. The formed pre-
cipitate was quickly filtered off while the mixture was still cold to give
meso-5 (189 mg, 38%) as a colorless solid, m.p. 49–528C. Evaporation of
the mother liquor furnished a sample enriched in d,l-5, an analytical
sample of which was obtained by preparative GC at 1008C.
A
[iodo(tri-n-butylphosphine)copper(i)] ([CuIBu3P]4)[43] were prepared ac-
cording to previously published procedures. Pentane for column chroma-
tography was shaken with conc. sulfuric acid for 12 h, then with a 0.5n
solution of KMnO4 in 3m H2SO4 for 24h, washed with a diluted aq. solu-
tion of oxalic acid, aq. 5% NaHCO3 solution, dried (MgSO4) and distil-
led from P4O10. Anhydrous diethyl ether and THF were obtained by dis-
tillation from sodium/benzophenone, CH2Cl2, DMSO and pyridine from
CaH2, ethanol and methanol from the corresponding magnesium alkox-
ides. Oxygen was dried by passing it through a glass tube packed with
P4O10 on glass wool, ammonia was recondensed through a glass column
packed with KOH pellets. All other chemicals were used as commercially
available (Merck, Acros, BASF, Bayer, Clariant, Degussa AG, and Hüls
AG). All operations in anhydrous solvents were performed under argon
in flame-dried glassware. Organic extracts were dried over MgSO4. The
In another run, the 1.6:1 mixture of meso-5/d,l-5 (329 mg) was separated
by column chromatography on silica gel impregnated with 5% of silver
nitrate (30 g of silica gel, 3”15 cm column, hexane/Et2O 150:1) to give
pure meso-5 (95 mg) and d,l-5 (88 mg).
1
compositions of solvent mixtures are given as volume per volume. H and
c) The reaction mixture which was obtained from dibromide 14 (15.36 g,
48.1 mmol) and tBuOK (11.9 g, 106 mmol) in DMSO (200 mL) according
to GP 4(24h stirring at ambient temperature, see below) was poured
into ice-cold water (200 mL) and extracted with hexane (3”100 mL).
The combined organic phases were washed with water (3”100 mL),
dried and carefully concentrated under reduced pressure at 08C. Column
chromatography of the residue (Rf =0.57, 10 g silica gel, 2”10 cm
column, hexane) gave a 1:1 mixture of meso-5 and d,l-5 (130 mg, 1.7%)
as a wax. meso-5: 1H NMR (200 MHz, CDCl3): d=2.01–1.96 (m, 2H;
2CH), 1.41–1.20 (m, 8H; 4CH2), 1.10–0.69 (m, 4H; 2CH2); 13C NMR
(50.3 MHz, CDCl3): d=113.7 (2C), 110.2 (2C), 16.3 (2 CH), 7.2 (2CH2),
3.0 (2CH2), 2.8 (2CH2).
13C NMR spectra were recorded at 250, 270, 300, 500, 600 (1H), and 50.3,
62.9, 75.5, 100.6 MHz [13C, additional DEPT (Distortionless Enhance-
ment by Polarization Transfer)] on Inova 600, Inova 500, Mercury 300,
Bruker AM 250, Unity 200 and Mercury 200 instruments, respectively, in
CDCl3 or CD2Cl2 solutions, CHCl3/CDCl3 or CH2Cl2/CD2Cl2 as internal
references; d in ppm, J in Hz. Mass spectra (EI) were measured with
Varian MAT 112 and Finnigan MAT 95 spectrometers at 70 eV, DCI
with NH3. Melting points were determined on a Büchi 510 capillary melt-
ing point apparatus, values are uncorrected. TLC analyses were per-
formed on precoated sheets, 0.25 mm Sil G/UV254 (Macherey-Nagel).
Silica gel grade 60, 230–400 mesh (Merck), was used for column chroma-
tography. GC analyses were performed with a Varian CP-3380 instrument
using a 25 m capillary column with CP-Sil-5-CB. Preparative GC separa-
tions were performed on Intersmat 130 and Varian Aerograph 920 instru-
ments (20% SE 30 on Chromosorb W-AW-DMCS, 1200”8.2 mm
column, or 15% OV101 on Chromosorb W-AW-DMCS, 1500”9.4mm
column).
d,l-5: 1H NMR (200 MHz, CDCl3): d=1.90–1.78 (m, 2H; 2CH), 1.40–
1.27 (m, 4H; 2CH2), 1.16–0.97 (m, 8H; 4CH2); 13C NMR (50.3 MHz,
CDCl3): d=112.9 (2C), 110.7 (2C), 17.0 (2CH), 9.9 (2CH2), 3.0 (4CH2).
meso-2,2’-Bis
N
G
d,l-2,2’-bis[(dispiro
A
ACHTREUNG
1,1-Dibromo-2-cyclopropylcyclopropane (6):[27] To a vigorously stirred
pre-cooled (À108C) solution of vinylcyclopropane (35.0 g, 514mmol),
CHBr3 (227.46 g, 78.7 mL, 900 mmol) and benzyltriethylammonium
chloride (TEBACl, 1.14g, 4.1 mmol) in anhydrous CH 2Cl2 (500 mL) was
added in three portions KOH (pellets, 196.0 g, 3.49 mol), and the result-
ing mixture was stirred for 2 h maintaining the temperature at 20–258C
by external cooling. Pentane (500 mL) was added and, after stirring for
chromatography (Rf =0.27, 5 g silica gel, 1.5”6.5 cm column, hexane) of
the residue (227 mg) obtained from 7-cyclopropylidenedispiro-
A
1.64m solution in hexane) and CuCN (93 mg, 1.04mmol) in THF
(20 mL) according to GP 1 gave a 1:1 mixture of meso-10 and d,l-10
(57 mg, 21%) as a wax. The two diastereomers were separated by two-
fold column chromatography (34g flash silica gel, 3”11 cm column,
hexane). meso-10: colorless oil; 1H NMR (250 MHz, CDCl3): d=1.86–
an additional 0.5 h, the mixture was filtered through
a pad of
172
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 167 – 177

Quatercyclopropanes
FULL PAPER
1.78 (m, 2H; 2CH), 1.20–0.80 (m, 20H; 10 CH2); 13C NMR (62.9 MHz,
CDCl3): d=120.6 (2C), 106.6 (2C), 15.9 (2C), 15.8 (2C), 15.3 (2CH), 8.5
(2CH2), 8.45 (2CH2), 8.3 (2CH2), 8.0 (2CH2), 6.5 (2CH2).
4H; CH2), 0.25–0.08 (m, 4H; CH2); 13C NMR (62.9 MHz, CDCl3): d=
114.0 (2C), 18.10 (2CH), 11.8 (2CH), 7.8 (2CH2), 3.4(2CH 2), 2.0
(2CH2).
d,l-10: colorless oil, 1H NMR (250 MHz, CDCl3): d=1.76–1.68 (m, 2H;
2CH), 1.30–0.76 (m, 20H; 10CH2); 13C NMR (62.9 MHz, CDCl3): d=
121.1 (2C), 106.2 (2C), 16.6 (2CH), 15.9 (2C), 15.7 (2C), 8.8 (2CH2), 8.7
(2CH2), 8.22 (2CH2), 8.2 (2CH2), 8.1 (2CH2); MS (DCI): m/z (%): 298/
297 (12/55) [M+NH4++NH3], 281/280 (20/100) [M+NH4+], 264/263 (2/
10) [M+H]+, 248 (4), 247 (15).
Hexadeuterio-g-butyrolactone ([D6]-24): To a vigorously stirred solution
of Ca(OCl)2 (71.0 g, 497 mmol) in H2O (400 mL) was added dropwise a
A
solution of octadeuteriotetrahydrofuran ([D8]-23) (19.7 g, 20 mL,
246 mmol) in a 3:2 mixture of MeCN and AcOH (250 mL) at 08C over a
period of 30 min, and the mixture was stirred at ambient temperature for
an additional 22 h. The reaction mixture was diluted with water (400 mL)
and extracted with CH2Cl2 (4”200 mL). The combined extracts were
washed with sat. aq. NaHCO3 solution and H2O (200 mL each), dried
and concentrated using a 100 cm rectification column. The residue was
distilled under reduced pressure to give [D6]-24 (14.45 g, 63%) as a color-
less liquid, b.p. 758C (14mbar). 13C NMR (75.5 MHz, CDCl3): d=177.8
(C), 67.7 (p, J=23.5 Hz, CD2), 27.0 (p, J=20.5 Hz, CD2), 21.1 (p, J=
20.8 Hz, CD2).
meso-Tetradecadeuteriobis(bicyclopropylidenyl) (meso-[D14]-5) and d,l-
tetradeca-deuteriobis(bicyclopropylidenyl) (d,l-[D14]-5): Column chroma-
tography (20 g silica gel, 2.0”20 cm column, hexane) of the residue ob-
tained
from
octadeuteriobicyclopropylidene
([D8]-3)
(2.0 mL,
19.37 mmol), nBuLi (38.78 mmol, 15.7 mL of a 2.47m solution in hexane)
and CuCN (867 mg, 9.69 mmol) in THF (50 mL) according to GP 1, but
the mixture of [D8]-3 and nBuLi was stirred at ambient temperature for
1 h, gave a 1:1 mixture of meso-[D14]-5 and d,l-[D14]-5 (1.36 g, 82%) as a
wax. The composition of this mixture was determined by GC in compari-
son with non-deuterated analogues. Repeated column chromatography
(30 g silica gel impregnated with 5% AgNO3, 2.8”14cm column,
hexane/Et2O 150:1) gave pure meso-[D14]-5 (352 mg) and d,l-[D14]-5
(123 mg).
Ethyl 4-Chlorohexadeuteriobutanoate ([D6]-25): Lactone [D6]-24 (26.5 g,
288 mmol) was stirred under reflux in thionyl chloride (35.97 g, 22.0 mL,
302 mmol) for 3 h, and the mixture then cooled to ambient temperature.
Anhydrous EtOH (14.62 g, 18.5 mL, 317 mmol) was added dropwise at
this temperature, and the reaction mixture was stirred under reflux for
1.5 h again, cooled to ambient temperature and concentrated under re-
duced pressure at 08C. Distillation of the residue under reduced pressure
meso-[D14]-5: colorless oil; 13C NMR (75.5 MHz, CDCl3): d=113.6 (2C),
110.0 (2C), 15.6 (t, J=24.8 Hz, 2CH), 6.4 (p, J=24.8 Hz, 2CH2), 2.1 (p,
J=24.8 Hz, 2CH2), 1.9 (p, J=24.8 Hz, 2CH2); MS (EI): m/z (%): 170 (3)
[M +ÀD], 154(9) [ M +ÀCD2ÀD], 152 (18) [M +ÀCD2À2D], 150 (16),
138 (42) [M +ÀC2D4ÀD], 136 (100) [M +ÀC2D4À2D], 126 (57), 122 (71)
furnished [D6]-25 (30.7 g, 69%) as
a colorless liquid, b.p. 74–758C
(22 mbar). 1H NMR (300 MHz, CDCl3): d=4.08 (q, J=7.2 Hz, 2H;
OCH2), 1.21 (t, J=7.2 Hz, 3H; CH3); 13C NMR (75.5 MHz, CDCl3): d=
172.7 (C), 60.5 (CH2), 43.3 (p, J=21.2 Hz, CD2), 32.2 (p, J=20.4Hz,
CD2), 27.0 (p, J=19.8 Hz, CD2), 14.1 (CH3).
[C9D7+], 110 (18), 98 (85) [C7D7+], 84(31) [C D6+], 82 (38) [C5D11+], 70
6
(29) [C5D5+], 54 (28), 42 (46).
Ethyl 2,2,3,3-tetradeuteriocyclopropanecarboxylate ([D4]-26): To a stirred
solution of sodium ethanolate [prepared from Na (5.03 g, 219 mmol) in
anhydrous EtOH (60 mL)] was added dropwise [D6]-25 (30.7 g,
196 mmol) over a period of 1.5 h, and the resulting mixture was stirred
under reflux for 1 h. After cooling to 08C, the reaction mixture was care-
fully brought to pH ꢁ6 by adding a 10m aq. H2SO4 solution, diluted with
H2O (100 mL) and extracted with benzene (2”100 mL). The combined
organic extracts were washed with sat. aq. NaHCO3 (2”100 mL), brine
(100 mL), dried and concentrated at ambient pressure applying a 10 cm
Vigreux column. The residue was distilled at ambient pressure with a
10 cm Vigreux column to give [D4]-26 (13.6 g, 58%) as a colorless liquid,
b.p. 1338C. 1H NMR (250 MHz, CDCl3): d=4.13 (q, J=7.1 Hz, 2H;
OCH2), 2.47 (s, 1H; CH), 1.17 (t, J=7.1 Hz, 3H; CH3); 13C NMR
(62.9 MHz, CDCl3): d=174.9 (C), 60.3 (CH2), 14.2 (CH3), 12.5 (CH), 7.5
d,l-[D14]-5: colorless oil; 13C NMR (75.5 MHz, CDCl3): d=112.8 (2C),
110.6 (2C), 16.2 (t, J=24.8 Hz, 2CH), 9.1 (p, J=24.8 Hz, 2CH2), 2.16 (p,
J=24.8 Hz, 2CH2), 2.12 (p, J=24.8 Hz, 2CH2).
Diethyl bicyclopropyl-2,2’-dicarboxylate (12): This compound was pre-
pared applying the previously reported protocol,[44] but with [Rh
(OAc)2]2
A
as a catalyst.[45] A 100 mL, three-necked, round-bottomed flask equipped
with a magnetic stirring bar, a thermometer and a reflux condenser
cooled with dry ice, was charged with a solution of butadiene (11)
(8.12 g, 13.1 mL, 150.1 mmol) in anhydrous dichloromethane (50 mL)
and dirhodium tetraacetate (199 mg, 450 mmol, 0.3 mol%). Under stirring
was added ethyl diazoacetate (17.14g, 15.8 mL, 150.2 mmol) at À5 to
08C over a period of 0.5 h. The same portion ethyl diazoacetate was
added over a period of 12 h at this temperature. The reaction mixture
was filtered through a pad of silica gel and concentrated under reduced
pressure. The residue was distilled in vacuo to give 12 (29.60 g, 87%) as
a mixture of isomers. 12: colorless liquid; b.p. 99–1028C (2 mbar) [lit.[43]
110–1158C (3 Torr)]; 1H NMR (250 MHz, CDCl3): d=4.20–3.95 (m, 4H;
2OCH2), 1.75–1.55 (m, 1H; cPr-H), 1.55–1.30 (m, 3H; cPr-H), 1.30–1.12
(m, 6H; 2CH3), 1.12–0.85 (m, 3H; cPr-H), 0.85–0.60 (m, 1H; cPr-H);
13C NMR (62.9 MHz, CDCl3): d=173.4, 172.7, 172.4, 171.9, 171.8 (C),
60.3, 60.2, 60.1 (CH2), 23.5, 23.2, 22.8, 22.7, 20.0, 19.97, 19.8, 19.5, 19.2,
19.1, 19.0, 18.7, 18.6, 18.5 (CH), 14.1, 14.0, 13.9, 13.8 (CH3), 15.4, 14.8,
13.7, 12.9, 12.8, 12.5 (CH2).
(p, J=25.1 Hz,
2
CD2); MS (EI): m/z (%): 119 (6) [M + (from
C3D5CO2Et)], 118 (10) [M +], 91 (22), 90 (21), 74(64) [ M +ÀC2H5O
(from C3D5CO2Et)], 73 (100) [M +ÀC2H5O], 46 (17), 45 (31) [C2H5O+].
Preparation of [1,1’;2’,1’’;2’’,1’’’]quatercyclopropane-1,1’’’-diol (13) and
[D8]-1-cyclopropylcyclopropanol ([D8]-27)
General procedure GP 2: To the well stirred solution of the respective
diester 12 or ester [D4]-26 (80 mmol) and titanium tetraisopropoxide
(20 mol% for each ethoxycarbonyl group) in anhydrous diethyl ether
(100 mL), was added the indicated quantity of ethylmagnesium bromide
at 20–258C over a period of 2 h. After stirring for an additional 1 h at the
same temperature, the reaction mixture was cooled to À58C, and the re-
action quenched by careful addition of 250 mL of ice-cold 10% aq. sulfu-
ric acid while the temperature was maintained between À5 and 08C. The
mixture was stirred at 08C for an additional 1 h, the ethereal phase was
washed with sat. aq. NaHCO3 (2”100 mL), brine (100 mL), dried and
concentrated under reduced pressure to give crude 13 or [D8]-27 which
were used without further purification.
(Z)-cis-2,2’-Dicyclopropylbicyclopropylidene [(Z)-cis-16]: To a solution
of 1,1-dibromo-2-cyclopropylcyclopropane (6) (3.60 g, 15.0 mmol) in an-
hydrous THF (30 mL), anhydrous CuCl2 (202 mg, 1.5 mmol) was added
in one portion, and the resulting slurry was cooled to À1008C. nBuLi
(15.0 mmol, 5.77 mL of a 2.60m solution in hexane) was added dropwise
at this temperature over a period of 1 h. The resulting mixture was stirred
at this temperature for an additional 1 h, then allowed to warm to room
temperature over 1 h. The reaction mixture was diluted with Et2O
(100 mL) and then poured into an ice-cold mixture of sat. aq. NH4Cl sol-
ution (100 mL). The aqueous layer was extracted with the same solvent
(2”50 mL), the combined organic phases were washed with H2O (1”
50 mL), brine (1”50 mL), dried and concentrated under reduced pres-
sure at 08C to give crude 16 (1.63 g, 69%) as a mixture of four stereo-
isomers from which (Z)-cis-16 (603 mg, 26%) was isolated by preparative
gas chromatography. (Z)-cis-16: oil, 1H NMR (250 MHz, CDCl3): d=
1.64–1.55 (m, 2H), 1.26–1.16 (m, 2H), 1.00–0.82 (m, 4H), 0.45–0.25 (m,
[1,1’;2’,1’’;2’’,1’’’]Quatercyclopropane-1,1’’’-diol (13): From the diester 12
(18.1 g, 80 mmol), Ti(OiPr)4 (9.07 g, 9.5 mL, 32 mmol, 40 mol%) and
A
EtMgBr (336 mmol, 96.8 mL of a 3.47m solution in Et2O), was obtained
according to GP 2 a mixture of isomeric diols 13 (15.6 g, 99%) as an
yellow oil.
1-(2,2,3,3-Tetradeuteriocyclopropyl)-2,2,3,3-tetradeuteriocyclopropanol
([D8]-27): From the ester [D4]-26 (13.6 g, 115 mmol), Ti(OiPr)4 (6.542 g,
G
6.85 mL, 23.0 mmol, 20 mol%) and C2D5MgBr [prepared in anhydrous
Et2O (100 mL) from magnesium (7.82 g, 322 mmol) and C2D5Br (32.90 g,
Chem. Eur. J. 2007, 13, 167 – 177
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
173

A. de Meijere, R. Boese et al.
21.5 mL, 288 mmol) which in turn was prepared from the less expensive
C2D5OH according to a published procedure[46] in 57% yield], was ob-
tained according to GP 2 [D8]-27 (8.78 g, 72%) as a yellow oil.
for an additional 1.5 h. The reaction was quenched by addition of several
drops of MeOH to the mixture, allowed to warm up to À358C and dilut-
ed with hexane (10 mL). After careful evaporation of the ammonia, ice-
cold water (10 mL) was added to the residue, and the reaction mixture
was extracted with pentane (3”10 mL). The combined extracts were
dried, filtered through a pad of silica gel and concentrated under reduced
pressure.
Preparation of quatercyclopropane dibromide 14 and bromide [D8]-28
General procedure GP 3: To a solution of triphenylphosphane (26.23 g,
100 mmol) in anhydrous dichloromethane (100 mL) was added bromine
(15.98 g, 5.15 mL, 100 mmol) under vigorous stirring at À30 to À158C
over a period of 0.5 h. After an additional 15 min of stirring, a mixture of
the respective diol (47.5 mmol) or alcohol (95 mmol) and anhydrous pyri-
dine (7.52 g, 95 mmol) was added dropwise at À158C over a period of
1 h. The reaction mixture was stirred at ambient temperature for the indi-
cated time and worked up as indicated below.
(1’R*,2’S*,1’’R*,2’’S*)-Quatercyclopropane
[(R*,S*,R*,S*)-17]
and
(1’R*,2’S*,1’’R*, 2’’R*)-quatercyclopropane [(R*,S*,R*,R*)-18]: From a
solution of meso-5 (100 mg, 0.632 mmol) in Et2O (6 mL) and Li (26.3 mg,
3.79 mmol) in liq. NH3 (30 mL) was obtained a 9:1 mixture (100 mg,
97%) of (R*,S*,R*,S*)-17 and (R*,S*,R*,R*)-18 according to GP 5 as a
1
colorless oil. (R*,S*,R*,S*)-17: H NMR (500 MHz, CDCl3): d=0.76–0.68
1,1’’’-Dibromo [1,1’;2’,1’’;2’’,1’’’]quatercyclopropane (14): The reaction
mixture obtained from diol 13 (15.60 g, 80 mmol), Ph3P (44.6 g,
170 mmol), Br2 (27.08 g, 8.7 mL, 170 mmol) and pyridine (13.40 g,
13.7 mL, 170 mmol) according to GP 3 (24h stirring at ambient tempera-
ture) was concentrated under reduced pressure. The residue was vigo-
rously stirred with pentane (400 mL), the solids were filtered off, and the
solution concentrated under reduced pressure. This operation was repeat-
ed twice with 300 and 200 mL of pentane, respectively, to give a crude
mixture of isomeric dibromides 14 (15.36 g, 60%) as a yellow oil, which
was used without further purification.
(m, 2H), 0.52–0.44 (m, 4H), 0.32–0.22 (m, 4H), 0.10–0.02 (m, 4H), À0.02
to À0.08 (m, 4H); 13C NMR (50.3 MHz, CDCl3): d=18.7 (2CH), 18.1
(2CH), 12.1 (2CH), 8.2 (2CH2), 3.0 (2CH2), 2.8 (2CH2).
(R*,S*,R*,R*)-18: 1H NMR: cannot be unequivocally attributed.
13C NMR (62.9 MHz, CDCl3): d=19.9 (CH), 19.8 (CH), 19.1 (CH), 15.5
(CH), 12.1 (CH), 10.1 (CH2), 9.6 (CH), 8.6 (CH2), 4.8 (CH2), 4.5 (CH2),
3.0 (CH2), 2.5 (CH2).
(1’R*,2’S*,1’’S*,2’’R*)-Quatercyclopropane
[(R*,S*,S*,R*)-19]
and
(1’R*,2’S*,1’’S*,2’’S*)-quatercyclopropyl [(R*,S*,S*,S*)-20]: From a solu-
tion of d,l-5 (76 mg, 0.480 mmol) in THF (2 mL) and Li (20.0 mg,
2.88 mmol) in liq. NH3 (20 mL) was obtained a 9:1 mixture (59.0 mg,
76%) of (R*,S*,S*,R*)-19 and (R*,S*,S*,S*)-20 according to GP 5 as a
colorless oil. (R*,S*,S*,R*)-19: 1H NMR (250 MHz, CDCl3): d=0.80–
0.68 (m, 2H), 0.57–0.47 (m, 4H), 0.32–0.23 (m, 4H), 0.12–0.01 (m, 4H),
0.00 to À0.05 (m, 4H); 13C NMR (62.9 MHz, CDCl3): d=18.8 (2CH),
18.0 (2CH), 12.1 (2CH), 8.0 (2CH2), 3.0 (2CH2), 2.8 (2CH2). Unfortu-
nately, attempted separation of enantiomers of 19 by preparative HPLC
on a Chiralcel OD-H column, eluent hexane/ethanol 95:5, UV detector
JASCO MD-2010, was unsuccessful.[47]
1-Bromo-1-(2,2,3,3-tetradeuteriocyclopropyl)-2,2,3,3-tetradeuteriocyclo-
propane ([D8]-28): All the volatile material from the reaction mixture,
which was obtained from the cyclopropanol [D8]-27 (8.78 g, 82.7 mmol),
Ph3P (23.9 g, 91.0 mmol), Br2 (13.88 g, 4.46 mL, 86.8 mmol) and pyridine
(6.87 g, 7.02 mL, 86.8 mmol) according to GP 3 (after 48 h of stirring at
ambient temperature), was “bulb-to-bulb” distilled into
a cold trap
(À788C) at first under water-aspirator vacuum and 308C oil bath temper-
ature, then under further reduced pressure (0.1 Torr) with a 1208C oil
bath. The distillation was continued until the temperature in the reaction
flask reached 908C. The receiver flask was allowed to warm up to 208C,
and the solvent was removed by distillation at ambient pressure using a
10 cm Vigreux column. The residue was distilled under reduced pressure
to give [D8]-28 (10.0 g, 72%) as a colorless liquid, b.p. 658C (120 mbar).
13C NMR (75.5 MHz, CDCl3): d=36.7 (C), 20.1 (CH), 13.7 (p, J=
24.5 Hz, 2CD2), 5.3 (p, J=25.1 Hz, 2CD2).
For the NMR data of hydrocarbon (R*,S*,S*,S*)-20 see below.
(1’R*,2’S*,1’’R*,2’’S*)-2,2,3,3,2’,3’,3’,1’’,3’’,3’’,2’’’,2’’’,3’’’,3’’’-Tetradecadeu-
terioquatercyclopropane
{(R*,S*,R*,S*)-[D14]-17}
and
(1’R*,2’S*,
1’’R*,2’’R*)-2,2,3,3,2’,3’,3’,1’’,3’’,3’’,2’’’,2’’’,3’’’,3’’’-tetradecadeuterioquater-
cyclopropane {(R*,S*,R*,R*)-[D14]-18}: From a solution of meso-[D14]-5
(352 mg, 2.04mmol) in THF (7 mL) and Li (85 mg, 12.25 mmol, 3 equiv)
in liq. NH3 (30 mL), and after purification by column chromatography
(50 g of silica gel, 3”14cm column, pentane) was obtained a 8:1 mixture
(133 mg, 37%) of (R*,S*,R*,S*)-[D14]-17 and (R*,S*,R*,R*)-[D14]-18 ac-
cording to GP 5 as an oil. (R*,S*,R*,S*)-[D14]-17: 1H NMR (600 MHz,
CD2Cl2): d=0.70 (d, J=4.1 Hz, 2H; CH), 0.46 (d, J=4.1 Hz, 2H; CH);
13C NMR (75.5 MHz, CDCl3): d=18.2 (2CH), 17.3 (t, J=24.0 Hz, 2CD2),
11.6 (2CH), 7.4(p, J=24.4 Hz, 2CD2), 2.1 (p, J=24.4 Hz, 2CD2), 1.9 (p,
J=24.5 Hz, 2CD2).
Preparation of bis(bicyclopropylidenyl)s meso-5, d,l-5 and octadeuterio-
bicyclopropylidene ([D8]-3)
General procedure GP 4: To a vigorously stirred solution of potassium
tert-butoxide (60 mmol) in anhydrous DMSO (100 mL) was added drop-
wise the respective dibromide (25 mmol) or bromide (50 mmol). The
temperature was maintained between 20 and 258C with a water bath.
The reaction mixture was stirred at ambient temperature for the indicat-
ed time and worked up as indicated below.
Octadeuteriobicyclopropylidene ([D8]-3): All the volatile material from
the reaction mixture, which was obtained from bromide [D8]-28 (10.0 g,
59.1 mmol) and tBuOK (7.99 g, 71.2 mmol) in DMSO (80 mL) according
to GP 4(48 h of stirring at ambient temperature), was “bulb-to-bulb” dis-
tilled to a cold trap (À788C) at first under water-aspirator vacuum and
308C oil bath temperature, then under further reduced pressure
(0.1 Torr) with a 508C oil bath. The receiver flask was allowed to warm
up to 208C, its contents was washed with three 10 mL portions of ice-
cold water and transferred into a pre-weighed glass bottle containing
some molecular sieve 4Š, to yield of [D 8]-3 (4.89 g, 94%), a colorless
liquid of 95% purity (according to GC analysis). 13C NMR (62.9 MHz,
CDCl3): d=110.2 (2C), 2.1 (p, J=24.7 Hz, 4CD2).
(R*,S*,R*,R*)-[D14]-18: 1H NMR (600 MHz, CD2Cl2): d=0.64(d, J=
5.9 Hz, 2H; CH), 0.49 (d, J=5.9 Hz, 2H; CH).
(1’R*,2’S*,1’’S*,2’’R*)-2,2,3,3,2’,3’,3’,1’’,3’’,3’’,2’’’,2’’’,3’’’,3’’’-Tetradecadeu-
terioquatercyclopropane {(R*,S*,S*,R*)-[D14]-19} and (1’R*,2’S*,1’’S*,
2’’S*)-2,2,3,3,2’,3’,3’,1’’,3’’,3’’,2’’’,2’’’,3’’’,3’’’-tetradecadeuterioquatercyclo-
propane {(R*,S*,S*,S*)-[D14]-20}: From a solution of d,l-[D14]-5 (123 mg,
0.71 mmol) in THF (3 mL) and Li (30 mg, 4.3 mmol, 3 equiv) in liq. NH3
(15 mL), and after purification by column chromatography (50 g of silica
gel, 1.2”14cm column, pentane) was obtained a 12:1 mixture (80 mg,
63%) of (R*,S*,S*,R*)-[D14]-19 and (R*,S*,S*,S*)-[D14]-20 according to
GP 5 as a colorless oil. (R*,S*,S*,R*)-[D14]-19: 1H NMR (600 MHz,
CD2Cl2): d=0.70 (d, J=4.7 Hz, 2H; CH), 0.47 (d, J=4.7 Hz, 2H; CH);
13C NMR (75.5 MHz, CDCl3): d=18.4(2 CH), 17.2 (t, J=24.0 Hz, 2CD),
11.6 (2CH), 7.2 (p, J=24.4 Hz, 2CD2), 2.12 (p, J=24.4 Hz, 2CD2), 1.95
(p, J=24.6 Hz, 2CD2).
Preparation of quatercyclopropanes by Birch reduction
General procedure GP 5: A 50 mL, three-necked, round-bottomed flask
equipped with a magnetic stirring bar, a thermometer and a reflux con-
denser cooled with dry ice was charged with liquid ammonia (30 mL).
Ammonia was dried by stepwise addition of lithium in milligram quanti-
ties until a persisting blue color had appeared. Then lithium (3–4equiv
per double bond) was added in one portion, and the mixture was stirred
until the lithium had completely dissolved. A solution of the respective
diene or monoene (0.5–1 mmol) in diethyl ether or THF was added drop-
wise at À788C, and the reaction mixture was stirred at this temperature
(R*,S*,S*,S*)-[D14]-20: 1H NMR (600 MHz, CD2Cl2): d=0.63 (d, J=
5.9 Hz, 2H; CH), the signals partly overlap with the signals of the major
diastereomer.
(1’R*,2’S*,1’’S*,2’’S*)-Quatercyclopropane [(R*,S*,S*,S*-20)]: From
a
solution of (Z)-cis-16 (241 mg, 1.50 mmol) in Et2O (10 mL) and Li
(42 mg, 6.0 mmol, 4 equiv) in liq. NH3 (50 mL) and after purification by
174
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 167 – 177

Quatercyclopropanes
FULL PAPER
column chromatography (50 g of silica
gel, 1.2”14cm column, pentane) was
obtained (R*,S*,S*,R*)-20 (238 mg,
96%) as the sole product according to
GP 5 as an oil. 1H NMR (250 MHz,
CDCl3): d=0.88–0.78 (m, 2H), 0.76–
0.60 (m, 2H), 0.59–0.35 (m, 4H), 0.34–
0.21 (m, 4H), 0.20–0.12 (m, 2H), 0.08–
0.00 (m, 2H), À0.06 to À0.13 (m, 2H);
13C NMR (63.9 MHz, CDCl3): d=20.4
(CH), 19.7 (CH), 19.3 (CH), 15.6
(CH), 12.3 (CH), 10.0 (CH2), 9.7 (CH),
8.6 (CH2), 4.8 (CH2), 4.4 (CH2), 2.85
(CH2), 2.80 (CH2).
Table 2. Crystal and data collection parameters for compounds meso-5, (Z)-cis-16, trans,trans-(R*S*R*S*)-17
and cis,cis-(S*S*R*R*)-21.
Compound
meso-5
(Z)-cis-16
(R*S*R*S*)-17
G
formula
molecular mass
crystal size [mm]
crystals
space group
a [Š]
b [Š]
c [Š]
a [8]
b [8]
C12H14
158.23
10.5
C12H16
160.25
C12H18
162.27
10.3
C12H18
162.27
10.5
monoclinic
P21/n
5.1770(10)
7.585(2)
12.498(3)
90
96.86(3)
90
1.00”0.20”0.20
monoclinic
P21/c
12.890(2)
5.0530(8)
triclinic
triclinic
¯
¯
P1
P1
5.0649(10)
10.551(2)
13.384(3)
75.370(2)
79.332(2)
80.893(3)
675.4(2)
3
4.949(2)
6.664(3)
8.209(3)
72.28(3)
81.30(3)
71.96(3)
244.69(17)
1
15.092
90
A
99.08(2)
90
970.7(4)
4
g [8]
Catalytic hydrogenation of bis(bicyclo-
propylidenyl)s meso-5 and d,l-5
V [Š3]
487.3(2)
2
Z
General procedure GP 6: A stirred
suspension of palladium on barium sul-
fate in MeOH was pre-hydrogenated
for 30 min (hydrogen pressure 1 bar).
The respective bis(bicyclopropylidenyl)
was added, and the reaction mixture
was stirred under the same pressure of
hydrogen for the indicated time until
the theoretically necessary volume of
H2 had been consumed. The reaction
mixture was filtered through a pad of
Celite and concentrated under reduced
pressure.
F
C
258
1.167
0.065
113(2)
30
66046860
3921
0.0218
0.1192
0.0408
352
90
1.101
0.061
150(2)
25
180
1.106
0.060
113(2)
25
]
]
1.097
0.061
230(1)
26
m [mmÀ1
T [K]
Vmax [8]
refl. collected
refl. independent
Rint
wR2
R1 [I=2s(I)]
no. parameters refined
GOOF
largest diff. peak
838
2059
1895
838
853
0.0406
0.1652
0.0540
173
1.037
0.168 and À0.196
0.0315
0.1195
0.0451
55
1.0641.099
0.158 and À0.165
0.0524
0.0957
0.0364
91
247
1.018
0.570 and À0.209
0.115 and À0.148
À3
(1’S*,2’S*,1’’R*,2’’R*)-Quatercyclopro-
pane [(S*,S*,R*,R*)-21]: From meso-5
(60.0 mg, 0.379 mmol) and 10% Pd/
BaSO4 (8.1 mg, 7.61 mmol, 2 mol%) in
and hole [eŠ
]
ing and Crystallization Device (OHCD), which uses a miniature zone
melting procedure with focused IR-laser light.[48] The device was mount-
ed on a four circle Nicolet R3m/V [meso-5, (R*S*R*S*)-17, (S*S*R*R*)-
21] or Bruker SMART CCD 6000 [(Z)-cis-16] diffractometer, and the
crystal formation detected using graphite monochromated MoKa radia-
tion. Correction for the cylindrical shape of the crystals (0.5 mm diame-
ter) was applied for meso-5 and (S*S*R*R*)-21. The structures were
solved by direct methods and refinements on F2 were performed with the
Bruker AXS SHELXTL program suite (Version 5.10). The hydrogen
atoms were located in the difference Fourier maps and refined isotropi-
cally. The parameters of the crystal data collections and structure refine-
ments are compiled Table 2.
MeOH (5 mL) was obtained (S*,S*,R*,R*)-21 (39.5 mg, 64%) according
to GP 6 as a colorless oil; 17 mL of hydrogen had been consumed.
(S*,S*,R*,R*)-21: 1H NMR (250 MHz, CDCl3): d = 0.98–0.35 (m, 12H),
0.24–0.12 (m, 4H), 0.02 to À0.06 (m, 2H); 13C NMR (62.9 MHz, CDCl3):
d=18.9 (2 CH), 15.7 (2CH), 10.0 (2CH2), 9.5 (2CH), 4.6 (2CH2), 4.3
(2CH2); MS (DCI): m/z (%): 180 (17) [M+NH4]+, 163 (100) [M+H]+;
elemental analysis calcd (%) for C12H18 (162.3): C 88.82, H 11.18; found:
C 88.62, H 11.26.
(1’R*,2’R*,1’’R*,2’’R*)-Quatercyclopropane [(R*,R*,R*,R*)-22]: From
d,l-5 (80.0 mg, 0.506 mmol) and 10% Pd/BaSO4 (10.7 mg, 10.1 mmol,
2 mol%) in MeOH (10 mL) was obtained (R*,R*,R*,R*)-22 (37.0 mg,
45%) according to GP 6 as a colorless oil; 23 mL of hydrogen had been
consumed. (R*,R*,R*,R*)-22: 1H NMR (250 MHz, CDCl3): d=0.98–0.35
(m, 12H), 0.26–0.10 (m, 4H), 0.04 to À0.06 (m, 2H); 13C NMR
(62.9 MHz, CDCl3): d=19.6 (2CH), 15.5 (2CH), 9.71 (2CH), 9.69
(2CH2), 4.6 (2CH2), 4.2 (2CH2); MS (DCI): m/z (%): 180 (17)
[M+NH4]+, 163 (100) [M+H]+; elemental analysis calcd (%) for C12H18
(162.3): C 88.82, H 11.18; found: C 88.70, H 11.06.
Acknowledgements
This work was supported by the State of Niedersachsen and the Fonds
der Chemischen Industrie as well as EPSRC (UK). M.v.S. is indebted to
the Hermann-Schlosser Foundation for a Graduate Student Fellowship.
The authors are grateful to the companies BASF AG, Bayer AG, Cheme-
tall GmbH, Degussa AG, and Hüls AG for generous gifts of chemicals.
We are particularly grateful to the late Dr. B. Knieriem, Universität Gçt-
tingen, for his careful reading of the final manuscript.
(1’R*,2’S*,1’’R*,2’’R*)-Quatercyclopropane
[(R*,S*,R*,R*)-18]
and
(1’S*,2’S*,1’’R*,2’’R*)-quatercyclopropane [(S*,S*,R*,R*)-21]: To a stir-
red solution of meso-5 (180 mg, 1.14mmol) in methanol (15 mL) was
added in one portion 2-nitrobenzenesulfonyl hydrazide (2.151 g,
9.90 mmol, 8.7 equiv), and the resulting mixture was stirred at ambient
temperature for 5 h. The reaction mixture was diluted with hexane
(90 mL) and poured into ice-cold water (90 mL). The organic phase was
washed with brine (2”90 mL), dried, filtered through a pad of silica gel
and concentrated under reduced pressure to give a 1:2 mixture (160 mg,
87%) of (R*,S*,R*,R*)-18 and (S*,S*,R*,R*)-21 as a colorless oil. A
sample of (S*,S*,R*,R*)-21 for X-ray crystal structure analysis was isolat-
ed by preparative gas chromatography. Its NMR data were identical to
those reported above.
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Crystal structure determinations: Suitable single crystals of hydrocarbons
meso-5, (Z)-cis-16, (R*,S*,R*,S*)-17, and (S*,S*,R*,R*)-21 were grown in
situ on the diffractometer in
(R*,S*,R*,S*)-17 and (S*,S*,R*,R*)-21 with the help of the Optical Heat-
a
Lindeman capillary, for meso-5,
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