Multiple asymmetric cyclopropanation: Synthesis and x-ray crystallographic studies of a prototype coronane and all anti-trans-1,15- quinquecyclopropanedimethanol

Article abstract of DOI:10.1055/s-1998-5930

Stepwise macrocyclization of the all syn-trans-1,15- quinquecyclopropanedimethanol (9) and the all syn-trans-1,21- septecyclopropanedimethanol (4) with phthalic acid gave the corresponding coronanes 16 and 6, dilactones with 18- and 22-membered rings respectively. The structure of 16 was confirmed by an X-ray crystallographic study. Bidirectional asymmetric cyclopropanation of dienediol 17 was used to elaborate the corresponding all anti-trans-1,15-quinquecyclopropanedimethanol 21 which was shown by X-ray crystallography to adopt an extended rigid-rod conformation.

Full text of DOI:10.1055/s-1998-5930

SYNTHESIS
Papers
490
Multiple Asymmetric Cyclopropanation: Synthesis and X-Ray Crystallographic
Studies of a Prototype Coronane and all anti-trans-1,15-Quinquecyclopropane-
dimethanol
Anthony G. M. Barrett,* Tim Gross, Dieter Hamprecht, Mitsuru Ohkubo, Andrew J.P. White, David J. Williams
Department of Chemistry, Imperial College of Science, Technology and Medicine, London, SW7 2AY, U.K.
Fax +44(171)5945805; E-mail: m.stow@ic.ac.uk
Received 4 September 1997
Abstract: Stepwise macrocyclization of the all syn-trans-1,15-
quinquecyclopropanedimethanol (9) and the all syn-trans-1,21-
septecyclopropanedimethanol (4) with phthalic acid gave the cor-
responding coronanes 16 and 6, dilactones with 18- and 22-mem-
bered rings respectively. The structure of 16 was confirmed by an
X-ray crystallographic study. Bidirectional asymmetric cyclopro-
panation of dienediol 17 was used to elaborate the corresponding
all anti-trans-1,15-quinquecyclopropanedimethanol 21 which was
shown by X-ray crystallography to adopt an extended rigid-rod
conformation.
Condensation of phthaloyl chloride with the septecyclo-
propanedimethanol (4)5b in the presence of pyridine and
DMAP under high dilution conditions gave the corre-
sponding coronane6 6 in poor yield (10%) (Scheme 1).
Alternatively, the same macrocyclic dilactone was pre-
pared in superior yield using a stepwise approach
(Scheme 2). Thus Steglich-esterification7 of (2-trimethyl-
Key words: FR-900848, coronanes, multiple cyclopropane sys-
tems, asymmetric cyclopropanation
In 1990, Yoshida et al. in the Fujisawa laboratories in Ja-
pan, reported the isolation and partial structural elucida-
tion of FR-900848 (1) from a fermentation broth of
Streptoverticillium fervens.1 The full stereochemical as-
signment of this substance was proven both by
degradation2 and total synthesis.3 FR-900848 (1) shows
potent, selective activity against filamentous fungi such as
Aspergillus niger, Mucor rouxianus, Aureobasidium pul-
lans, various Trichophyton sp., etc.1 The fatty acid side
chain of FR-900848 (1) bears a striking resemblance to
the side chain of U-106305 (2) a cholesteryl ester transfer
protein inhibitor isolated from Streptomyces sp. by work-
ers at Upjohn Laboratories4 and also first synthesized in
our laboratories.5 Both fatty acid side chains of FR-
900848 (1) and U-106305 (2) contain all syn-trans-disub-
stituted quarter- and quinquecyclopropane systems which
undoubtedly conformationally restrict these lipophilic do-
mains. Indeed, we have shown by extensive crystallogra-
phy that all-syn-trans-disubstituted cyclopropane
oligomers with 3–7 rings are helical, at least in the solid
state.2,5 We questioned whether the preference for an ex-
tended helical structure was principally dictated by crystal
packing since examination of molecular models shows
considerable conformational mobility. Indeed we were in-
trigued by the possibility of utilizing an all syn-trans-
cyclopropene oligomer to conformationally restrict a
macrocyclic ring system as generically depicted by struc-
ture 3 and this would clearly not be possible with an ex-
tended helical conformation. In addition, we sought to
examine the conformations of all anti-trans-cyclopropene
oligomers with the expectation of finding a preference for
an extended rigid-rod conformation. Herein we report the
synthesis and full characterization of an all anti-trans-
1,15-quinquecyclopropanedimethanol and the first syn-
thesis of two coronanes as prototypes for a novel class of
macrocyclic compounds.
Scheme 1

SYNTHESIS
April 1998
491
silylethyl) phthalate (8) with alcohol 11 gave the unsym- Much to our delight, the smaller coronane 16 was ob-
metrical diester 13. Following double deprotection, the tained as a crystalline solid suitable for an X-ray crystal-
resultant hydroxy acid was macrocyclized under Yamagu- lographic study. The crystals were found to contain two
chi conditions8 to provide 6 in superior yield (67% over- independent macrocycles in the asymmetric unit.9,10 Both
all). The stepwise approach was extended to synthesis of macrocycles have essentially the same “chaise-longue”
the corresponding 18-membered coronane 16 starting like conformation, Figure 1. One of the molecules exhibits
from 1,15-quinquecyclopropanedimethanol 95b which a 65:35 disorder involving a ca. 180° “flip” about bond e
was also obtained in excellent yield (74%).
of the orthogonally oriented ester group. In both mole-
cules the other ester group is essentially coplanar with the
aromatic ring (ca. 3° rotation about bond f). Four of the
five cyclopropyl rings have all-anti H–C–C–H linkages
between them (a to c) whereas that to the fifth is gauche
(bond d), a consequence of satisfying the macrocyclic
ring constraints. The observed conformation clearly indi-
cates that for a system containing cyclopropyl rings all of
the same chirality it should be possible to construct a rel-
atively unstrained all-anti cyclocyclopropane containing
just six cyclopropane units.
The coronane 6 showed a remarkable affinity for the sol-
vent diethyl ether. After dissolving a sample in this sol-
vent and drying under high vacuum for 2 hours, it still
contained 0.5 equivalent of diethyl ether as revealed by
NMR spectroscopy. ES-MS analysis of this compound
showed a weak [M+H]+ peak and an intense [M+H2O]+
peak. No complexes were observed with Et2O, benzene,
EtOH, CH2Cl2 or MeCN by mass spectrometry, however,
upon addition of methylamine in aqueous THF, the ES-
MS spectrum displayed an intense [M+MeNH3]+ peak. In
the same way, the ES-MS spectrum of a mixture of 4-
(dimethylamino)pyridine and macrocycle 6 showed an in-
tense [M+HDMAP]+ ion. In both cases the macrocycle
appeared intact after these observations in TLC control
experiments thus excluding the possibility of covalent ad-
ducts. It is possible that the interactions are host-guest in
nature but full characterization must await further studies.
Figure 1. Molecular Structure of One of the Macrocyclic Rings Pre-
sent in the Crystals of 16
Secondly, we have examined the synthesis of a represen-
tative cyclopropene oligomer with the all anti-trans stere-
ochemistry. We expected such compounds to adopt an
extended rigid-rod conformation rather than the helix of
the all syn-trans stereoisomers. Following our standard bi-
directional methodology3,5 dienediol 175b was cyclopro-
panated using Charette conditions11 utilizing the boron
auxiliary 22 to produce the all anti-tercyclopro-
panedimethanol 1812,13 (90%). Sequential Dess–Martin
oxidation,14 Wittig homologation, and DIBAl-H reduc-
tion gave dienediol 20 which was cyclopropanated in the
presence of auxiliary 23 to yield the all anti-trans-quinque-
cyclopropanedimethanol 21 (Scheme 3). A single crystal
X-ray analysis10,15 shows the molecule to adopt an ex-
tended rod-like conformation with the methylene portions
of the syn cyclopropanes eclipsing, i.e. the H–C–C–H
linkages a to d in Figure 2 are all-anti. It is interesting to
note that the change from a system containing linked cy-
clopropyl units all of the same chirality to one of alternat-
Scheme 2

SYNTHESIS
Papers
492
was evaporated and chromatographed (hexanes/EtOAc, 1:1) to give 8
(730 mg, 81%) as a colorless oil which was used directly without fur-
ther purification; Rf 0.43 (CH2Cl2/MeOH, 9:1).
ing chiralities, but retaining an all-trans geometry for the
linkages, produces a change from a helical to a linear con-
formation for the product. Molecules of 21 exhibit a
lamella packing motif, the ends of adjacent chains being
cross-linked by O–H···O hydrogen bonds.
IR (film): ν = 2955, 1727, 1704, 1412, 1289, 1252, 1125, 1073, 933,
857 839 cm–1.
1H NMR (300 MHz, CDCl3): δ = 10.13 (br, 1H), 7.93 (dd, J = 1.8, 7.0
Hz, 1 H), 7.72 (dd, J = 1.8, 7.0 Hz, 1 H), 7.69–7.28 (m, 2 H), 4.48–
4.42 (m, 2 H), 1.17–1.11 (m, 2 H), 0.07 (s, 9H).
13C NMR (75 MHz, CDCl3): δ = 172.1, 168.3, 133.6, 132.1, 130.8,
130.2, 129.9, 128.8, 64.4, 17.1, –1.5.
MS (CI, NH4 ): m/z = 284 (M+NH4)+, 267 (M+H)+.
+
(1R,3S,4R,6S,7R,9S,10R,12R,13S,15R,16S,18R,19S,21R)-1-[(tert-
Butyldimethylsilyloxy)methyl]-21-septecyclopropanemethanol
(11):
To diol 4 (81 mg, 0.24 mmol) in CH2Cl2 (5 mL) were added imidazole
(18 mg, 0.26 mmol) and t-BuMe SiCl (37 mg, 0.24 mmol). After stir-
2
ring for 1.5 h, H2O was added, and the mixture extracted with EtOAc
(3 × 10 mL). The extract was dried (Na SO ), rotary evaporated, and
2
4
chromatographed (hexanes/EtOAc, 5:1 to 0:1) to give recovered diol
4 (25 mg, 30%) and ether 11 (57 mg, 52%) as a colorless oil; Rf 0.51
(hexane/EtOAc, 2:1); [α]D –177.7 (c =1.1, CHCl3).
IR (film): ν = 3064, 2996, 1470, 1255, 1088, 1027, 837, 775 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.46–3.39 (m, 4 H), 0.90 (s, 9 H),
0.86–0.65 (m, 4 H), 0.53–0.47 (m, 10 H), 0.30–0.17 (m, 4 H), 0.11–
0.02 (m, 10 H), 0.05 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 66.9, 66.7, 26.0, 19.8, 19.6, 18.7,
18.6, 18.50, 18.47, 18.42, 18.37, 18.27, 18.25, 18.1, 8.44, 8.39, 8.3,
8.24, 8.16, –5.09, –5.12.
MS (CI, NH4 ): m/z = 474 (M+NH4)+, 457 (M+H)+.
+
HRMS (FAB, NaI): [C29H48O2SiNa, (M + Na)+], m/z
calcd
Scheme 3
479.3321, found 479.3339.
(1R,3S,4R,6S,7R,9S,10R,12R,13S,15R,16S,18R,19S,21R)-1-[(tert-
Butyldimethylsilyloxy)methyl]-21-septecyclopropanemethyl
2-(Trimethylsilyl)ethyl Phthalate (13):
A mixture of acid 8 (39 mg, 0.14 mmol), alcohol 11 (57 mg,
0.12 mmol), DCC (50 mg, 0.24 mmol) and DMAP (7 mg, 0.057
mmol) in CH2Cl2 was stirred overnight, when CH2Cl2 (10 mL) and
H2O (2 mL) were added. The organic layer was separated, dried
(Na2SO4), rotary evaporated, and chromatographed (hexanes/Et2O,
1:0 to 9:1) to give diester 13 (76 mg, 90 %) as a colorless oil; Rf = 0.43
(hexanes/EtOAc, 9:1); [α]D –111.9 (c =2.3, CHCl3).
Figure 2. Molecular Structure of 21
Further studies on related multiple cyclopropane systems
will be reported in due course.
IR (film): ν = 2996, 2954, 1728, 1284, 1122, 1070, 838 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.74–7.72 (m, 2 H), 7.56–7.53 (m,
2 H), 4.44–4.38 (app t J = 8.7 Hz, 2 H), 4.15–4.08 (m, 2 H), 3.46–3.42
(m, 2 H), 1.12 (app t J = 8.7 Hz, 2 H), 0.96–0.84 (m, 2 H), 0.93 (s, 9
H), 0.74–0.01 (m, 26 H), 0.09 (s, 9 H), 0.05 (s, 6 H).
All reactions were carried out in an atmosphere of dry N2 or argon at
r.t. unless otherwise stated. Reaction temperatures other than r.t. were
recorded as bath temperatures unless otherwise stated. Chromatogra-
phy was carried out on BDH silica 60, 230-400 mesh ASTM, using
flash techniques16 (eluants are quoted in parenthesis). Analytical TLC
was performed on Merck precoated silica 60 F254 plates. Petroleum
ether, bp 40–60°C (hexanes) used as a chromatography eluant was
distilled; all other chromatography eluants were BDH GPR grade and
undistilled. The following reaction solvents/reagents were purified by
distillation: benzene (PhH) (P2O5, N2), CH2Cl2 (CaH2, N2), 1,2-
dimethoxyethane (DME) (CaH2, N2), pyridine (CaH2, N2), and THF
(Ph2CO/K, N2). All other organic solvents and reagents were obtained
from commercial sources and used without further purification. Or-
ganic extracts were concentrated using a rotary evaporator at < 40°C
bath temperature. Involatile oils and solids were vacuum dried at
< 2 Torr. Optical rotations were measured at 25°C.
13C NMR (75 MHz, CDCl3): δ = 167.7, 132.5, 132.3, 130.9, 128.9,
128.8, 69.7, 66.7, 64.0, 26.0, 19.6, 18.9, 18.5, 18.4, 18.2, 17.8, 17.3,
15.7, 8.8, 8.3, 8.23, 8.16, –1.5, –5.1.
MS (FAB, NaI): m/z = 727 (M+Na)+.
HRMS (FAB, NaI): [C42H64O5Si2Na, (M + Na)+], m/z calcd
727.4190, found 727.4194.
Coronane 6:
A solution of the diester 13 (90 mg, 128 µmol) and Bu4NF (1 M in
THF, 638 µL) in THF (1.5 mL) was stirred for 1 h, when Et2O
(15 mL) and satd aq NH Cl were added. After a few min, 1N HCl was
4
added, the organic layer was separated and the aqueous layer extract-
ed with Et2O (3 × 10 mL). The combined organic layer was dried
(Na2SO4), rotary evaporated, and the residue was dissolved in THF
(8 mL). Et3N (25 µL, 179 µmol) and 2,4,6-trichlorobenzoyl chloride
(26 µL, 166 µmol) were added, the mixture was stirred for 2 h and
diluted with toluene (60 mL). The resultant solution was added drop-
wise over 4.5 h (syringe pump) to 4-(dimethylamino)pyridine (94 mg,
766 µmol) in toluene (15 mL) at reflux. After cooling to r.t., satd aq
2-(Trimethylsilyl)ethyl Hydrogen Phthalate (8):
2-(Trimethylsilyl)ethanol (0.58 mL, 4.05 mmol) was added to NaH
(60 % in oil, 120 mg, 4.05 mmol) in THF (5.0 mL), the mixture was
stirred for 3 h when a solution of anhydride 7 (500 mg, 3.38 mmol) in
THF (5.0 mL) was added and further stirred overnight. The mixture
was quenched with 1 N HCl and extracted with EtOAc, the extract

SYNTHESIS
April 1998
493
NH4Cl was added and the mixture was extracted with EtOAc. The
separated organic layer was dried (Na2SO4), rotary evaporated, and
chromatographed (hexanes/Et2O, 10:1 to 1:1) to give 6 (45 mg, 74%)
as a colorless oil:
the aqueous layer extracted with CH2Cl2 and iso-PrOH (5:1,
5 × 60 mL). The combined organic layers were dried (Na2SO4), fil-
tered, rotary evaporated, and chromatographed (EtOAc/hexanes/iso-
PrOH, 5:5:1) to yield the known12 tercyclopropanedimethanol 18
(0.4105 g, 90%); Rf 0.35 (EtOAc).
Rf 0.54 (EtOAc/hexanes, 1:3); [α]D –67.9 (c = 0.76, t-BuOMe).
IR (film from CDCl3): ν = 3063, 2994, 1725, 1283, 1119, 1064, 954,
874 cm–1.
HRMS (CI, NH ): [C11H22NO2, (M + NH4)+], calcd 200.1651, found
3
200.1651.
1H NMR (CDCl3, 400 MHz): δ = 7.76–7.70 (m, 2 H), 7.56–7.50 (m,
2 H), 4.81 (dd, J = 11.2, 5.0 Hz, 2 H), 3.55 (dd, J = 11.2, 9.7 Hz, 2 H),
1.29–1.20 (m, 2 H), 0.59–0.50 (m, 4 H), 0.46–0.29 (m, 12 H), 0.27–
0.15 (m, 10 H).
Anal calcd for C11H18O2: C, 72.44; H, 9.96; found C, 72.35; H, 9.88.
(1S,3R,4R,6R,7R,9S)-1,9-Bis[(E)-3-hydroxyprop-1-en-1-yl]ter-
cyclopropane (20):
13C NMR (CDCl3, 101 MHz): δ = 167.8 (2 C), 132.4 (2 C), 130.9 (2
C), 129.0 (2 C), 69.9 (2 C), 22.1 (2 C), 21.7 (4 C), 21.6 (4 C), 19.9 (2
C), 17.2 (2 C), 10.8 (2 C), 10.6 (2 C), 9.9 (2 C), 9.3.
MS (FAB): m/z = 473 [M + H]+, 393, 322, 149.
Dienediol 20 (0.1966g, 0.84 mmol, 95%), which was prepared from
tercyclopropanedimethanol 18 without purification of intermediates,
via diester 19 [(0.2893g, 61%): Rf 0.16 (EtOAc/hexanes, 9:91)] and
using the general procedure of Dess–Martin oxidation, Wittig ho-
mologation and DIBAl-H reduction described in detail elsewhere,5b
was obtained as a colorless oil; Rf 0.56 (EtOAc).
HRMS (FAB): [C31H37O4, (M + H)+], m/z calcd 473.2692, found
473.2737.
IR (film): ν = 3330, 3066, 2999, 2922, 2866, 1666, 1086, 1003,
962 cm–1.
(1R,3S,4R,6S,7R,9R,10S,12R,13S,15R)-1-[(t-Butyldimethylsilyl-
oxy)methyl]-15-quinquecyclopropane-methyl 2-(Trimethyl-
silyl)ethyl Phthalate (12):
Compound 12 (81 mg, 100%), which was prepared by condensation
of 8 and 105b according to the procedure for 11, was obtained as a col-
orless oil; Rf 0.46 (hexanes/EtOAc, 9:1); [α]D –78.9 (c =1.1, CHCl3).
IR (film): ν = 2997, 2952, 2931, 1728, 1284, 1253, 1122, 1070,
837 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 5.68 (dt, J = 15.3, 5.9 Hz, 2 H), 5.25
(dd, J = 8.8, 15.3 Hz, 2 H), 4.08 (t, J = 5.9 Hz, 4 H), 1.3–1.1 (m, 4 H),
0.83 (m, 2 H), 0.60 (m, 2 H), 0.53–0.47 (m, 4 H), 0.25 (m, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 136.7, 126.2, 63.7, 22.4, 19.8, 17.9,
12.3.
CIMS (NH3): m/z (%) = 252 (4, M + NH4)+, 234 (7, M + NH4 –
H2O)+, 199 (33), 157 (45), 145 (48), 131 (65), 119 (67).
HRMS (FAB): [C15H26NO2, (M + NH4)+], calcd 252.1964, found
252.1964.
1H NMR (400 MHz, CDCl3): δ = 7.75–7.71 (m, 2 H), 7.57–7.53 (m,
2 H), 4.44–4.39 (m, 2 H), 4.16 (dd, J = 11.4, 7.2 Hz, 1 H), 4.08 (dd, J
= 11.4, 7.4 Hz, 1 H), 3.47 (dd, J = 10.8, 6.2 Hz, 1 H), 3.42 (dd, J =
10.8, 6.4 Hz, 1 H), 1.15–1.10 (m, 2 H), 0.97–0.84 (m, 2 H), 0.91 (s, 9
H), 0.75–0.47 (m, 7 H), 0.44–0.40 (m, 1 H), 0.36–0.32 (m, 1 H), 0.28–
0.18 (m, 2 H), 0.09 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H), 0.18–0.03 (m,
7 H).
(1R,3S,4S,6R,7R,9R,10R,12S,13S,15R)-1,15-quinquecyclopro-
panedimethanol (21):
Cyclopropanation of diene 20 as described above for 17 and using
ligand 23 gave the diol 21 (0.1326 g, 86%) as colorless crystals; Rf
0.49 (EtOAc); mp 76–78°C (EtOAc/hexanes); [α]D –7.3 (c = 0.64,
EtOH).
13C NMR (100 MHz, CDCl3): δ = 167.7, 132.5, 132.2, 130.9, 130.8,
128.8, 128.7, 69.7, 66.7, 64.0, 26.0, 19.5, 18.8, 18.5, 18.4, 18.2, 18.1,
17.7, 17.3, 15.6, 8.7, 8.2, 8.1, 8.0, –1.5, –5.09, –5.12.
MS (FAB, NaI): m/z = 647 (M+Na)+.
IR (film): ν = 3350, 3066, 2997, 2918, 2870, 1452, 1414, 1309, 1024,
910, 870, 733 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 3.39 (m, 4 H), 1.32 (s, 2 H), 0.79
(m, 2 H), 0.67 (m, 2 H), 0.54–0.42 (m, 6 H), 0.28 (m, 4 H), 0.09 (m,
6 H).
HRMS (FAB, NaI): [C36H56O5Si2Na, (M+Na)+], m/z calcd 647.3564,
found 647.3530.
13C NMR (CDCl3, 100 MHz): δ = 66.9, 19.6, 18.5, 18.4, 18.3, 17.9,
8.9, 8.7, 8.4.
Coronane 16:
16 (28 mg, 74 %), which was prepared from 12 in a similar manner to
that of 6 without purification of intermediate 14, was obtained as a
white crystalline solid; mp 110–112°C (Et2O/EtOH); Rf 0.57 (hex-
anes/EtOAc, 4:1); [α]D +87.0 (c =1.4, CHCl3).
CIMS (NH3): m/z (%) = 280 (10, M + NH4)+, 262 (2, M + NH4 –
H2O)+, 105 (64), 93 (85), 91 (100).
HRMS (CI, NH ): [C17H30NO2, (M + NH4)+], calcd 280.2277, found
3
IR (film): ν = 3062, 2995, 1726, 1279, 1265, 1116, 1063, 941 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.72–7.68 (m, 2 H), 7.53–7.48 (m,
2 H), 4.47 (dd, J = 6.7, 11.1 Hz, 2 H), 3.89 (dd, J = 7.4, 11.1 Hz, 2 H),
1.38–1.28 (m, 2 H), 0.78–0.69 (m, 4 H), 0.51–0.47 (m, 2 H), 0.44–
0.35 (m, 6 H), 0.33–0.28 (m, 2 H), 0.05 to –0.06 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 167.9, 132.9, 130.7, 128.7, 70.1,
23.5, 21.9, 21.5, 18.9, 17.6, 10.5, 10.0, 9.4.
280.2279.
Anal calcd for C17H26O2: C, 77.80; H, 10.00; found C, 77.81; H, 9.84.
We thank GlaxoWellcome for their most generous endowment (to
A.G.M.B.), the European Commission for a TMR Research Fellow-
ship (to D.H.), the Fujisawa Pharmaceutical Company Ltd. for sup-
port (for M.O), the Wolfson Foundation for establishing the Wolfson
Centre for Organic Chemistry in Medical Science at Imperial Col-
lege, the Engineering and Physical Science Research Council, and
G.D. Searle & Company for generous unrestricted support.
MS (CI, NH4 ): m/z = 393 (M+H)+.
+
+
HRMS (CI, NH4 ): [C25H29O4, (M+H+)], m/z calcd 393.2066, found
393.2073.
(1S,3R,4R,6R,7R,9S)-1,9-Tercyclopropanedimethanol (18):
DME (1.6 mL, 15.0 mmol) and CH2Cl2 (15 mL) were stirred and
cooled to –20°C when Et2Zn (1.5 mL, 15.0 mmol) was added drop-
wise at a rate that the temperature remained at –20°C. CH2I2 (2.4 mL,
30.1 mmol), was also slowly added at –20°C and the resultant zinc
complex was added to a precooled (–78°C) stirred solution of diene-
diol (17)5b (0.386 mL, 2.5 mmol) and the boronate 22 (1.421g, 5.3
mmol) in CH2Cl2 (19 mL). After 3 h at –78°C, the mixture was al-
lowed to warm to r.t. with continued stirring overnight and then
(1) (a) Yoshida, M.; Ezaki, M.; Hashimoto, M.; Yamashita, M.;
Shigematsu, N.; Okuhara, M.; Kohsaka, M.; Horikoshi, K.
J. Antibiotics 1990, 43, 748.
(b) Yoshida, M.; Horikoshi, K. EP 286 330 (1988), US Patent,
4 803 074 (1989); Chem. Abstr. 1989, 110, 210961.
(2) (a) Barrett, A.G.M.; Kasdorf, K.; Williams, D.J. J. Chem. Soc.,
Chem.Comm. 1994, 1781.
(b) Barrett, A.G.M.; Doubleday, W.W.; Tustin, G.J.; White,
A.J.P.; Williams, D.J. J. Chem. Soc., Chem. Commun. 1994,
1783.
quenched with satd aq NH Cl (33 mL) and iso-PrOH (7 mL) followed
4
by vigorous stirring for 30 min. The organic layer was separated and

SYNTHESIS
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494
(c) Barrett, A.G.M.; Tustin, G.J. J. Chem. Soc., Chem. Commun.
1995, 355.
(124)˚], 2986 (1247) had |Fo| > 4σ(|Fo|) and were considered to
be observed. The structures were solved by direct methods and
in 21 disorder was found in the positions of one of the hydroxyl
oxygen atoms—this was resolved into two partial occupancy
orientations, both of which were refined anisotropically. In 16
disorder was found in the position of the o-phthalate moiety of
one of the independent molecules; two partial occupancy orien-
tations were identified, the atoms of the major occupancy orien-
tation being refined anisotropically, those of the minor
occupancy orientation isotropically. The remaining full occu-
pancy non-hydrogen atoms in both structures were refined
anisotropically (with the C–H hydrogen atoms placed in calcu-
lated positions—the hydroxyl hydrogen atoms could not be lo-
cated) by full-matrix least squares based on F2 to give R1 =
0.067 (0.056), wR2 = 0.162 (0.152) for the observed data and
572 (183) parameters. The chiralities of both structures were as-
signed by internal reference. Computations were carried out us-
ing the SHELXTL PC program system version 5.03 and atomic
coordinates, bond lengths and angles, and thermal parameters
have been deposited with the Cambridge Crystallographic Data
Centre.
(d) Barrett, A.G.M.; Doubleday, W.W.; Kasdorf, K.; Tustin,
G.J.; Williams, D.J. J. Chem. Soc., Chem. Commun. 1995, 407.
(e) Barrett, A.G.M.; Kasdorf, K.; Williams, D.J. J. Chem. Soc.,
Chem. Commun. 1995, 649.
(f) Barrett, A.G.M.; Kasdorf, K.; Tustin, G.J.; Williams, D.J.
J. Chem. Soc.,Chem. Commun. 1995, 1143.
(g) Barrett, A.G.M.; Doubleday, W.W.; Kasdorf, K.; Peña, M.;
Tustin, G.J.; Willardsen, J.A. J. Heterocycl. Chem. 1996, 33,
1545.
(h) Barrett, A.G.M.; Doubleday, W.W.; Kasdorf, K.; Tustin,
G.J. J. Org. Chem. 1996, 61, 3280.
(i) Barrett, A.G.M.; Doubleday, W.W.; Tustin, G.J. Tetrahe-
dron 1996, 52, 15325.
(j) Barrett, A.G.M.; Doubleday, W.W.; Hamprecht, D.; Kas-
dorf, K.; Tustin, G.J. Pure Appl. Chem. 1997, 69, 383.
(k) Barrett, A.G.M.; Doubleday, W.W.; Hamprecht, D.; Kas-
dorf, K.; Tustin, G.J.; White, A.J.P.; Williams, D.J. J. Chem.
Soc., Chem. Commun. 1997, in press.
(3) (a) Barrett, A.G.M.; Kasdorf, K. J. Chem. Soc., Chem. Com-
mun. 1996, 325.
(11) (a) Charette, A.B.; Juteau, H. J. Am. Chem. Soc. 1994, 116,
2651.
(b) Barrett, A.G.M.; Kasdorf, K. J. Am. Chem. Soc. 1996, 118,
11030.
(b) Charette, A.B.; Prescott, S.; Brochu, C. J. Org. Chem. 1995,
60, 1081.
(c) For a second total synthesis see Falck, J. R.; Mekonnen, B.;
Yu, J.; Lai, J.-Y. J. Am. Chem. Soc. 1996, 118, 6096.
(4) Kuo, M. S.; Zielinski, R. J.; Cialdella, J. I.; Marschke, C. K.;
Dupuis, M. J.; Li, G.P.; Kloosterman, D. A.; Spilman, C. H.;
Marshall, V. P. J. Am. Chem. Soc. 1995, 117, 10629.
(5) (a) Barrett, A.G.M.; Hamprecht, D.; White, A.J.P.; Williams,
D.J. J. Am. Chem. Soc. 1996, 118, 7863.
(12) For the synthesis and characterization of the antipode of 18 us-
ing Charette cyclopropanation, see:McDonald, W.S.;Verbicky,
C.A.; Zercher, C.K. J. Org.Chem. 1997, 62, 1215.
(13) For other recent publications regarding the synthesis of oligocy-
clopropene arrays, see:
(a) Theberge, C.R.; Zercher, C.K. Tetrahedron Lett. 1994, 35,
9181; 1995, 36, 5495.
(b) Theberge, C.R.; Verbicky, C.A.; Zercher, C.K. J. Org.
Chem. 1996, 61, 8792.
(c) Cebula, R.E.J.; Hanna, M.R.; Theberge, C.R.; Verbicky,
C.A.; Zercher, C.K. Tetrahedron Lett. 1996, 37, 8341.
(d) Armstrong, R.W.; Maurer, K.W. Tetrahedron Lett. 1995,
36, 357.
(e) Charette, A.B.; Giroux, A. J. Org. Chem. 1996, 61, 8718.
(f) Charette, A. B.; De Freitas-Gil, R.P. Tetrahedron Lett. 1997,
38, 2809.
(b) Barrett, A.G.M.; Hamprecht, D.; White, A.J.P.; Williams,
D.J. J. Am. Chem. Soc. 1997, 119, 8608.
(c) For a second total synthesis, see: Charette, A. B.; Lebel, H.
J. Am.Chem. Soc. 1996, 118, 10327.
(6) Fitjer and co-workers have introduced the term coronane as
name for cyclic alkanes globally fused to another cycloalkane;
for examples, see: Wehle, D.; Fitjer, L. Angew. Chem. 1987, 99,
135; Angew. Chem., Int. Ed. Engl. 1987, 26, 130.
(7) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522.
(8) Inanaga, J; Hirata, K.; Saeki, H.; Katuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn 1979, 52, 1989.
(g) Charette, A. B.; Juteau, H.; Lebel, H.; Deschênes, D. Tetra-
hedron Lett. 1997, 38, 2809.
(9) Crystal data for 16: C25H28O4, M = 392.5, monoclinic, space
group P21 (no. 4), a = 19.146(2), b = 5.215(1), c = 23.478(2) Å,
β = 110.28(1)˚, V = 2199.0(4) Å3, Z = 4 (there are two crystal-
lographically independent molecules in the asymmetric unit),
Dc = 1.185 g cm–3, µ(Cu-Kα) = 0.63 mm–1, F(000) = 840, T =
293 K.
(10) For 16 (21) data for a clear needle of dimensions 0.50 × 0.08 ×
0.07 mm (thin clear plate of dimensions 1.00 × 0.73 × 0.01 mm)
were measured on a Siemens P4/RA diffractometer with graph-
ite monochromated Cu-Kα radiation using ω-scans. Of the
4088 (1475) independent reflections measured [2θ ≤ 124
(h) Charette, A.B.; Juteau, H.; Lebel, H.; Deschênes, D. Tetra-
hedron Lett. 1996, 37, 7925.
(i) Taylor, R.E.; Ameriks, M.K.; LeMarche, M.J. Tetrahedron
Lett. 1997, 38, 2057.
(14) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(15) Crystal data for 21: C17H26O2, M = 262.4, monoclinic, space
group C2 (no. 5), a = 32.039(3), b = 4.811(1), c = 10.680(1) Å,
β = 107.91(1)˚, V = 1566.3(2) Å3, Z = 4, Dc = 1.113 g cm–3,
µ(Cu-Kα) = 0.55 mm–1, F(000) = 576, T = 293 K.
(16) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.