Iterative cyclopropanation: A concise strategy for the total synthesis of the hexacyclopropane cholesteryl ester transfer protein inhibitor U-106305

Article abstract of DOI:10.1021/ja9708326

The first enantioselective total synthesis of the hexacyclopropane natural product U-106305, which is produced by Streptomyces sp. UC 11136, is described in full detail. Considerations on the biosynthesis of U-106305 and its close resemblance to the penta

Full text of DOI:10.1021/ja9708326

8608
J. Am. Chem. Soc. 1997, 119, 8608-8615
Iterative Cyclopropanation: A Concise Strategy for the Total
Synthesis of the Hexacyclopropane Cholesteryl Ester Transfer
Protein Inhibitor U-106305
Anthony G. M. Barrett,* Dieter Hamprecht, Andrew J. P. White, and
David J. Williams
Contribution from the Department of Chemistry, Imperial College of Science,
Technology and Medicine, London, SW7 2AY, U.K.
ReceiVed March 14, 1997X
Abstract: The first enantioselective total synthesis of the hexacyclopropane natural product U-106305, which is
produced by Streptomyces sp. UC 11136, is described in full detail. Considerations on the biosynthesis of U-106305
and its close resemblance to the pentacyclopropane bacterial metabolite FR-900848 (10) led to the proposal that its
previously unknown stereostructure should be represented as 11. The central C2-symmetrical quinquecyclopropane
unit of 11 was assembled by repeatedly using a three-step cyclopropane “homologation” sequence in an efficient
bidirectional approach. Desymmetrized quinquecyclopropane 23 was converted to dienol 13 which was mono-
cyclopropanated stereo- and regioselectively to provide hexacyclopropane 25. Deoxygenation was achieved by
conversion to thioether 29 and desulfurization. The synthesis was completed by a one-pot deprotection-oxidation-
Wittig olefination sequence to give 11. The synthetically derived material was found to be identical in all respects
to an authentic sample of U-106305 thus establishing the stereochemical identity of this natural product for the first
time. In the course of our studies, several oligocyclopropane derivatives were found to be crystalline compounds
and their structures were determined by X-ray crystallography. Among others, X-ray structures of two diastereomeric
heptecyclopropanes 27 and 28 are presented. The synthesis of five analogs of U-106305 including the structural
hybrid with FR-900848 (41) are described. An approach to FR-900848 (10) using a late desymmetrization of a
C2-symmetrical quatercyclopropane tetraene 52 is outlined.
Introduction
Cholesteryl ester transfer protein (CETP) catalyzes the
redistribution of cholesteryl esters from high-density lipoproteins
(HDLs) to low-density lipoproteins (LDLs). High levels of
LDLs are the most important risk factor for coronary heart
disease, the major cause of death in many industrialized
countries.1 Consequently, the proposal that inhibition of CETP
should slow the progression of atheriosclerosis has stimulated
the search for inhibitors of this blood protein. U-106305 was
isolated as a potent inhibitor of the CETP reaction in the Upjohn
Laboratories, and its structure (1) was published in 1995 (Figure
1).2 This astonishing natural product is produced by Strepto-
myces sp. UC 11106. In addition to its interesting biological
activity, U-106305 possesses remarkable structural features: six
cyclopropane rings, five of which are contiguous. The natural
product is the N-isobutylamide of the unusual fatty acid that is
graced with these six cyclopropane units.
Figure 1.
Scheme 1. Two Plausible Biosynthetic Routes to U-106305a
The Upjohn group have shown that the C18 backbone of the
fatty acid is biosynthetically derived from head-to-tail-linked
acetate units, while the cyclopropane methylene carbons stem
from methionine.2 On the basis of these findings, they propose
a biosynthetic route where an 8-fold unsaturated carboxylic acid
(2) is formed Via the polyketide pathway and subsequently
modified by introduction of the six additional carbon atoms to
form the cyclopropane rings as shown in Scheme 1a.2 Such a
biocyclopropanation mechanism has been suggested previously
for the formation of lactobacillic acid.3 However, we believe
a RR′S+-CH3 ) (S)-adenosyl methionine; R′′ ) growing side chain
less C3 unit; ACP ) acyl carrier protein.
that, with the evidence available at present, a different biosyn-
thetic route cannot be ruled out: incomplete reduction of the
growing polyketide chain gives rise to Michael acceptors (6).
At this stage, cyclopropanation of the polarized double bond
of 6 could occur Via conjugate addition of the (S)-adenosyl-
methionine-derived sulfur ylide 7, followed by ring closure of
enolate intermediate 8 (Scheme 1b). Similar chemistry is well-
X Abstract published in AdVance ACS Abstracts, August 15, 1997.
(1) Yalpani, M. Chem. Ind. 1996, 85-89.
(2) 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, 10629-10634.
(3) Mann, J. Secondary Metabolism, 2nd ed.; Oxford University Press:
Oxford, 1992; p 42.
S0002-7863(97)00832-9 CCC: $14.00 © 1997 American Chemical Society

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J. Am. Chem. Soc., Vol. 119, No. 37, 1997 8609
Scheme 2. Retrosynthetic Analysis of U-106305 (11)
Figure 2.
known in Vitro, using dimethylsulfoxonium methylide4 and the
involvement of (S)-adenosylmethionine-derived sulfur ylides
was also suggested to play a role in other biotransformations,
e.g., in the biosynthesis of tuberculostearic acid.3 Cyclopro-
panation according to Scheme 1b would occur during polyketide
synthesis, and in this case, the enzyme responsible for the
cyclopropanation would probably be part of the polyketide
synthase enzyme complex.
Scheme 3. Assembly of Quinquecyclopropane 14
1
By analyzing the H NMR coupling patterns and the 2D
NOESY and NMR signal simulation, the Upjohn scientists could
assign the two alkene units as trans and all of the cyclopropane
rings as trans-disubstituted.2 This leaves 26 ) 64 possible
stereoisomeric structures for this exquisite natural product since
the authors did not determine the absolute stereochemistry of
any chiral center. However, there is indirect information about
the stereostructure of U-106305 from the clear resemblance to
the side chain of FR-900848 (10, Figure 2). This pentacyclo-
propane microbial metabolite, a potent and selective antifungal
agent, was found in fermentation broths of StreptoVerticillium
ferVens.5 The stereostructure of 10 was recently determined
by our group using a combination of degradation studies, partial
synthesis, and X-ray crystallography.6 Subsequently, the first
total synthesis of FR-900848 (10) was achieved by our group,7
followed by a total synthesis by Falck and co-workers.8 The
five cyclopropane rings in 10 are located on the same face of
an all-anti carbon backbone. It is thus likely that similar
enzymes are used in the biosynthesis of each of these cyclo-
propanes. Taking into account the structural similarities between
U-106305 and FR-900848 and the producing organisms being
related, it is reasonable to speculate that both of these bacterial
strains use similar cyclopropanating enzymes. In conclusion,
the cyclopropanated fatty acid moieties of FR-900848 and
U-106305 should be isostructural, and consequently, we pro-
posed stereostructure 11 for U-106305. Herein, we report the
first total synthesis of U-106305 (11) which proved our
assumptions to be correct. The results were previously reported
in preliminary format.9 Subsequent to our publication, a
synthesis of the unnatural enantiomer of U-106305 has been
reported.10
using a Wittig type olefination of aldehyde 12. This could be
derived from diene 13 by selective cyclopropanation of the
double bond that is in proximity to the hydroxyl group, as
demonstrated in the synthesis of FR-900848 (10).7 The C2-
symmetrical core quinquecyclopropane 14 might be efficiently
produced from the chiral cyclopropanedimethanol (15) using a
bidirectional approach.
Results and Discussion
Cyclopropanation of the readily available 2(E)-butene-1,4-
diol (16),11 using preformed Zn(CH2I)2‚DME in the presence
of the chiral dioxaborolane 20 according to Charette’s protocol,12
gave 15 in excellent yields. Material of good optical purity
(89% enantiomeric excess (ee)) was produced when using 2.1
equiv of 20, whereas in the presence of 1.1 equiv of 20 only
74% ee was obtained. This synthesis is significantly easier than
the literature synthesis of diol 15 Via the resolution of trans-
1,2-cyclopropanedicarboxylic acid and subsequent reduction.13
Oxidation of diol 15 to the corresponding dialdehyde proceeded
Retrosynthetic analysis of 11 (Scheme 2) shows that the R,â-
unsaturated N-isobutylamide moiety should be easily introduced
(4) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-
1364.
(5) Yoshida, M.; Ezaki, M.; Hashimoto, M.; Yamashita, M.; Shigematsu,
N.; Okuhara, M.; Kohsaka, M.; Horikoshi, K. J. Antibiot. 1990, 18, 748-
754.
(6) Barrett, A. G. M.; Kasdorf, K.; White, A. J. P.; Williams, D. J. J.
Chem. Soc., Chem. Commun. 1995, 649-650. Barrett, A. G. M.; Kasdorf,
K.; Tustin, G. J.; Williams, D. J. J. Chem. Soc., Chem. Commun. 1995,
1143-1144. Barrett, A. G. M.; Doubleday, W. W.; Kasdorf, K.; Tustin, G.
J. J. Org. Chem. 1996, 61, 3280-3288.
(7) Barrett, A. G. M.; Kasdorf, K. J. Chem. Soc., Chem. Commun. 1996,
325-326. Barrett, A. G. M.; Kasdorf, K. J. Am. Chem. Soc. 1996, 118,
11030-11037.
(8) Falck, J. R.; Mekonnen, B.; Yu, J.; Lai, J.-Y. J. Am. Chem. Soc.
1996, 118, 6096-6097.
(9) Barrett, A. G. M.; Hamprecht, D.; White, A. J. P.; Williams, D. J. J.
Am. Chem. Soc. 1996, 118, 7863-7864.
(10) Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327-
10328.
(11) Cowie, J. S.; Landor, P. D.; Landor, S. R. J. Chem. Soc., Perkin
Trans. 1 1973, 720-724.
(12) Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651-
2652. Charette, A. B.; Prescott, S.; Brochu, C. J. Org. Chem. 1995, 60,
1081-1083.
(13) Inouye, Y.; Sugita, T.; Walborsky, H. M. Tetrahedron 1964, 20,
1695-1699. Inamasu, S.; Horiike, M.; Inouye, Y. Bull. Chem. Soc. Jpn.
1969, 42, 1393-1398.

8610 J. Am. Chem. Soc., Vol. 119, No. 37, 1997
Barrett et al.
Figure 4. The molecular structure of 19.
Figure 3. The molecular structure of one of the enantiomers present
in the crystals of (R,R)(S,S)-17. The two crystallographically inde-
pendent molecules in the structure of (R,R)-17 also have essentially
this same conformation.
Scheme 4. Synthesis of the Hexacyclopropane 25
Table 1. Influence of Acetic Acid-Pyridine (py) on the Reactivity
of Stabilized Phosphorus Ylides, Formation of Methyl
2-Octadecenoate from Hexadecanal and Ph3PdCHCO2Mea
10 min
1 h
2 h
52 (34:1) 55 (33:1) 58 (35:1)
50 (21:1) 55 (27:1) 58 (36:1)
63 (64:1) 96 (63:1) 99 (57:1)
1.5 equiv of py
1.5 equiv of HOAc
0.7 equiv of py + 0.7 equiv of HOAc 60 (56:1) 94 (56:1) 99 (58:1)
1.5 equiv of py + 1.5 equiv of HOAc 62 (59:1) 95 (48:1) 99 (52:1)
3 equiv of py + 3 equiv of HOAc
61 (72:1) 95 (71:1) 99 (69:1)
One-pot oxidation-Wittig olefination of 19 gave the diester
21 (81% from 19) which was reduced with DIBAl-H to give
the diene diol 22 in 97% yield. Double Charette cyclopropan-
ation12 of bis(allylic alcohol) 22 afforded the quinquecyclopro-
pane 14 in quantitative yield (Scheme 3). A single recrystal-
lization gave the desired stereoisomer as a highly crystalline
compound (83% from 22). Its structure was also confirmed
by single-crystal X-ray analysis and is shown in the preliminary
paper.9 It should be noted that all of the isolated intermediates
in the sequence from 15 to 14 are crystalline compounds. This
facilitates the purification processes and the removal of any
traces of undesired stereoisomers formed in the cyclopropanation
reactions.
The C2-symmetrical diol 14 was desymmetrized by formation
of the mono-tert-butyldimethylsilyl (TBS) ether 23. Mono-
silylation under the conditions reported by McDougal16 (NaH,
THF) proceeded with selectivity for the formation of the desired
monoether 23; however, conversion was low (45% 23; 10%
di-TBS ether). It was found that use of the standard silylation
conditions imidazole in CH2Cl2 was more practical, although
the reaction showed only a slight selectivity for monosilylation
(58% of 23). Unreacted starting material 14 and the di-TBS
ether were isolated in 22 and 19% yields, respectively. The
di-TBS ether was easily recycled to the diol 14 in quantitative
yield by desilylation with Bu4NF. Dess-Martin oxidation of
23 and subsequent Wadsworth-Emmons homologation with
(E)-(MeO)2P(O)CH2CHdCHCO2Me, NaH, and 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU) could be performed in one
pot if DMSO was used as the solvent to give an excellent 88%
yield of (E,E)-ester 24 in addition to 12% of the (E,Z)- and
(Z,E)-isomers (Scheme 4). DIBAl-H reduction of 24 and
Charette cyclopropanation of the derived diene 13 (95%) at -25
°C proceeded with excellent stereoselectivity and good regio-
selectivity to give hexacyclopropane 25 (72%).
a Percent conversion (E:Z ratio) with or without added pyridine and/
or HOAc. Conditions: hexadecanal (1.0 equiv; 0.25 mmol) and
Ph3PdCHCO2Me (1.5 equiv; 0.375 mmol) in dry CH2Cl2 (2.0 mL) at
0 °C; GC-MS detection.
smoothly with Dess-Martin periodinane.14 In a one-pot
procedure, excess oxidant was reduced with PPh3 and the
volatile dialdehyde was directly converted into the diester 17
[96% from 15, (E,E):(E,Z) ) 28:1] by olefination with
Ph3PdCHCO2Et (Scheme 3). Fractional recrystallization of 17
(81% ee) from Et2O/hexanes gave first the racemic (17%) and
subsequently enantiomerically pure (E,E)-diester 17 (75%). The
structures for both the enantiomerically pure (E,E)-diester 17
and the corresponding racemic modification were confirmed by
X-ray crystallography and are shown in Figure 3.
The Wittig reaction leading to 17 proceeded with both
extraordinarily high speed and trans-selectivity. In order to
elucidate the cause for this desirable reactivity, we investigated
the influence of additives that are present in the complex reaction
mixture during the formation of 17, using the Wittig reaction
between hexadecanal and Ph3PdCHCO2Me as a model. One
such species is acetic acid, generated in situ from Dess-Martin
periodinane. We found that pyridine-acetic acid buffer or
acetic acid alone accelerates the Wittig reaction significantly
and leads to increased trans-selectivity (Table 1). Catalysis of
the Wittig reaction by carboxylic acids has been observed
previously.15 The bis(allylic alcohol) 18 was obtained from
diester 17 by diisobutylaluminum hydride (DIBAl-H) reduction
in 96% yield (Scheme 3). Previous work by our group has
shown that Charette asymmetric cyclopropanation12 can be
applied to the construction of contiguous cyclopropane arrays.7
Thus, on cyclopropanation of 18, tercyclopropanedimethanol
(19) was obtained. Small amounts of unwanted diastereomers
were easily removed by recrystallization to give pure stereo-
isomer 19 (89% yield). The structure of 19 was confirmed by
X-ray analysis (Figure 4).
Septicyclopropane 26 (27%) was formed as a side product
in the Charette cyclopropanation of 13. Deprotection of 26 gave
a nonsymmetrical diol 27 with the undesired additional cyclo-
propane ring in an anti-arrangement to the other cyclopropanes
(Scheme 5). Similar stereoselectivity was previously observed
for the Simmons-Smith cyclopropanation of simple trans-3-
(14) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
(15) Ru¨chardt, C.; Eichler, S.; Panse, P. Angew. Chem., Int. Ed. Engl.
1963, 2, 619; Angew. Chem. 1963, 75, 858. Bose, A. K.; Manhas, M. S.;
Ramer, R. M. J. Chem. Soc. C 1969, 2728-2730. Vedejs, E.; Peterson, M.
J. AdV. Carbanion Chem. 1996, 2, 1; Top. Stereochem. 1994, 21, 1.
(16) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388-3390.

IteratiVe Cyclopropanation
J. Am. Chem. Soc., Vol. 119, No. 37, 1997 8611
Scheme 5. Formation of the Crystalline septicyclopropane
Dimethanols 27 and 28
Figure 5. The molecular structure of 27.
alkenyl-1-cyclopropanemethanol derivatives which provide anti-
bicyclopropanes upon Simmons-Smith cyclopropanation.17 It
is probable that the predominant formation of the septicyclo-
propane 26 with the anti-stereochemistry is the result of
stereoelectronic effects.17 Thus, delocalization of the more
electron rich σ-bonds (bonds a in structure 25) should enhance
the nucleophilicity of the alkene unit. In consequence, the zinc
carbenoid should be preferentially delivered to the opposite face
thereby providing the anti-isomer 26. It is possible that the
preferential formation of the anti-isomer results from steric
approach control and the minimization of 1,3-allylic strain. We
favor the stereoelectronic argument since 1,2-dicyclopropyl-
alkenes such as 25 are especially reactive toward further
cyclopropanation reactions relative to simple alkenes. The
structure and stereochemistry of septicyclopropane 27 were
confirmed by X-ray crystallography and are shown in Figure
5. This also provides indirect proof for the stereochemistry of
the isolated cyclopropane ring in intermediate 25. In order to
study the conformational effect of the anti-cyclopropane ring,
the all-syn septicyclopropane 28 was prepared for comparison
by repeating the bidirectional cyclopropane “homologation”
sequence (Scheme 5, 56% overall yield). Crystals suitable for
single-crystal X-ray analysis were obtained by slow evaporation
of a THF solution of 28, and the X-ray structure is shown in
Figure 6. An overlay of the structures of 27 and 28 shows that
their all-syn quinquecyclopropane units possess identical con-
formations while the anti-cyclopropane in 27 induces a bend
in the carbon backbone (Figure 6).
Figure 6. (a) The molecular structure of one of the four crystallo-
graphically independent molecules present in the crystals of 28. All
four molecules have very similar conformations. (b) A best fit of the
five cochiral cyclopropane rings in 27 (- - -) and 28 (s).
Deoxygenation of alcohol 25 was achieved via phenyl sulfide
29 using a strategy which was employed in our recent synthesis
of FR-900848 (10).7 Thus, treatment of alcohol 25 with the
reagent18 derived from N-(phenylsulfenyl)succinimide19 (31) and
tributylphosphine resulted in smooth formation of thioether 29
(91%, Scheme 6). Much to our relief, desulfurization with
Raney nickel proceeded readily to provide 30. It was found
that yields varied when different batches of Raney nickel were
used. The best results (58% yield calculated at 86% conversion)
were obtained when some ethylenediamine was added and the
reaction was stopped on incomplete conversion. Under these
conditions, intact unreacted starting material (14%) was recov-
ered. The synthesis of U-106305 (11) was completed by
desilylation, Dess-Martin oxidation to the aldehyde, and Wittig
olefination to introduce the unsaturated isobutylamide. All of
these reactions proceeded effectively in a one-pot procedure to
give 11 in 91% yield from 30 as a crystalline solid. Both the
synthetic material and an authentic sample of U-106305 were
compared by 1H NMR, 13C NMR, [R]D, CD, UV, chiral HPLC,
melting point, and mixed melting point. They were found to
be identical in all respects. Sections of the proton NMR spectra
of both compounds are shown in Figure 7. Our results clearly
establish the full structure and stereochemistry of U-106305 (11).
In addition to the total synthesis of U-106305 (11), we have
examined methods for the synthesis of analogs for biological
assay. As examples of this chemistry, we herein report the
(17) Barrett, A. G. M.; Tustin, G. J. J. Chem. Soc., Chem. Commun.
1995, 355-356. Barrett, A. G. M.; Doubleday, W. W.; Tustin, G. J.
Tetrahedron 1996, 52, 15325-15338.
(18) Walker, K. A. M. Tetrahedron Lett. 1977, 4475-4478.
(19) Bu¨chel, K. H.; Conte, A. Chem. Ber. 1967, 100, 1248-1251.
(20) Barrett, A. G. M.; Doubleday, W. W.; Hamprecht, D.; Kasdorf, K.;
Tustin, G. J. Pure Appl. Chem. 1997, 69, 383. Barrett, A. G. M.; Doubleday,
W. W.; Hamprecht, D.; Kasdorf, K.; Tustin, G. J.; White, A. J. P.; Williams,
D. J. J. Chem. Soc., Chem. Commun. In press.
(21) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-
2925.
(22) SHELXTL PC version 5.03, Siemens Analytical X-Ray Instruments,
Inc., Madison, WI, 1994.
(23) Schlosser, M.; Fouquet, G. Chem. Ber. 1974, 107, 1162-1170.
(24) Bohlmann, F.; Hu¨hn, C. Chem. Ber. 1977, 110, 1183-1185.
(25) These [R]25 values were determined by weighing in the synthetic
D
material and dissolving it in 2.00 mL of CDCl3 containing 1.96 × 10-3
mmol L-1 MeOAc as a concentration standard (1H NMR integration). The
concentration of the authentic material in the same solvent was then
1
determined by H NMR.

8612 J. Am. Chem. Soc., Vol. 119, No. 37, 1997
Barrett et al.
Scheme 6. Completion of the Synthesis of U-106305 (11)
Figure 7. Sections of the 1H NMR spectra (500 MHz, CDCl3) of
authentic U-106305 (upper trace) and synthetically derived 11 (lower
trace).
synthesis of representative derivatives 37-41 (Scheme 7). The
aldehyde 33 was condensed with the keteneylidene
Ph3PdCdCdO26 and benzylamine or morpholine to provide
the corresponding R,â-unsaturated amides 37 (20%) and 38
(67%). These reactions presumably take place via nucleophilic
addition26 of the amines and Wittig reaction of the corresponding
amide ylides. Since this strategy only proceeded in modest
yields, aldehyde 33 was converted into carboxylic acid 34 by
Horner-Emmons condensation with trimethylsilyl (dimethoxy-
phosphono)acetate. In this reaction, aqueous work-up resulted
in hydrolysis of the trimethylsilyl ester to provide the carboxylic
acid 34 (35%). Alternatively, the same acid 34 was more
conveniently prepared from aldehyde 33 by Horner-Emmons
condensation with 2-(trimethylsilyl)ethyl (dimethoxyphos-
phono)acetate to produce ester 35 (98%) and subsequent
deprotection using tetrabutylammonium fluoride. The carbox-
ylic acid 34 was converted using EDCI-mediated27 coupling into
the pentachlorophenyl ester 36 which was condensed with
tris(hydroxymethyl)methylamine and 5′-amino-5′-deoxy-5,6-
dihydrouridine28 to produce the amides 39 (73%) and 41 (55%).
Clearly, amide 41 represents a direct U-106305 (11)/FR-900848
(10) hybrid. Finally, tetrabutylammonium fluoride mediated
deprotection of ester 35 and in-situ coupling of the resultant
acid 34 with norephedrine using HBTU29 gave the amide 40
(93%). These methods have been applied for the assembly of
further analogs, and this work will be reported elsewhere in
due course.
Scheme 7. Synthesis of Representative Analogs of U-106305
(11)
In our original total synthesis of FR-900848 (10), we prepared
quatercyclopropane 53 using a bidirectional double Charette
cyclopropanation sequence.7 This diol 53 was desymmetrized
by mono-tert-butyldimethylsilylation, homologated using chem-
istry closely following the methods for U-106305 (11) (see
Schemes 4 and 6), and converted into FR-900848 (10). This
strategy did not make maximum use of the inherent masked
C2-symmetry of FR-900848 (10). We therefore sought to
explore a more concise total synthesis of FR-900848 (10) as
outlined in retrosynthetic format in Scheme 8. FR-900848 (10)
should be available from tetraenes 48 or 49 via the ester 42. In
turn, tetraenes 48 or 49 should be available from the quater-
cyclopropane 53 using a bidirectional oxidation and Horner-
Emmons sequence. The two potential routes via tetraenes 48
or 49 differ in the methods of desymmetrization and the
oxidation level. Herein, we also report our attempts to realize
these strategies (also outlined in Scheme 8). Dess-Martin
oxidation of diol 53 and Horner-Emmons homologation gave
the all-trans-tetraene 52 (55%). Other minor geometric isomers
were formed in the reaction (22%) but were not characterized.
All of our attempts to cleanly monohydrolyze diester 52 were
unsuccessful although the use of lithium hydroxide on silica
gave acid 51 (22%); this was reduced by formation of the mixed
anhydride with ethyl chloroformate and treatment with sodium
borohydride to provide alcohol 48 (72%). Alternatively, double
reduction of diester 52 with DIBAl-H (97%) and standard
desymmetrization (47%) gave the corresponding alcohol 49.
Both alcohols 48 and 49 were converted into the corresponding
pentacyclopropanes 46 (67%) and 47 (91%). In turn, both
cyclopropanemethanol derivatives 46 and 47 were smoothly
(26) Bestmann, H. J.; Sandmeier, D. Angew. Chem., Int. Ed. Engl. 1975,
14, 634.
(27) EDCI [1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydro-
chloride], see: Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. I. J. Org.
Chem. 1961, 26, 2525.
(28) Skaric, V.; Katalenic, D.; Skaric, D.; Salaj, I. J. Chem. Soc., Perkin
Trans. 1 1982, 2091.
(29) HBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluo-
rophosphate], see: Dourtoglou, V.; Ziegler, J. C.; Gross, B. Tetrahedron
Lett. 1978, 1269.

IteratiVe Cyclopropanation
J. Am. Chem. Soc., Vol. 119, No. 37, 1997 8613
without further purification. Organic extracts were concentrated using
a rotary evaporator at e40 °C bath temperature. Involatile oils and
solids were vacuum dried at <2 mmHg.
Scheme 8. Retrosynthetic Analysis of FR-900848 (10)
andSynthesis of Pentacyclopropanes 43 and 45
Crystallographic Data. A summary of the crystal data, data
collection, and refinement parameters for 14, (R,R)(S,S)-17, (R,R)-17,
19, 27, and 28 are given in Table 2. Data for 14, (R,R)(S,S)-17, (R,R)-
17, 19, and 27 were collected using ω scans, while for 28 ω-2θ scans
were employed. All of the structures were solved by direct methods,
and all of the non-hydrogen atoms were refined anisotropically using
full-matrix least-squares based on F2. The C-H hydrogen atoms were
placed in calculated positions, assigned isotropic thermal parameters,
U(H) ) 1.2Ueq(C) [U(H) ) 1.5Ueq(C-Me)], and allowed to ride on
their parent atoms. The O-H hydrogen atoms in 14, 19, 27, and 28
were located from ∆F maps and refined subject to a distance constraint
(0.90 Å). The absolute chiralities of 14, (R,R)-17, 19, 27, and 28 were
all determined by internal reference. Computations were carried out
using the SHELXTL PC program system.22 The crystallographic data
(excluding structure factors) for the structures reported in Table 2 have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC-xxxx-x. Copies of the data
can be obtained free of charge on application to The Director, CCDC,
12 Union Road, Cambridge, CB12 1EZ, U.K. (fax international code
+(1223)336-033; e-mail teched@chemcrys.cam.ac.uk).
(R,R)-1,3-Bis(hydroxymethyl)cyclopropane (15).23 To diol 1611
(3.57 g, 40.5 mmol, 1.00 equiv) in dry CH2Cl2 (200 mL) were added
dioxaborolane 20 (23.0 g, 85.1 mmol, 2.10 equiv) and 4 Å molecular
sieves (3.24 g). The mixture was cooled to -45 °C which resulted in
a slurry. According to the literature procedure,12 a solution of
Zn(CH2I)2‚DME (263 mmol, 6.49 equiv) in dry CH2Cl2 (250 mL) was
added over 30 min Via canula, which resulted in dissolution of the
slurry. The bath temperature was maintained between -30 and -40
°C during the addition. The mixture was allowed to warm to room
temperature and left for 16 h. Saturated aqueous NH4Cl (300 mL)
and i-PrOH were added with cooling in an ice bath and vigorous stirring.
After 1 h, the mixture was filtered and the layers were separated. The
aqueous layer was continuously extracted (24 h) with Et2O. The
combined organic extracts were concentrated and chromatographed
twice (silica, EtOAc/i-PrOH ) 6:1 f 3:1 f 2:1) to give 15 (3.75 g,
36.7 mmol, 91%) as a slightly yellow oil: Rf 0.32 (EtOAc/i-PrOH )
5:1); bp ca. 120 °C (0.4 mbar); IR (film) 3342 (br), 3004, 2875, 1649,
1425, 1066, 1024; 1H NMR (CDCl3, 300 MHz) δ 4.28 (br s, 2H), 3.87
(dd, J ) 11.2, 3.9 Hz, 2H), 3.02 (dd, J ) 11.0, 8.8 Hz, 2H), 0.98-
1.06 (m, 2H), 0.44 (t, J ) 7.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ
66.14 (2C), 20.01 (2C), 7.23.
converted into the corresponding sulfides 43 (52%) and 45
(14%). Unfortunately and notwithstanding this progress, all of
our attempts to desulfurize either sulfides 43 or 45 using Raney
nickel failed to provide either triene 42 or 44. This second
approach to FR-900848 (10) was abandoned.
Conclusion
The isolation of the two microbial metabolites FR-900848
(10) and U-106305 (11) has stimulated considerable interest in
the stereoselective construction of contiguous cyclopropane
arrays.20 The results presented herein demonstrate that iterative
bidirectional Charette asymmetric cyclopropanation is a most
useful strategy for the assembly of structures such as the central
quinquecyclopropane unit of U-106305 (11). The finding that
many of these cyclopropane derivatives are crystalline com-
pounds has two important implications: rigorous purification
of the desired stereoisomer is facilitated and structural aspects
of these unique compounds can be studied by means of X-ray
crystallography. The methodology is both simple and flexible
and amenable for the synthesis of analogs. Further studies on
related multiple cyclopropane systems will be reported in due
course.
In order to determine the optical purity, a sample of 15 was distilled
in a Kugelrohr apparatus to give a viscous colorless oil of [R]22D -17.44
(c 20.4, EtOH). This material was diacetylated (pyridine, Ac2O, dry
CH2Cl2) to give the corresponding diacetate of [R]22 -15.76 (c 2.1,
D
EtOH) corresponding to 89% ee [lit.13 [R]25 -17.75 (c 2.0, EtOH)].
D
(R,R)-1,3-Bis[(E)-2-(ethoxycarbonyl)ethenyl]cyclopropane (17).
To a solution of cyclopropane 15 of 81% ee (4.14 g, 40.5 mmol, 1.00
equiv) in dry CH2Cl2 (250 mL) were added dry pyridine (33 mL) and
Dess-Martin periodinane (41.3 g, 97.4 mmol, 2.40 equiv). TLC control
after 30 min indicated complete conversion. The reaction mixture was
cooled to 0 °C, and PPh3 (30.0 g, 114 mmol, 2.82 equiv) was added.
After 15 min, Ph3PdCHCO2Et (41.0 g, 118 mmol, 2.90 equiv) was
added and the cold bath was removed. TLC control indicated
completion of the reaction after 45 min. H2O was added, the layers
were separated, and the aqueous phase was extracted with Et2O. The
organic phases were combined and successively washed with aqueous
HCl (2 M), H2O, saturated aqueous NaHCO3, and brine. The solvent
was evaporated, and the residue was dissolved in a minimum amount
of CH2Cl2 at 40 °C. The mass of Ph3PO precipitated upon addition of
Et2O (50 mL) and hexanes (250 mL) and was removed. Rotary
evaporation and chromatography (silica, EtOAc/hexanes ) 1:4 f 1:3)
yielded a colorless oil that was fractionally crystallized from Et2O and
hexanes. Almost racemic material (1.65 g, 6.9 mmol, 17%) crystallized
first, and then 17 was obtained as colorless crystals. A second crop of
17 was obtained from the mother liquor by chromatography (silica,
EtOAc/hexanes ) 1:4) in addition to its (E,Z)-isomer (0.32 g, 1.3 mmol,
3%) to give a total of 7.26 g (30.5 mmol, 75%) of 17: Rf 0.37 (EtOAc/
hexanes ) 1:4); mp 42.5-43.5 °C (Et2O/hexanes); IR (diffuse
Experimental Section
All reactions were carried out in an atmosphere of dry nitrogen or
argon at room temperature unless otherwise stated. Reaction temper-
atures other than room temperature were recorded as bath temperatures
unless otherwise stated. Chromatography was carried out on BDH silica
60, 230-400 mesh ASTM, using flash techniques.21 Analytical thin-
layer chromatography (TLC) was performed on Merck precoated silica
60 F254 plates (40-60 °C). Petroleum ether (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),
dichloromethane (CH2Cl2) (CaH2, N2), dimethyl sulfoxide (DMSO)
(CaH2, N2), 1,2-dimethoxyethane (DME) (CaH2, N2), pyridine (CaH2,
N2), and tetrahydrofuran (THF) (Ph2CO/K, N2). All other organic
solvents and reagents were obtained from commercial sources and used

8614 J. Am. Chem. Soc., Vol. 119, No. 37, 1997
Barrett et al.
Table 2. Crystal Data, Data Collection, and Refinement Parametersa
data
14
C17H26O2
262.4
clear platy ribbons clear platy needles clear plates
(R,R)(S,S)-17
C13H18O4
238.3
(R,R)-17
C13H18O4
238.3
19
27
C23H34O2
342.5
28
formula
C11H18O2
182.3
clear plates
C23H34O2
342.5
formula weight
color, habit
clear platy needles clear plates
cryst size (mm)
0.80 × 0.23 ×
0.77 × 0.23 ×
0.67 × 0.60 × 0.67 × 0.53 × 0.20 x 0.17 ×
0.77 × 0.63 ×
0.02
0.03
0.17
0.13
0.03
0.03
lattice type
space group symbol, number P21, 4
monoclinic
monoclinic
P21/c, 14
monoclinic
P21, 4
orthorhombic
P212121, 19
orthorhombic
P212121, 19
monoclinic
P21, 4
cell dimensions
a (Å)
b (Å)
c (Å)
5.221(1)
17.019(1)
9.572(2)
8.328(3)
94.98(1)
1351.6(5)
4
1.171
512
Cu KR
0.71
8.460(1)
9.789(1)
17.089(1)
90.83(1)
1415.0(2)
4b
1.118
512
Cu KR
0.68
5.127(1)
9.146(1)
22.152(1)
5.179(1)
8.655(1)
42.980(4)
5.181(1)
88.825(7)
8.573(1)
90.20(1)
3944.9(5)
8c
8.912(1)
16.514(1)
98.03(1)
760.9(1)
2
â (deg)
V (Å3)
1038.7(1)
4
1.165
400
Cu KR
0.62
1926.5(4)
4
1.181
752
Cu KR
0.56
Z
Dc (g cm-3
F(000)
)
1.145
1.153
288
1504
radiation used
Cu KRd
0.57
Cu KRd
0.55
µ (mm-1
θ range (deg)
no. of unique reflns
measd
2.7-62.5
2.6-60.0
2.6-63.0
4.0-62.0
2.1-62.0
2.0-60.0
1287
1997
2436
988
1819
5858
obsd, |Fo| > 4σ(|Fo|)
1231
180
0.042
0.112
0.075, 0.072
0.14, -0.14
1452
163
0.052
0.135
0.062, 0.428
0.23, -0.12
1958
324
0.053
0.148
0.097, 0.111
0.20, -0.11
965
127
0.034
0.093
0.053, 0.106
0.12, -0.12
1435
235
0.051
0.121
0.055, 0.384
0.22, -0.16
5312
934
0.050
0.140
0.091, 0.579
0.16, -0.18
no. of variables
e
R1
f
wR2
weighting factors a, bg
largest difference peak
(hole/eÅ-3
)
a Details in common: graphite-monochromated radiation, Siemens P4 diffractometer, 293 K, refinement based on F2. b There are two
crystallographically independent molecules in the asymmetric unit. c There are four crystallographically independent molecules in the asymmetric
2
2
2
unit. dRotating anode source. e R1 ) ∑||Fo| - |Fc||/∑|Fo|. f wR2 ) x{∑[w(Fo - Fc2)2]/∑[w(Fo )2]}. g w-1 ) σ2(Fo ) + (aP)2 + bP.
reflectance) 3048, 2984, 1712, 1647, 1368, 1275, 1249, 1151, 1049,
983; H NMR (CDCl3, 300 MHz) δ 6.47 (dd, J ) 15.4, 9.5 Hz, 2H),
was stirred for 15 min. After filtration, the layers were separated and
the aqueous layer was extracted with five portions of CH2Cl2/i-PrOH
(5:1). Rotary evaporation and chromatography (silica, EtOAc/hexanes/
i-PrOH (5:5:1 f 20:10:6)) gave a viscous oil. Colorless crystals of
19 (1.81 g, 10.1 mmol, 89%) were obtained by crystallization from
EtOAc/hexanes (1:3) at 4 °C: Rf 0.32 (EtOAc); mp 67.5-69.5 °C
(Et2O/hexanes); IR (diffuse reflectance) 3285, 1421, 1060, 1016, 730;
1H NMR (CDCl3, 300 MHz) δ 3.40 (d, J ) 6.9 Hz, 4H), 1.64 (s, 2H),
0.80-0.89 (m, 2H), 0.69-0.77 (m, 2H), 0.58-0.64 (m, 2H), 0.25-
0.30 (m, 4H), 0.15 (t, J ) 6.9 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ
1
5.93 (d, J ) 15.4 Hz, 2H), 4.19 (q, J ) 7.1 Hz, 4H), 1.84 (q, J ) 15.5,
8.1 Hz, 2H), 1.28 + 1.30 (t, J ) 7.1 Hz + t, J ) 7.1 Hz, 8H); 13C
NMR (CDCl3, 75 MHz) δ 166.32 (2C), 149.45 (2C), 119.99 (2C), 60.25
(2C), 25.14 (2C), 17.46, 14.27 (2C); λmax 268.0 (ꢀ 20 100, EtOH); [R]26
D
-333.1 (c 1.7, EtOH); MS (CI, NH3) m/z 256 [M + NH4]+, 239 [M +
H]+; exact mass (CI, NH3) calcd for C13H22NO4 [M + NH4]+ 256.1549,
found 256.1551. Anal. Calcd for C13H18O4: C, 65.53; H, 7.61.
Found: C, 65.23; H, 7.35.
66.86 (2C), 19.75 (2C), 18.33 (2C), 18.23 (2C), 8.33, 8.18 (2C); [R]24
(R,R)-1,3-Bis[(E)-3-hydroxy-1-propen-1-yl]cyclopropane (18). To
a solution of diester 17 (3.01 g, 12.6 mmol) in dry CH2Cl2 (150 mL)
at -78 °C was added DIBAl-H in hexanes (1 M, 63 mL) dropwise
over 40 min. After 15 min, saturated aqueous NH4Cl (10 mL), i-PrOH
(30 mL), some silica, and some Celite were added. The mixture was
allowed to warm to room temperature and filtered, and the residues
were washed with EtOAc/i-PrOH (3:1). Rotary evaporation and
chromatography (silica, EtOAc/i-PrOH ) 19:1 f 10:1) gave an oil
that crystallized from EtOAc/hexanes ) 1:1 at -20 °C to yield 18:
colorless crystals (1.87 g, 12.1 mmol, 96%); Rf 0.41 (EtOAc); mp 46.5-
48 °C (Et2O/hexanes); IR (diffuse reflectance) 3357, 3285, 3011, 1667,
D
-158.1 (c 0.96, EtOH); MS (CI, NH3) m/z 200 [M + NH4]+, 182 [M
+ H]+; exact mass (CI, NH3) calcd for C11H22NO2 [M + NH4]+
200.1651, found 200.1637. Anal. Calcd for C11H18O2: C, 72.49; H,
9.95. Found: C, 72.25; H, 9.93.
(1R,3S,4R,6S,7R,9S,10R,12R,13S,15R)-1-[((tert-Butyldimethyl-
silyl)oxy)methyl]-15-{(E)-2-[(1S,3R)-3-(hydroxymethyl)-1-cyclo-
propyl]ethenyl}quinquecyclopropane (25). Dienol 13 (602 mg, 1.40
mmol, 1.00 equiv) was dissolved in CH2Cl2 (10 mL). Molecular sieves
(4 Å, 56 mg) and dioxaborolane 20 (397 mg, 1.47 mmol, 1.05 equiv)
were added, and the mixture was cooled to -50 °C. A solution of
Zn(CH2I)2‚DME (5.56 mmol) in CH2Cl2 (15 mL), prepared according
to the literature procedure,12 was added to the reaction mixture over
20 min. The mixture was allowed to warm to -25 °C over 20 min
and kept at that temperature for 2 h. TLC control showed that the
starting material was essentially consumed and some septicyclopropane
material had already been formed. Saturated aqueous NH4Cl (20 mL)
was added, and the mixture was vigorously stirred for 1 h. The layers
were separated, and the aqueous layer was extracted with CH2Cl2 (3×).
Rotary evaporation and chromatography (silica, EtOAc/hexanes/i-PrOH
(3:30:1 f 4:16:1)) with repeated chromatography of mixed fractions
yielded septicyclopropane 26 (172 mg, 0.38 mmol, 27%) in addition
to the desired hexacyclopropane alkene 25 (449 mg, 1.01 mmol, 72%),
as a colorless oil: Rf 0.40 (EtOAc/hexanes ) 1:2); IR (film) 3340 (br),
1
1451, 998, 977, 958; H NMR (CDCl3, 300 MHz) δ 5.73 (dt, J )
15.3, 6.1 Hz, 2H), 5.29 (dd, J ) 15.3, 8.3 Hz, 2H), 4.09 (d, J ) 6.0
Hz, 4H), 1.43-1.71 (m, 4H), 0.88 (t, J ) 7.0 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) δ 134.76 (2C), 127.38 (2C), 63.45 (2C), 23.27 (2C),
15.10; [R]24 -139.0 (c 1.0, EtOH); MS (CI, NH3) m/z 172 [M +
D
NH4]+, 154 [M + H]+, 137, 119; exact mass (CI, NH3) calcd for
C9H18NO2 [M + NH4]+ 172.1338, found 172.1329. Anal. Calcd for
C9H14O2: C, 70.10; H, 9.15. Found: C, 70.03; H, 8.80.
(1R,3S,4R,6R,7S,9R)-1,9-Bis(hydroxymethyl)tercyclopropane (19).
The bis(allylic alcohol) 18 (1.75 g, 11.3 mmol, 1.00 equiv) was
dissolved in CH2Cl2 (90 mL). Molecular sieves (4 Å, 0.90 g) and
dioxaborolane 20 (6.72 g, 24.9 mmol, 2.20 equiv) were added, and the
mixture was cooled to -40 °C. A solution of Zn(CH2I)2‚DME (91
mmol) in CH2Cl2 (90 mL), prepared according to the literature
procedure,12 was added to the reaction mixture over 30 min. The
initially cloudy mixture turned into a clear solution which was allowed
to warm and kept at room temperature for 17 h. Saturated aqueous
NH4Cl (150 mL) and i-PrOH (30 mL) were added, and the mixture
1
3065, 2988, 2954, 2930, 2857, 1087, 1028, 838; H NMR (CDCl3,
400 MHz) δ 4.99-5.09 (m, 2H), 3.37-3.52 (m, 4H), 1.34 (br s, 1H),
1.21-1.28 (m, 1H), 1.00-1.14 (m, 2H), 0.88 (s, 9H), 0.68-0.79 (m,
2H), 0.61-0.68 (m, 1H), 0.44-0.61 (m, 8H), 0.32-0.37 (m, 2H), 0.23
(dt, J ) 8.5, 4.8 Hz, 1H), 0.18 (dt, J ) 8.3, 4.8 Hz, 1H), 0.01-0.11 +

IteratiVe Cyclopropanation
J. Am. Chem. Soc., Vol. 119, No. 37, 1997 8615
0.03 + 0.04 (m + s + s, 12H); 13C NMR (CDCl3, 101 MHz) δ 131.96,
129.33, 66.73, 66.58, 25.98 (3C), 22.74, 21.90, 20.00, 19.50 (2C), 18.53,
18.43, 18.37, 18.33, 18.27, 18.13 (2C), 18.06, 11.51, 11.37, 8.25, 8.10
(2C), 7.72, -5.09, -5.11; [R]26D -209.4 (c 0.96, EtOH); MS (CI, NH3)
m/z 460 [M + NH4]+, 311, 293; exact mass (CI, NH3) calcd for
C28H50NO2Si [M + NH4]+ 460.3611, found 460.3658. Anal. Calcd
for C28H46O2Si: C, 75.96; H, 10.47. Found: C, 75.99; H, 10.21.
Septicyclopropane 26: colorless oil; Rf 0.45 (EtOAc/hexanes )
1:2); IR (film) 3346 (br), 3064, 2996, 1463, 1255, 1086, 1026; 1H NMR
(CDCl3, 300 MHz) δ 3.34-3.51 (m, 4H), 1.40 (br s, 1H), 0.90 (s, 9H),
0.78-0.86 (m, 1H), 0.62-0.78 (m, 3H), 0.42-0.57 (m, 10H), 0.16-
0.33 (m, 4H), 0.05 (s) + -0.02-0.16 (m, 16H); 13C NMR (CDCl3, 75
MHz) δ 66.96, 66.75, 26.01 (3C), 19.66, 19.54, 18.51 (3C), 18.38 (4C),
18.31 (2C), 18.20 (2C), 17.99, 8.97, 8.46 (2C), 8.32, 8.21, 8.15 (2C),
-5.07 (2C), SiC(CH3)3 not detected; MS (CI, NH3) m/z 474 [M +
NH4]+, 457 [M + H]+, 439 [M + H - H2O]+, 399, 381, 360.
(1R,3S,4R,6S,7R,9S,10R,12R,13S,15R,16R,18S,19S,21R)-1,21-
Bis(hydroxymethyl)septicyclopropane (27). TBS ether 26 (62 mg,
0.14 mmol) was dissolved in dry THF (5 mL) and Bu4NF (1 M in
THF, 0.4 mL) was added. After 1 h, rotary evaporation and chroma-
tography (silica, EtOAc/hexanes ) 2:1 f EtOAc) gave a slightly yellow
solid (42 mg, 0.12 mmol, 90%). Crystals suitable for X-ray analysis
were obtained by slow evaporation of an EtOAc solution at 4 °C.
Septicyclopropane 27: colorless crystals; Rf 0.50 (EtOAc); mp 85-87
°C (CH2Cl2); IR (film from CH2Cl2) 3314 (br), 3069, 1994, 1464, 1405,
0.46 cm, 5% EtOH in hexane, flow 1000 µL min-1); mp 111.5-112.5
°C (t-BuOMe/hexanes); IR (diffuse reflectance) 3326, 3069, 3004, 2953,
1664, 1625, 1555, 1467, 1261, 1167, 1075, 977, 959, 920; H NMR
1
(CDCl3, 500 MHz) δ 6.32 (dd, J ) 15.0, 10.0 Hz, 1H), 5.76 (d, J )
15.0 Hz, 1H), 5.34 (br, 1H), 4.97-5.05 (m, 2H), 3.09-3.18 (m, 2H),
1.78 (septet, J ) 6.7 Hz, 1H), 1.22-1.28 (m, 1H), 0.94-1.06 + 1.03
(m + d, J ) 6.0 Hz, 5H), 0.85-0.93 + 0.91 (m + d, J ) 6.7 Hz, 7H),
0.72-0.80 (m, 1H), 0.44-0.71 (m, 10H), 0.32-0.40 (m, 3H), 0.00-
0.12 (m, 6H); 13C NMR (CDCl3, 126 MHz) δ 166.03, 148.50, 131.07,
130.53, 120.23, 46.88, 28.66, 24.16, 22.47, 21.97, 20.70, 20.10 (2C),
20.04, 19.04, 18.63, 18.56, 18.52, 18.37 (2C), 18.16, 14.90, 14.84,
13.52, 11.63, 8.26, 7.99 (2C); λmax 220 (ꢀ 24 900, EtOH), 244 (sh);
[R]25 -325.8 (c 0.045, CDCl3);25 MS (CI, NH3) m/z 408 [M + H]+;
D
exact mass (CI, NH3) calcd for C28H42NO [M + H]+ 408.3266, found
408.3322. Anal. Calcd for C28H41NO: C, 82.50; H, 10.14; N, 3.44.
Found: C, 82.45; H, 9.89; N, 3.29.
U-106305 authentic sample: HPLC Rf 18.07 min (Chiralpak AD
25 cm × 0.46 cm, 5% EtOH in hexane, flow 1000 µL min-1); mp
110-112.5 °C (t-BuOMe), mixed melting point with synthetic sample
1
110-112.0 °C; H NMR (CDCl3, 500 MHz) δ 6.32 (dd, J ) 15.0,
10.0 Hz, 1H), 5.75 (d, J ) 15.0 Hz, 1H), 5.34 (br, 1H), 4.97-5.05 (m,
2H), 3.09-3.18 (m, 2H), 1.78 (septet, J ) 6.7 Hz, 1H), 1.22-1.28
(m, 1H), 0.96-1.06 + 1.03 (m + d, J ) 6.0 Hz, 5H), 0.85-0.93 +
0.92 (m + d, J ) 6.7 Hz, 7H), 0.72-0.79 (m, 1H), 0.44-0.71 (m,
10H), 0.31-0.40 (m, 3H), 0.00-0.12 (m, 6H); 13C NMR (CDCl3, 126
MHz) δ 166.04, 148.51, 131.07, 130.54, 120.23, 46.89, 28.67, 24.17,
22.47, 21.98, 20.70, 20.10 (2C), 20.04, 19.05, 18.64, 18.57, 18.52, 18.38
(2C), 18.18, 14.91, 14.85, 13.53, 11.64, 8.27, 8.00 (2C); λmax 220 (ꢀ
1
1081, 1028; H NMR (CDCl3, 400 MHz) δ 3.35-3.45 (m, 4H), 1.43
(br s, 2H), 0.76-0.86 (m, 2H), 0.64-0.73 (m, 2H), 0.40-0.55 (m,
10H), 0.22-0.29 (m, 4H), -0.02-0.13 (m, 10H); 13C NMR (CDCl3,
101 MHz) δ 66.96 (2C), 19.73, 19.62, 18.54, 18.47, 18.39 (2C), 18.34
(2C), 18.29, 18.28, 18.26, 18.21, 17.96, 17.93, 8.92, 8.42, 8.37, 8.21,
8.17, 8.11, 8.06; [R]26D -188.1 (c 0.44, EtOH); MS (CI, NH3) m/z 360
[M + NH4]+, 225, 211, 199, 185; exact mass (CI, NH3) calcd for
C23H38NO2 [M + NH4]+ 360.2903, found 360.2906.
24 900, EtOH), 244 (sh); [R]25 -324.4 (c 0.037, CDCl3).25
D
Acknowledgment. We thank Dr. M. S. Kuo for a sample
of U-106305, the EPSRC National Chiroptical Spectroscopy
Facility for CD spectra on natural and synthetic U-106305,
GlaxoWellcome for the most generous endowment (to A.G.M.B.),
the European Commission for a TMR Research Fellowship (to
D.H.), the Wolfson Foundation for establishing the Wolfson
Centre for Organic Chemistry in Medical Science at Imperial
College, the Engineering and Physical Science Research Coun-
cil, Millennium Pharmaceuticals Inc. for support of our research
on antifungal agents, and G. D. Searle & Company for generous
unrestricted support.
(1R,3S,4R,6S,7R,9S,10R,12S,13R,15S)-1-[(E)-2-((N-Isobutyl-
amino)carbonyl)ethenyl]-15-{(E)-2-[(1R,3R)-3-methyl-1-cyclo-
propyl]ethenyl}quinquecyclopropane (11). To a solution of the TBS
ether 30 (29 mg, 68 µmol, 1.0 equiv) in THF (1.5 mL) was added
tetrabutylammonium fluoride (1 M in THF, 0.15 mL, 2.2 equiv). After
15 min, benzene (2 mL) was added, the solvent was removed by rotary
evaporation, and DMSO (2.5 mL) and pyridine (0.1 mL, 1.2 mmol, 18
equiv) were added. After 20 min, no TBS ether remained and Dess-
Martin periodinane (57 mg, 0.13 mmol, 2.0 equiv) was added. More
periodinane (60 mg, 0.14 mmol, 2.1 equiv) was added after 25 min,
which led to completion of the oxidation after an additional 12 min.
PPh3 (124 mg, 0.47 mmol, 7.0 equiv) was added with cooling in a
cold water bath which was removed after 10 min. Phosphonium
chloride 3224 (84 mg, 0.20 mmol, 3.0 equiv) and DBU (0.20 mL, 1.3
mmol, 20 equiv) were added, which resulted in a color change to brown.
After 90 min, Et2O and H2O were added, and the layers were separated.
The aqueous layer was extracted with Et2O, and the combined organic
phases were washed with aqueous HCl (1 M), H2O, saturated aqueous
NaHCO3, and brine. Rotary evaporation and chromatography (silica,
EtOAc/hexanes (1:3 f 1:2)) gave essentially pure (NMR) (E)-alkene
11 (26 mg) and some of the corresponding (Z)-isomer (2 mg, 5 µmol,
7%). Two batches of analytically pure 11 were obtained by crystal-
lization from t-BuOMe/hexanes (ca. 1:4) at room temperature and then
at -20 °C (25 mg, 61 µmol, 91%) as small colorless needles: Rf 0.24
(EtOAc/hexanes ) 1:3); HPLC Rf 18.09 min (Chiralpak AD 25 cm ×
Supporting Information Available: X-ray crystallographic
details for (R,R)(S,S)-17, (R,R)-17, 19, 27, and 28 (data for
structure 14 has already been deposited at the Cambridge
1
Crystallographic Data Centre9 and H NMR, 13C NMR, CD,
and chiral HPLC results for 11 and authentic U-106305 are
contained in the Supporting Information of the preliminary
paper9) and full experimental details for the preparation and
characterization of 13, 14, 21-24, (1R,3S,4R,6S,7R,9R,10S,
12R,13S,15R)-1,15-bis[(E)-2-methoxycarbonylethenyl]quinque-
cyclopropane, (1R,3S,4R,6S,7R,9R,10S,12R,13S,15R)-1,15-bis[(E)-
3-hydroxy-1-propen-1-yl]quinquecyclopropane, 28-30, 34-41,
43, and 45-52 (54 pages). See any current masthead page for
ordering and Internet access instructions.
JA9708326