Total synthesis of the pentacyclopropane antifungal agent FR-900848

Article abstract of DOI:10.1021/ja960964j

Quatercyclopropane 31 was oxidized, homologated, reduced, and monocyclopropanated to provide the pentacyclopropane alcohol 35. Subsequent deoxygenation of alcohol 35 was effected using N-(phenylthio)succinimide (24) and tributylphosphine followed by Raney

Full text of DOI:10.1021/ja960964j

11030
J. Am. Chem. Soc. 1996, 118, 11030-11037
Total Synthesis of the Pentacyclopropane Antifungal Agent
FR-900848
Anthony G. M. Barrett* and Krista Kasdorf
Contribution from the Department of Chemistry, Imperial College of Science, Technology and
Medicine, London SW7 2AY, U.K.
ReceiVed March 25, 1996X
Abstract: Quatercyclopropane 31 was oxidized, homologated, reduced, and monocyclopropanated to provide the
pentacyclopropane alcohol 35. Subsequent deoxygenation of alcohol 35 was effected using N-(phenylthio)succinimide
(24) and tributylphosphine followed by Raney nickel desulfurization and deprotection to produce the alcohol 3.
This was oxidized, homologated, and hydrolyzed to provide the fatty acid 2. BOP-Cl-mediated coupling of acid 2
and the nucleoside amine 40 gave amide 1, which was spectroscopically identical with an authentic sample of FR-
900848 (1).
Introduction
FR-900848 (1) is a nucleoside isolated from the fermentation
broth of StreptoVerticillium ferVens.1 It shows potent, selective
activity against filamentous fungi such as Aspergillus niger but
is essentially inactive against nonfilamentous fungi such as
Candida albicans and Gram-positive and -negative bacteria.
Structurally this natural product is quite remarkable since it
contains five cyclopropane units, four of which are contiguous.
In a recent paper2 and in communication format,3-6 we have
reported degradation and synthetic studies on FR-900848 (1)
which allowed us to establish its full structure and absolute
stereochemistry. During the course of this work ourselves,7
Armstrong8 and Zercher9 have independently reported stereo-
selective methods for the preparation of bicyclopropanes.
Herein we report the total synthesis of FR-900848 (1) which
was previously reported in communication format.10 Subsequent
to our original publication, Falck and co-workers have reported
an alternative total synthesis of FR-900848 (1).11
Although the condensation of a monocyclopropane derivative
and a quatercyclopropane unit is an obvious route to assemble
the side chain of FR-900848 (1), such a strategy has the
disadvantage of poor geometric selectivity in the construction
of ∆18. For example, Nishida and co-workers12 have used a
X Abstract published in AdVance ACS Abstracts, October 15, 1996.
(1) Yoshida, M.; Ezaki, M.; Hashimoto, M.; Yamashita, M.; Shigematsu,
N.; Okuhara, M.; Kohsaka, M.; Horikoshi, K. J. Antibiot. 1990, 43, 748.
(2) Barrett, A. G. M.; Doubleday, W. W.; Kasdorf, K.; Tustin, G. J. J.
Org. Chem. 1996, 61, 1082.
(3) Barrett, A. G. M.; Kasdorf, K.; Williams, D. J. J. Chem. Soc., Chem.
Commun. 1994, 1781.
(4) Barrett, A. G. M.; Doubleday, W. W.; Kasdorf, K.; Tustin, G. J.;
White, A. J. P.; Williams, D. J. J. Chem. Soc., Chem. Commun. 1995, 407.
(5) Barrett, A. G. M.; Kasdorf, K.; White, A. J. P.; Williams, D. J. J.
Chem. Soc., Chem. Commun. 1995, 649.
(6) Barrett, A. G. M.; Kasdorf, K.; Tustin, G. J.; Williams, D. J. J. Chem.
Soc., Chem. Commun. 1995, 1143.
(7) (a) Barrett, A. G. M.; Doubleday, W. W.; Tustin, G. J.; White, A. J.
P.; Williams, D. J. J. Chem. Soc., Chem. Commun. 1994, 1783. (b) Barrett,
A. G. M.; Tustin, G. J. J. Chem. Soc., Chem. Commun. 1995, 355.
(8) Armstrong, R. W.; Maurer, K., W. Tetrahedron Lett. 1995, 36, 357.
(9) Theberge, C. R.; Zercher, C. K. Tetrahedron Lett. 1994, 35, 9181.
Theberge, C. R.; Zercher, C. K. Tetrahedron Lett. 1995, 36, 5495.
(10) Barrett, A. G. M.; Kasdorf, K. J. Chem. Soc., Chem. Commun. 1996,
325.
(11) Falck, J. R.; Mekonnen, B.; Yu, J.; Lai, J.-Y. J. Am. Chem. Soc.
1996, 118, 6096. For earlier model studies see: Falck, J. R.; Mekonnen,
B.; Yu, J. Abstracts of Papers, 209th American Chemical Society National
Meeting, Anaheim, CA, April 2-6, 1995; American Chemical Society:
Washington, DC, 1995; Abstract 057.
Figure 1.
Wittig reaction to prepare 1,2-dicyclopropylethene as a mixture
of cis- and trans-isomers. Julia-Lythgo coupling13 should be
more trans selective, but not geometrically specific. In con-
sequence of these considerations, the retrosynthetic approach
outlined in Figure 1 was adopted. We envisioned that FR-
900848 (1) should be available from the acylation of the
corresponding nucleoside unit with the side chain acid 2. In
turn, acid 2 should be obtained from the oxidation, homologa-
tion, and hydrolysis of alcohol 3. A key step in our retrosyn-
thetic approach should be the deoxygenation of alcohol 4 to
reveal the terminal methyl of pentacyclopropane 3, followed
(13) Julia, M.; Paris, M.-J. Tetrahedron Lett. 1973, 4833. Kocienski, P.
J.; Lythgoe, B.; Waterhouse, I. J. Chem. Soc., Perkin Trans. 1 1980, 1045
and references therein.
(12) Teraji, T.; Moritani, I.; Tsuda, E.; Nishida, S. J. Chem Soc. C 1971,
3252.
S0002-7863(96)00964-X CCC: $12.00 © 1996 American Chemical Society

Pentacyclopropane Antifungal Agent FR-900848
J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11031
Scheme 2
Figure 2.
Scheme 1
was bicyclopropanated19a (Scheme 2) in the presence of the
chiral auxiliary 15 to provide diol 14 in high yield (89%).
Monoprotection of C2-symmetrical diol 14 was effected using
the procedure reported by McDougal.21 Diol 14 was treated
with 1 equiv of sodium hydride followed by 1 equiv of tert-
butyldimethylsilyl chloride to obtain alcohol 16 (49%), recov-
ered diol 14 (20%), and the corresponding diprotected compound
(10%). Both diol 14 and the deprotected disilyl ether could be
recycled to give more of the desired alcohol 16. PCC oxidation
of alcohol 16 followed by Wittig homologation of the corre-
sponding aldehyde provided a separable 19:1 mixture of (E)-
ester 17 and (Z)-ester 18 (85% from 16). Unfortunately, there
was no applicable isomerization protocol available at this time
to convert (Z)-ester 18 into more of the desired (E)-ester 17.
(E)-Ester 17 was reduced using DIBAL-H to provide the alcohol
19, which was cyclopropanated using Charette’s methodology19a
to give tercyclopropane 20 in high yield (91% from 17).
Although various methods of converting alcohol 20 into the
corresponding halides were attempted, all were unsuccessful and
resulted in cyclopropane degradation. This precluded synthesis
of the Wittig fragment 9. Indeed, it appears that as soon as the
primary alcohol was replaced with any good leaving group,
spontaneous ring opening and rearrangement occurred.
Previous work had shown that polycyclopropane systems such
as alcohol 20 were stable to oxidation. Therefore, synthesis of
aldehyde 21 should not present any difficulties. One example
is present in the literature for the formation and use of a
dioxolane ylide related to acetal 22.22 However, these ylides
are prone to â-elimination, and Schlosser’s conditions would
definitely induce such decomposition. An alternative method
for obtaining (E)-alkenes from unstabilized ylides is by variation
of the phosphine ligands, and isopropyldiphenylphosphoranes
favor the formation of trans-alkenes (E:Z ) 4.6:1).23 Unfor-
tunately, we were not successful in attempting to induce reaction
between the ylide of dioxolane 22 (R3 ) Ph2-i-Pr) and aldehyde
21, and this route was abandoned altogether.
by deprotection. In turn, alkene 4 should arise from the
stereoselective monocyclopropanation of diene 5, which should
be available from oxidation, homologation, and reduction of
alcohol 6. We have already utilized quatercyclopropane 6 (P
) H) in our stereochemical elucidation studies of FR-900848
(1).2,4,6
Results and Discussion
Our initial retrosynthetic approach for obtaining alcohol 3 is
outlined in Figure 2 utilizing methodology we developed for
the synthesis of the structural models of the isolated alkene
unit.2,3,5 It was envisioned that substrate-directed bicyclopro-
panation of diene 7 followed by Whitham elimination14 of the
vicinal diol unit should give alcohol 3. Diene 7 is expected to
arise from a Wittig reaction between aldehyde 8 and the
tercyclopropane 9.
Marshall and co-workers15 had recently made use of aldehyde
10 in a synthesis of long-chain polyols. Wittig homologation
of aldehyde 10 (Scheme 1) under Schlosser’s conditions16
provided a 6.1:1 mixture of (E)-alkene 11 and the corresponding
(Z)-alkene which was inseparable using normal chromatography
techniques (55%). However, chromatotron separation on silver
nitrate loaded silica17 provided geometrically pure (E)-alkene
11 (43%) with a minor, yellow impurity. Ammonium fluoride
deprotection of (E)-alkene 11 gave alcohol 12 (39% from 10)
with none of the purification difficulties encountered when
tetrabutylammonium fluoride was used. Swern oxidation18 of
alcohol 12 should provide the desired aldehyde 8.
We chose to apply the elegant new cyclopropanation meth-
odology recently reported by Charette19 for the formation of
all five cyclopropanes present in FR-900848 (1). Therefore,
in an improvement of our previous synthesis,2,4 mucondiol (13)20
(14) Hines, J. N.; Peagram, M. J.; Thomas E. J.; Whitham, G. H. J. Chem.
Soc., Perkin Trans. 1 1973, 2332.
(15) Marshall, J. A.; Beaudoin, S.; Lewinski, K. J. Org. Chem. 1993,
58, 5876.
(16) Schlosser, M.; Christmann, K. F. Angew. Chem., Int. Ed. Engl. 1966,
5, 126.
(17) Harrison, I. T. Chromatotron Instruction Manual; Harrison Re-
search: Palo Alto, 1985; p 23.
(18) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(19) (a) Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651.
(b) For a less hazardous procedure see Charette, A. B.; Prescott, S.; Brochu,
C. J. Org. Chem. 1995, 60, 1081.
We then devised the alternative route described in Figure 1,
which makes use of deoxygenation to reveal the terminal methyl
as a key step. Alcohol 20 was chosen as an appropriate model
system to probe such a deoxygenation. We have been generally
frustrated in our attempts to deoxygenate multiple cyclopro-
panemethanol derivatives. Much of the deoxygenation meth-
odology available in the literature makes use of radical fragmen-
(21) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388.
(20) Barrett, A. G. M.; Tustin, G. J. J. Chem. Soc., Chem. Commun.
1995, 355. Naruta, Y.; Nagai, N.; Yokoda, T.; Maruyama, K. Chem. Lett.
1986, 1185.
(22) Valverde, S.; Herradon, B.; Rabanal, R. M.; Martin-Lomas, M. Can.
J. Chem. 1987, 65, 332.
(23) Vedejs, E.; Marth, C. F. J. Am. Chem. Soc. 1988, 110, 3948.

11032 J. Am. Chem. Soc., Vol. 118, No. 45, 1996
Barrett and Kasdorf
Scheme 3
Scheme 4
Scheme 5
Scheme 6
tations,24 which are clearly unsuitable for cyclopropanated
substrates since ring opening occurs rapidly upon R-radical
formation.25 Attempted hydroxyl group activation Via meth-
anesulfonylation or trifluoromethanesulfonylation and displace-
ment led to extensive ring-opening and degradation. In the same
vein, attempted formation of the corresponding halides as
mentioned previously resulted in cyclopropane loss. Presumably
these failures were the result of (cyclopropylmethyl)carbenium
ion rearrangements. Therefore, no direct method of deoxygen-
ation was feasible. However, treatment of alcohol 20 with the
Walker reagent26 (Scheme 3), formed upon mixing N-(phe-
nylthio)succinimide (24) and tributylphosphine, cleanly gave
the sulfide 23 (81%). At that time, reduction of the corre-
sponding sulfone was considered more feasible than desulfur-
ization of sulfide 23 itself. Therefore, oxidation of sulfide 23
using a buffered potassium hydrogen persulfate system27 gave
sulfone 25 in fair yield (56%) and recovered sulfide 23 (32%).
Sodium amalgam28 and various dissolving metal reduction
systems29 were attempted for the desulfurization of sulfone 25;
however, all afforded ring-opening rearrangement products.
Reduction of sulfide 23 was then studied. Attempted reductive
desulfurization of sulfide 23 Via a nickel hydridic species formed
in situ [NiBr2‚DME, Ph3P, LiAlH4]30 or lithium (dimethylami-
no)naphthalenide31 also led to cyclopropane obliteration. How-
ever, Raney nickel reduction of sulfide 23 fortuitously gave the
corresponding terminal methyl compound 26 in good yield
(69%). Although Raney nickel reduction of the alkene moiety
of the actual substrate was a potential problem, there was
literature precedent that the W-2 catalyst might leave the alkene
intact.32 The less well known and less active Raney cobalt33
was also considered applicable, due to its ability to reduce
sulfones in the presence of alkenes.
allowed to react with LiTi(OiPr)4(SPh) and was smoothly
converted into diester 27. This reaction gave additional diester
27 (50%) and recovered (E,Z)-isomer 28 (40%) which was
further isomerized. DIBAL-H reduction of diester 27 proceeded
uneventfully to provide diol 29 in high yield (94%). Cyclo-
propanation of diene 29 under the new Charette conditions19b
using the chiral auxiliary 15 provided diol 30 (93%) essentially
as one isomer by 13C NMR. The spectroscopic and optical
rotation data for compounds 27, 29, and 30 were comparable
with those of authentic samples prepared using an alternate, less
concise, route.2
Attention was then turned to synthesis of the FR-900848
intermediate. PCC oxidation of diol 14 followed by Wittig
homologation provided an 8.7:1 separable mixture of (E,E)-
diester 27 and the (E,Z)-isomer 28 (67% from 14) as shown in
Scheme 4. We had found in related cyclopropane-substituted
R,â-unsaturated esters that classical methods to isomerize Z
to E were unsuccessful. Fortunately, a reagent introduced by
Hunter34 for the isomerization of R,â-unsaturated esters had just
come to our attention. The unwanted (E,Z)-diester 28 was
Subsequent monoprotection of diol 30 using the McDougal21
method gave the desired alcohol 31 (44%), recovered diol 30
(44%), and diprotected material (10%) (Scheme 5). Both the
starting material 30 and the corresponding disilyl ether were
recycled to provide more of the desired alcohol 31. PCC
oxidation of alcohol 31 and subsequent Wadsworth-Emmons
homologation gave a separable 5.0:1 mixture of esters 32 and
33 (71% from 31). Again, Hunter isomerization34 was utilized
to convert the undesired (E,Z)-isomer 33 into additional (E,E)-
ester 32 (63%).
(24) Larock, R. C. ComprehensiVe Organic Reactions; VCH Publishers,
Inc.: New York, 1989; p 27.
(25) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic Chemistry;
John Wiley & Sons: Chichester, 1995; p 159.
(26) Walker, K. A. M. Tetrahedron Lett. 1977, 4475.
(27) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287.
(28) Julia, M.; Ugen, D. Bull. Chem. Soc. Fr. 1976, 513 and references
therein.
(29) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 3477.
(30) Ho, K. M.; Lam, C. H.; Luh, T.-Y. J. Org. Chem. 1989, 54, 4474.
(31) Cohen, T.; Guo, B.-S. Tetrahedron 1986, 42, 2803.
(32) For the Raney nickel mediated removal of benzyl protecting groups
without concomitant alkene reduction see: Horita, K.; Yoshioka, T.; Tanaka,
T., Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986, 42, 3021.
(33) For an active catalyst see: Aller, B. V. J. Appl. Chem. 1957, 130.
(34) Hunter, R. Frank Warren Conference, Orange Free State, South
Africa, April 4-7, 1995.
Treatment of (E,E)-ester 32 with DIBAL-H provided alcohol
34 in high yield (91%) as shown in Scheme 6. Modification
of the Charette asymmetric cyclopropanation protocol19b using
prolonged reaction at -40 °C was necessary in order to obtain
the desired pentacyclopropanealcohol 35 (90%). In contrast,
cyclopropanation at -15 °C to room temperature gave pre-
dominately the corresponding sextacyclopropane 37 (84%). The

Pentacyclopropane Antifungal Agent FR-900848
J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11033
Experimental Section
Scheme 7
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. Column chromatography was carried out on
Merck or BDH silica gel 60, 230-400 mesh ASTM, using flash
chromatography techniques.41 Analytical thin-layer chromatography
(TLC) was performed on Merck precoated silica gel 60 F254 plates.
Petroleum ether (petrol) (40-60 °C) used as a chromatography eluant
was distilled; all other chromatography eluants were BDH GPR grade
and undistilled. The following reaction solvents were purified by
distillation: benzene (PhH) (P2O5, N2), dichloromethane (CH2Cl2)
(CaH2, N2), N,N-dimethylacetamide (DMA) (BaO, 12 mmHg), diethyl
ether (Et2O) (Ph2CO/Na, N2), and tetrahydrofuran (THF) (Ph2CO/K,
N2). The following organic reagents were purified by distillation:
diiodomethane (CH2I2) (Cu powder, 2 mmHg), 1,2-dimethoxyethane
(DME) (CaH2, N2), and triethylamine (Et3N) (CaH2, N2). All other
organic solvents and reagents were obtained from commercial sources
and used without further purification. Organic extracts were dried over
magnesium sulfate, filtered, and concentrated using a rotary evaporator
at e40 °C bath temperature. Involatile oils and solids were vacuum
dried at <2 mmHg.
(4S,5S)-2,2-Dimethyl-4-(hydroxymethyl)-5-[1(E)-propen-1-yl]-1,3-
dioxolane (12). Following the procedure reported by Schlosser and
co-workers,16 PhLi (8.4 mL, 1.2 M in Et2O, 10 mmol) was added to a
stirred suspension of ethyltriphenylphosphonium bromide (3.72 g, 10.1
mmol) in THF (20 mL) and Et2O (8.0 mL). After 10 min, the mixture
was cooled to -70 °C, and a solution of aldehyde 1015 (2.77 g, 10.1
mmol) in Et2O (12 mL) was added. The reaction mixture was warmed
to -40 °C over 5 min, PhLi (8.4 mL, 1.2 M in Et2O, 10 mmol) was
added, and the reaction mixture was warmed to -30 °C over 5 min.
HCl solution (4.94 mL, 2.25 M in Et2O, 11.1 mmol) was added followed
by 1:1 t-BuOK/t-BuOH complex (2.87 g, 15.1 mmol). The reaction
mixture was allowed to warm to room temperature and, after 16 h,
was diluted with Et2O (100 mL) and filtered though Celite. The filtrate
was washed with H2O (3 × 200 mL), dried, and concentrated.
Chromatography on silica (2:98 to 5:95 EtOAc/petrol) provided an
inseparable 6.1:1 (E)/(Z)-alkene mixture (1.60 g, 55%). Chromatotron
separation on AgNO3/silica17 (petrol to 2:98 EtOAc/petrol) provided
(E)-alkene 11 (1.25 g, 43%) as an oil with a yellow impurity: 1H NMR
(270 MHz, CDCl3) δ 5.80 (dq, 1H, J ) 15.3, 6.5 Hz), 5.48 (ddq, 1H,
J ) 15.3, 7.8, 1.7 Hz), 4.31-4.25 (m, 1H), 3.78-3.67 (m, 3H), 1.72
(dd, 3H, J ) 6.5, 1.7 Hz), 1.42 (s, 3H), 1.40 (s, 3H), 0.89 (s, 9H), 0.06
(s, 6H).
deoxygenation methodology developed in Scheme 3 was then
applied to the real system. Treatment of alcohol 35 with the
Walker reagent26 cleanly gave the sulfide 36 (89%). Fortu-
itously, when sulfide 36 was allowed to react with Raney nickel
at -40 °C in EtOH, regioselective desulfurization took place
without concomitant alkene reduction. Subsequent deprotection
using ammonium fluoride provided alcohol 3 (49% from 36).
PCC oxidation of alcohol 3 (Scheme 7), followed by
Wadsworth-Emmons homologation provided a separable 3.2:1
mixture of esters 38 and 39 (63% from 3). Again Hunter
isomerization34 of the unwanted (E,Z)-ester 39 was used to
reclaim additional (E,E)-ester 38 in fair yield (51%). While
saponification of ester 38 resulted in decomposition, hydrolysis
using potassium trimethylsilanolate35 gave the FR-900848 side
chain carboxylic acid 2 in good yield (85%). Finally, BOP-
Cl36 activation of acid 2 followed by the addition of amine 4037
and triethylamine gave FR-900848 (1) in good yield (69%) and
recovered acid 2 (10%). The synthetic sample of FR-900848
(1) was spectroscopically and chromatographically identical with
an authentic sample of the natural product. However, we
observed a different specific rotation (-167.0°, c 0.40, DMSO-
d6) for synthetic FR-900848 (1) from that reported38 for the
natural product (-35°, c 0.5, DMSO). As a consequence, we
have remeasured the specific rotation of authentic FR-900848
(1) under the same conditions as those used for the synthetic
amide 1. Under these conditions, we observed a value of [R]D
-168.1° (c 0.42, DMSO-d6) which is in good agreement with
our synthetic material. Clearly, the optical rotation value
reported in the patent is therefore incorrect. Finally, the CD
spectrum of the synthetic amide 1 correlated well with that from
the natural product, confirming the identity of the absolute
stereochemistry.
NH4F (1.44 g, 38.7 mmol) was added to a stirred solution of (E)-
alkene 11 (1.11 g, 3.87 mmol) in MeOH (45 mL), and the mixture
was heated to 60 °C. After 3 h, the reaction mixture was allowed to
cool, silica was added, and the mixture was concentrated. Chroma-
tography on silica (20:80 EtOAc/petrol) provided alcohol 12 (0.605 g,
39% from 10) as a colorless oil: [R]26 ) -5.2° (c 1.00, CHCl3); Rf
D
0.24 (20:80 EtOAc/petrol); IR (film) 3450 (br), 2986, 2935, 2920, 2877,
1676, 1452, 1379, 1371, 1242, 1220 cm-1; 1H NMR (270 MHz, CDCl3)
δ 5.85 (dq, 1H, J ) 15.3, 6.5 Hz), 5.46 (ddq, 1H, J ) 15.3, 8.2, 1.6
Hz), 4.28 (t, 1H, J ) 8.2 Hz), 3.86-3.74 (m, 2H), 3.62-3.53 (m, 1H),
1.89-1.84 (m, 1H), 1.73 (dd, 3H, J ) 6.4, 1.6 Hz), 1.44 (s, 3H), 1.42
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 132.0, 127.8, 108.9, 81.1, 78.2,
60.8, 27.1, 27.0, 17.8; MS (CI, NH3) m/e 173 (M + H)+, 155, 132,
115, 97; exact mass (CI, NH3) calcd for C9H17O3 (M + H)+ 173.1178,
found 173.1165.
(1R,3S,4S,6R)-1,6-Bis(hydroxymethyl)bicyclopropane (14). The
following procedure is a modification of that reported by Charette and
Juteau.19a CH2I2 (2.26 mL, 28.5 mmol) was added slowly to a stirred
solution of Et2Zn (58 µL, 0.56 mmol) in CH2Cl2 (2.0 mL) at 0 °C.
After 10 min, a white slurry had formed, and a suspension of mucondiol
(13)20 (0.371 g, 3.24 mmol) and dioxaborolane 15 (0.192 g, 7.13 mmol)
in CH2Cl2 (5.0 mL) was added. The reaction mixture was stirred at
room temperature for 20 h, cooled to 0 °C, and quenched by slow
addition of saturated NH4Cl solution (20 mL). The aqueous layer was
Conclusion
It is clear from these results that Charette19 triple asymmetric
cyclopropanation is appropriate for the elaboration of FR-900848
(1) with excellent overall stereochemical control. Alternative
strategies involving the condensation of monocyclopropane and
quatercyclopropane derivatives to elaborate ∆18 have the
disadvantages of low geometric control and/or degradation. The
methodology outlined in this paper should additionally be
relevant for the synthesis of U-106305 (41), which has recently
been shown to be a CETP inhibitor,39 and related molecules.
Further studies in this area will be reported in due course.40
(35) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.
(36) Cabre, J.; Palomo, A. L. Synthesis 1984, 413.
(37) Skaric, V.; Katalenic, D.; Skaric, D.; Salaj, I. J. Chem. Soc., Perkin
Trans. I 1982, 2091.
(38) Yoshida, M.; Horikoshi, K. (Fujisawa Pharmaceutical Co., Ltd.,
Japan). U.S. Patent 4,803,074, Feb 7, 1989.
(39) 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.
(40) For a total synthesis of U-106305 see Barrett, A. G. M.; Hamprecht,
D.; White, A. J. P.; Williams, D. J. J. Am. Chem. Soc. 1996, 118, 7863.
(41) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

11034 J. Am. Chem. Soc., Vol. 118, No. 45, 1996
Barrett and Kasdorf
salted (NaCl) and extracted with CH2Cl2 (50 mL) using a continuous
extractor. Chromatography on silica (EtOAc) provided bicyclopropane
maintained at -78 °C for 4 h. The mixture was quenched by slow
addition of MeOH (15 mL) and allowed to warm to room temperature.
The resulting thick slurry was filtered though Celite and the filtrate
concentrated. The residue was treated with EtOAc and filtered though
Celite and the filtrate reconcentrated. Chromatography on silica (20:
80 EtOAc/petrol) gave the alcohol 19 (0.663 g, 98%) as a colorless
14 (0.408 g, 89%) as a gummy, off-white solid: [R]27 ) -71.4°
D
(CHCl3, c ) 1.00); Rf 0.25 (EtOAc); IR (film) 3326 (br), 2999, 2869,
1
2367, 1460, 1419, 1016 cm-1; H NMR (CDCl3, 270 MHz) δ 3.49
(ABXdd, 2H, J ) 11.1, 6.8 Hz), 3.35 (ABXdd, 2H, J ) 11.1, 7.4 Hz),
1.89 (s, 2H), 0.92-0.85 (m, 2H), 0.75-0.70 (m, 2H), 0.38-0.30 (m,
4H); 13C NMR (CDCl3, 75 MHz) δ 66.6, 20.0, 18.8, 8.5; MS (CI, NH3)
m/e 160 (M + NH4)+, 142, 125, 107, 83; exact mass (CI, NH3) calcd
for C8H18NO2 (M + NH4)+ 160.1338, found 160.1334. Anal. Calcd
for C8H14O2: C, 67.57; H, 9.92. Found: C, 67.27; H, 9.68.
oil: [R]25 ) -89.6° (c 1.00, CHCl3); Rf 0.25 (20:80 EtOAc/petrol);
D
IR (film) 3346 (br), 2954, 2928, 2857, 1670, 1471, 1463, 1255 cm-1
;
1H NMR (270 MHz, CDCl3) δ 5.65 (dt, 1H, J ) 15.2, 6.2 Hz), 5.24
(dd, 1H, J ) 15.2, 8.8 Hz), 4.05 (app t, 2H, J ) 6.2 Hz), 3.50 (ABXdd,
1H, J ) 10.8, 5.8 Hz), 3.42 (ABXdd, 1H, J ) 10.8, 6.3 Hz), 1.22-
1.14 (m, 2H), 0.89 (s, 9H), 0.85-0.70 (m, 3H), 0.54-0.43 (m, 2H),
0.32-0.21 (m, 2H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 136.5,
126.3, 66.5, 63.6, 26.0, 22.1, 20.0, 19.8, 18.4, 17.8, 11.9, 7.7, -5.0;
MS (CI, NH3) m/e 300 (M + NH4)+, 282, 265, 225, 211; exact mass
(CI, NH3) calcd for C16H34NO2Si (M+NH4)+ 300.2359, found 300.2345.
Anal. Calcd for C16H30O2Si: C, 68.02; H, 10.70. Found: C, 68.17;
H, 10.45.
(1R,3S,4S,6R)-1-[[(tert-Butyldimethylsilyl)oxy]methyl]-6-(hydroxy-
methyl)bicyclopropane (16). The following procedure is a modifica-
tion of that reported by McDougal.21 Prewashed NaH (0.325 g, 60%
dispersion in oil, 8.12 mmol) was suspended in THF (2.0 mL), and a
solution of diol 14 (1.15 g, 8.12 mmol) in THF (5.0 mL) was added.
A thick slurry formed and was stirred for 45 min before TBSCl (1.22
g, 8.12 mmol) was added. The slurry partially dissolved and was stirred
for 45 min. The mixture was quenched by pouring into saturated
NaHCO3 solution (100 mL), and the aqueous layer was salted (NaCl)
and extracted with CH2Cl2 (5 × 200 mL). The combined organic layers
were dried and concentrated. Chromatography on silica (20:80 EtOAc/
petrol to EtOAc) provided alcohol 16 (1.02 g, 49%) as a faintly yellow
oil, recovered diol 14 as a gummy, off-white solid (0.235 g, 20%),
and the corresponding diprotected compound (0.304 g, 10%) as a light
(1R,3S,4R,6R,7S,9R)-1-[[(tert-Butyldimethylsilyl)oxy]methyl]-9-
(hydroxymethyl)tercyclopropane (20). Following the procedure
described for the preparation of bicyclopropane 14, alcohol 19 (0.431
g, 1.53 mmol) was treated with a mixture of Et2Zn (0.359 mL, 3.51
mmol) and CH2I2 (0.557 mL, 7.02 mmol) in the presence of diox-
aborolane 15 (0.473 mg, 1.76 mmol) to provide, after chromatography
on silica (10:90 to 20:80 EtOAc/petrol), tercyclopropane 20 (0.424 mg,
yellow oil. Alcohol 16: [R]25 ) -54.8° (c 1.01, CHCl3); Rf 0.27
93%) as a colorless oil: [R]26 ) -91.2° (c 1.00, CHCl3); Rf 0.29
D
D
(20:80 EtOAc/petrol); IR (film) 3347 (br), 2954, 2928, 2885, 2857,
1471, 1255 cm-1; 1H NMR (270 MHz, CDCl3) δ 3.54-3.38 (m, 4H),
1.26 (br s, 1H), 0.89 (s, 9H), 0.87-0.71 (m, 4H), 0.37-0.23 (m, 4H),
0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 66.9, 66.6, 26.1, 19.9,
19.7, 18.4, 18.2, 17.8, 8.3, 8.1, -5.0; MS (CI, NH3) m/e 274 (M +
NH4)+, 257, 239, 199, 181, 157, 142; exact mass (CI, NH3) calcd for
C14H32NO2Si (M + NH4)+ 274.2202, found 274.2216.
(20:80 EtOAc/petrol); IR (film) 3349 (br), 2998, 2954, 2928, 2857,
1
1471, 1463, 1408, 1255 cm-1; H NMR (270 MHz, CDCl3) δ 3.51-
3.37 (m, 4H), 1.21 (t, 1H, J ) 5.7 Hz), 0.89 (s, 9H), 0.86-0.76 (m,
2H), 0.76-0.65 (m, 2H), 0.64-0.55 (m, 2H), 0.32-0.20 (m, 4H), 0.19-
0.06 (m, 2H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 67.0, 66.7,
26.1, 19.8, 19.6, 18.5 (3C), 18.18, 18.15, 8.4, 8.3, 8.1, -5.0; MS (CI,
NH3) m/e 314 (M + NH4)+, 279, 239, 221, 197; exact mass (CI, NH3)
calcd for C17H36NO2Si (M + NH4)+ 314.2515, found 314.2538. Anal.
Calcd for C17H32O2Si: C, 68.86; H, 10.88. Found: C, 68.79; H, 10.85.
(1R,3S,4S,6R)-1-[[(tert-Butyldimethylsilyl)oxy]methyl]-6-[3-ethoxy-
3-oxo-1(E)-propen-1-yl]bicyclopropane (17) and (1R,3S,4S,6R)-1-
[[(tert-Butyldimethylsilyl)oxy]methyl]-6-[3-ethoxy-3-oxo-1(Z)-propen-
1-yl]bicyclopropane (18). PCC (0.723 g, 3.35 mmol), NaOAc (0.274
g, 3.35 mmol), and silica (0.8 g) were added to a stirred solution of
alcohol 16 (0.572 g, 2.23 mmol) in CH2Cl2 (30 mL) at 0 °C. The
mixture was stirred at 0 °C for 1.5 h and at room temperature for 1 h,
and filtered though Celite using CH2Cl2. The filtrate was concentrated
to half-volume, and (carbethoxymethylene)triphenylphosphorane (1.18
g, 3.35 mmol) was added to this stirred solution. After 16 h, silica
was added and the mixture concentrated. Chromatography on silica
(2:98 to 5:95 EtOAc/petrol) provided (E)-ester 17 (0.586 g, 81%) as a
colorless oil and (Z)-ester 18 (31.3 mg, 4%) as a colorless oil. (E)-
(1R,3S,4R,6R,7S,9R)-1-[[(tert-Butyldimethylsilyl)oxy]methyl]-9-
[(phenylthio)methyl]tercyclopropane (23). The following procedure
is a modification of that reported by Walker.26 N-(phenylthio)-
succinimide (24) (82.5 mg, 0.400 mmol) was added to a stirred solution
of n-Bu3P (0.13 mL, 0.40 mmol) in PhH (1.0 mL). After 10 min, a
dark purple solution was obtained, and half of the solution was added
to a stirred solution of alcohol 20 (54.0 mg, 0.182 mmol) in PhH (2.0
mL). After 30 min, the remaining reagent solution was added to the
reaction solution. After 1 h, the reaction mixture was diluted with Et2O
(5 mL) and washed with H2O (3 × 5 mL). The organic layer was
dried and concentrated. Chromatography on silica (petrol to 2:98
EtOAc/petrol) provided sulfide 23 (57.3 mg, 81%) as a light yellow
oil: 1H NMR (270 MHz, CDCl3) δ 7.37-7.27 (m, 4H), 7.22 (m, 1H),
3.52-3.41 (m, 2H), 2.88 (ABXdd, 1H, J ) 12.8, 6.6 Hz), 2.78 (ABXdd,
1H, J ) 12.8, 7.3 Hz), 0.89 (s, 9H), 0.84-0.63 (m, 4H), 0.56-0.50
(m, 2H), 0.35-0.29 (m, 2H), 0.28-0.18 (m, 2H), 0.17-0.05 (m, 2H),
0.04 (s, 6H).
Ester 17: [R]25 ) -119.7° (c 1.02, CHCl3); Rf 0.25 (5:95 EtOAc/
D
petrol); IR (film) 2954, 2929, 2869, 1716, 1644, 1472, 1255, 1144 cm-1
;
1H NMR (270 MHz, CDCl3) δ 6.45 (dd, 1H, J ) 15.4, 10.2 Hz), 5.81
(d, 1H, J ) 15.4 Hz), 4.16 (q, 2H, J ) 7.2 Hz), 3.54 (ABXdd, 1H, J
) 10.8, 5.8 Hz), 3.41 (ABXdd, 1H, J ) 10.8, 6.3 Hz), 1.37-1.32 (m,
1H), 1.30 (t, 3H, J ) 7.2 Hz), 1.14-1.10 (m, 1H), 0.89 (s, 9H), 0.86-
0.78 (m, 2H), 0.78-0.71 (m, 2H), 0.36-0.26 (m, 2H), 0.04 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 166.9, 153.3, 117.8, 66.2, 60.1, 26.1,
24.4, 21.2, 20.1, 18.4, 17.6, 14.4, 14.0, 7.6, -5.0; MS (CI, NH3) m/e
325 (M + H)+, 267, 221, 210, 193; exact mass (CI, NH3) calcd for
C18H33O3Si (M + H)+ 325.2199, found 325.2196. Anal. Calcd for
C18H32O3Si; C, 66.61; H, 9.94. Found: C, 66.38; H, 9.84. (Z)-Ester
18: [R]25D ) -14.9° (c 0.86, CHCl3); Rf 0.32 (5:95 EtOAc/petrol); IR
(film) 2962, 2939, 2857, 1716, 1632, 1472, 1256, 1184 cm-1; 1H NMR
(270 MHz, CDCl3) δ 5.64 (d, 1H, J ) 11.2 Hz), 5.46 (app t, 1H, J )
11.2 Hz), 4.18 (q, 2H, J ) 7.2 Hz), 3.48 (dd, 2H, J ) 5.8, 2.1 Hz),
2.70-2.63 (m, 1H), 1.30 (t, 3H, J ) 7.2 Hz), 1.15-1.09 (m, 1H), 0.88
(s, 9H), 0.86-0.74 (m, 2H), 0.65-0.58 (m, 2H), 0.36-0.28 (m, 2H),
0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 167.2, 154.5, 116.6, 66.3,
59.8, 26.1, 24.5, 19.9, 18.8, 18.5, 17.3, 14.4, 14.2, 7.7, -5.0; MS (CI,
NH3) m/e 325 (M + H)+, 267, 210, 193, 182; exact mass (CI, NH3)
calcd for C18H33O3Si (M + H)+ 325.2199, found 325.2202.
(1R,3S,4R,6R,7S,9R)-1-[[(tert-Butyldimethylsilyl)oxy]methyl]-9-
[(phenylsulfonyl)methyl]tercyclopropane (25). The following pro-
cedure is a modification of that reported by Trost and Curran.27 Oxone
(31.3 mg, 0.102 mmol KHSO5) in pH 5 buffer (1.0 mL) was added to
a stirred solution of sulfide 23 (13.2 mg, 0.0340 mmol) in MeOH (1
mL) at 0 °C. The resulting thick slurry was allowed to warm to room
temperature and was stirred for 2 h before more Oxone (20.9 mg, 0.0680
mmol KHSO5) was added. After 3.5 h, the reaction mixture was diluted
with H2O (5 mL) and extracted with CHCl3 (3 × 5 mL). The combined
organic layers were washed with H2O (5 mL) and brine (5 mL), dried,
and concentrated. Chromatography on silica (10:90 EtOAc/petrol)
provided sulfone 25 (8.0 mg, 56%) as a colorless oil and recovered
sulfide 23 (4.2 mg, 32%) as a gummy, white solid. Sulfone 25: 1H
NMR (270 MHz, CDCl3) δ 7.96-7.92 (m, 2H), 7.67-7.55 (m, 3H),
3.52-3.41 (m, 2H), 3.05-2.99 (m, 2H), 0.89 (s, 9H), 0.76-0.42 (m,
6H), 0.29-0.22 (m, 2H), 0.20-0.13 (m, 2H), 0.12-0.05 (m, 2H), 0.04
(s, 6H).
(1R,3S,4S,6R)-1-[[(tert-Butyldimethylsilyl)oxy]methyl]-6-[3-hydroxy-
1(E)-propen-1-yl]bicyclopropane (19). DIBAL-H (8.4 mL, 1.0 M
in hexanes, 8.4 mmol) was added to a solution of ester 17 (0.776 g,
2.39 mmol) in CH2Cl2 (20 mL) at -78 °C, and the solution was
(1R,3S,4R,6R,7S,9R)-1-[[(tert-Butyldimethylsilyl)oxy]methyl]-9-
methyltercyclopropane (26). W-2 Raney nickel (0.20 g, 50% in H2O)

Pentacyclopropane Antifungal Agent FR-900848
J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11035
was washed with H2O (3 × 1 mL) and EtOH (3 × 1 mL), suspended
in EtOH (1 mL), and added to a vigorously stirred solution of sulfide
23 (13.2 mg, 0.0340 mmol) in EtOH (2 mL). After 2.5 h, the reaction
mixture was filtered though Celite using EtOH. Atmospheric distillation
removed most of the EtOH, and the residue was dissolved in pentane
(2 mL), washed with H2O (3 × 2 mL), dried, and concentrated.
Chromatography on silica (pentane) provided the terminal methyl
compound 26 (6.6 mg, 69%) as a colorless oil: 1H NMR (270 MHz,
CDCl3) δ 3.45-3.41 (m, 2H), 0.96 (d, 3H, J ) 5.7 Hz), 0.88 (s, 9H),
0.80-0.63 (m, 2H), 0.57-0.50 (m, 2H), 0.45-0.39 (m, 2H), 0.25-
0.18 (m, 2H), 0.16-0.05 (m, 4H), 0.04 (s, 6H).
(1R,3S,4S,6R)-1,6-Bis[3-ethoxy-3-oxo-1(E)-propen-1-yl]bicyclo-
propane (27). Following the procedure described for the preparation
of esters 17 and 18, diol 14 (0.926 g, 6.51 mmol) was treated with
PCC (4.23 g, 19.5 mmol), NaOAc (1.60 g, 19.5 mmol), and silica (5
g) followed by (carbethoxymethylene)triphenylphosphorane (7.29 g,
19.5 mmol) to provide, after chromatography on silica (5:95 to 10:90
EtOAc/petrol), (E,E)-diester 27 (1.09 g, 60%) as a gummy, off-white
solid and (E,Z)-diester 28 (0.125 g, 7%) as a colorless oil.
The following procedure is a modification of that reported by Hunter
and co-workers.34 n-BuLi (56 µL, 2.0 M in hexanes, 0.11 mmol) was
added to a stirred solution of thiophenol (12 µL, 0.11 mmol) in THF
(1.0 mL) at 0 °C, and the mixture was maintained at 0 °C for 5 min.
A solution of Ti(O-i-Pr)4 (31.5 mg, 0.112 mmol) in THF (1.0 mL)
was added, and after 5 min, the resulting solution was added to a stirred
solution of (E,Z)-diester 28 (0.125 g, 0.449 mmol) in THF (5.0 mL) at
0 °C. The reaction mixture was allowed to warm to room temperature.
After 72 h, the reaction mixture was diluted with Et2O (50 mL) and
washed with saturated NH4Cl solution (2 × 50 mL), followed by
saturated NaHCO3 solution (2 × 50 mL). The organic layer was dried
and concentrated. Chromatography on silica (5:95 to 10:90 EtOAc/
petrol) gave (E,E)-diester 27 (63.1 mg, 50%) as a colorless oil and
recovered (E,Z)-diester 28 (49.3 mg, 40%) as a colorless oil. (E,E)-
Diester 27: [R]27D ) -272.5° (c 0.51, CHCl3) [lit.2 [R]30D ) -246° (c
1.01, CHCl3)]; spectroscopic data were identical with those of diester
27 made using an alternate route.2
(1R,3S,4S,6R)-1,6-Bis[3-hydroxy-1(E)-propen-1-yl]bicyclopro-
pane (29). Following the procedure described for the preparation of
alcohol 19, diester 27 was treated with DIBAL-H (21 mL, 1.0 M in
hexanes, 21 mmol) to provide, after chromatography on silica (20:80
to 35:65 to 50:50 EtOAc/petrol), diol 29 (0.759 g, 94%) as a gummy,
white solid: [R]27D ) -196.8° (c 1.04, CHCl3); [lit.2 [R]30D ) -202.7°
(c 1.03, CHCl3)]; spectroscopic data were identical with those of diol
29 made using an alternate route.2
MHz, CDCl3) δ 3.47-3.36 (m, 4H), 1.25 (br s, 1H), 0.89 (s, 9H), 0.87-
0.79 (m, 2H), 0.73-0.63 (m, 2H), 0.56-0.49 (m, 4H), 0.29-0.16 (m,
4H), 0.14-0.05, (m, 4H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
67.0, 66.8, 26.1, 19.8, 19.6, 18.7, 18.6, 18.5 (2C), 18.30, 18.26, 18.1,
8.4 (2C), 8.3, 8.2, -5.0; MS (CI, NH3) m/e 354 (M + NH4)+, 319,
279, 205, 187; exact mass (CI, NH3) calcd for C20H40NO2Si (M +
NH4)+ 354.2828, found 354.2849. Anal. Calcd for C20H36O2Si: C,
71.36; H, 10.78. Found: C, 71.61; H, 10.97.
(1R,3S,4R,6S,7S,9R,10S,12R)-1-[[(tert-Butyldimethylsilyl)oxy]-
methyl]-12-[5-methoxy-5-oxo-1,3(E,E)-pentadien-1-yl]quatercyclo-
propane (32). PCC (0.292 g, 1.36 mmol), NaOAc (0.111 g, 1.36
mmol), and silica (0.3 g) were added to a stirred solution of alcohol
31 (0.305 g, 0.906 mmol) in CH2Cl2 (15 mL) at 0 °C. The reaction
mixture was stirred for 2 h at 0 °C and for 2 h at room temperature
and filtered though a silica plug using CH2Cl2 and Et2O, and the filtrate
was concentrated to provide a crude oil. Prewashed NaH (72.5 mg,
60% dispension in oil, 1.81 mmol) was suspended in THF (5.0 mL),
cooled to 0 °C, and stirred while a solution of (E)-MeO2CCHdCHCH2P-
(O)(OMe)2 (0.377 g, 1.81 mmol) in THF (5.0 mL) was added slowly.
An orange solution developed, and after 30 min, a solution of the
residual oil, prepared above, in THF (5.0 mL) was added. The reaction
mixture was stirred at 0 °C for 1 h and at room temperature for 1 h
and quenched by pouring into brine (50 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 50 mL) and the combined organic layers
were dried and concentrated. Chromatography on silica (5:95 EtOAc/
petrol) provided (E,E)-ester 32 (0.224 g, 59%) as a colorless oil and
(E,Z)-ester 33 (45.1 mg, 12%) as a light yellow oil. (E,Z)-Ester 33:
1H NMR (270 MHz, CDCl3) δ 7.74 (ddd, 1H, J ) 15.3, 11.8, 1.0 Hz),
6.01 (app t, 1H, J ) 11.2 Hz), 5.86 (d, 1H, J ) 15.3 Hz), 5.17 (app t,
1H, J ) 10.5 Hz), 3.76 (s, 3H), 3.52-3.42 (m, 2H), 1.66-1.58 (m,
1H), 1.03-0.98 (m, 1H), 0.89 (s, 9H), 0.75-0.52 (m, 8H), 0.27-0.14
(m, 2H), 0.13-0.08, (m, 4H), 0.04 (s, 6H). The (E,Z)-ester 33 was
isomerized directly without further characterization.
Following the procedure described for the isomerization of (E,Z)-
diester 28, (E,Z)-ester 33 (45.0 mg, 0.108 mmol) was treated with a
mixture of n-BuLi (25 µL, 2.2 M in hexanes, 0.054 mmol), thiophenol
(5.7 µL, 0.054 mmol), and Ti(O-i-Pr)4 (15.2 mg, 0.0540 mmol) to give,
after chromatography on silica (5:95 EtOAc/petrol), (E,E)-ester 32 (28.5
mg, 63%, 67% total from 31) as a colorless oil: [R]33 ) -197.0° (c
D
1.05, CHCl3); Rf 0.22 (5:95 EtOAc/petrol); IR (film) 3066, 2998, 2952,
2932, 2890, 2957, 1718, 1636, 1464, 1436, 1302 cm-1; 1H NMR (270
MHz, CDCl3) δ 7.21 (ddd, 1H, J ) 15.3, 11.1, 0.6 Hz), 6.18 (dd, 1H,
J ) 14.9, 11.1 Hz), 5.73 (d, 1H, J ) 15.3 Hz), 5.63 (dd, 1H, J ) 14.9,
9.4 Hz), 3.72 (s, 3H), 3.47 (ABXdd, 1H, J ) 10.8, 6.1 Hz), 3.40
(ABXdd, 1H, J ) 10.8, 6.3 Hz), 1.28-1.21 (m, 1H), 1.08-0.95 (m,
1H), 0.89 (s, 9H), 0.76-0.51 (m, 8H), 0.28-0.15 (m, 2H), 0.13-0.06,
(m, 4H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 167.9, 148.4,
145.2, 125.5, 117.4, 66.7, 51.4, 26.1, 24.4, 21.7, 19.7, 19.0, 18.5, 18.4,
18.3, 18.23, 18.18, 13.8, 8.4, 8.2, 7.9, -5.0; MS (CI, NH3) m/e 417
(M + H)+, 391, 359, 302, 285, 253; exact mass (CI, NH3) calcd for
C25H41O3Si (M + H)+ 417.2825, found 417.2842. Anal. Calcd for
C25H40O3Si: C, 72.06; H, 9.68. Found: C, 72.20; H, 9.53.
(1R,3S,4R,6S,7S,9R,10S,12R)-1,12-Bis(hydroxymethyl)quatercy-
clopropane (30). The following procedure is a modification of that
reported by Charette and co-workers.19b CH2I2 (3.7 mL, 46 mmol) was
slowly added to a stirred solution of Et2Zn (2.3 mL, 23 mmol) and
DME (2.4 mL, 23 mmol) in CH2Cl2 (45 mL) at -10 °C. After 10
min, the solution was slowly added to a stirred solution of diol 29
(0.738 g, 3.80 mmol) and dioxaborolane 15 (2.26 g, 8.36 mmol) in
CH2Cl2 (40 mL) at -10 °C. The reaction mixture was allowed to warm
slowly to room temperature. After 40 h, the reaction mixture was
cooled to 0 °C and quenched by the slow addition of saturated NH4Cl
solution (100 mL). The aqueous layer was salted (NaCl) and extracted
with CH2Cl2 (5 × 150 mL), and the combined organic layers were
dried and concentrated. Chromatography on silica (20:80 to 35:65 to
50:50 EtOAc/petrol) gave quatercyclopropane 30 (0.788 g, 93%) as a
colorless oil: [R]27D ) -181.4° (c 1.00, CHCl3); [lit.2 [R]26D ) -182.0°
(c 1.02, CHCl3)]; spectroscopic data were identical with those of diol
30 made using an alternate route.2
(1R,3S,4R,6S,7S,9R,10S,12R)-1-[[(tert-Butyldimethylsilyl)oxy]-
methyl]-12-[5-hydroxy-1,3(E,E)-pentadien-1-yl]quatercyclopro-
pane (34). Following the procedure described for the preparation of
alcohol 19, (E,E)-ester 32 (0.255 g, 0.612 mmol) was treated with
DIBAL-H (1.5 mL, 1.0 M in hexanes, 1.5 mmol) to give, after
chromatography on silica (20:80 EtOAc/petrol), alcohol 34 (0.216 g,
91%) as a colorless oil: [R]33 ) -184.5° (c 1.01, CHCl3); Rf 0.29
D
(20:80 EtOAc/petrol); IR (film) 3341 (br), 3066, 2998, 2953, 2931,
1
2887, 2858, 1659, 1520, 1254 cm-1; H NMR (270 MHz, CDCl3) δ
(1R,3S,4R,6S,7S,9R,10S,12R)-1-[[(tert-Butyldimethylsilyl)oxy]-
methyl]-12-(hydroxymethyl)quatercyclopropane (31). Following the
procedure described for the preparation of alcohol 16, diol 30 (0.640
g, 2.88 mmol) was treated with NaH (0.115 g, 60% dispension in oil,
2.88 mmol) followed by TBSCl (0.434 g, 2.88 mmol) to give, after
chromatography on silica (10:90 to 20:80 to 50:50 EtOAc/petrol to
EtOAc), alcohol 31 (0.426 g, 44%) as a light yellow oil, recovered
diol 30 (0.281 g, 44%) as a white solid, and disilyl ether (0.135 g,
6.15-6.05 (m, 2H), 5.69 (dt, 1H, J ) 14.4, 6.1 Hz), 5.26 (dd, 1H, J )
14.4, 8.7 Hz), 4.15-4.12 (m, 2H), 3.47 (ABXdd, 1H, J ) 10.9, 6.1
Hz), 3.40 (ABXdd, 1H, J ) 10.9, 6.4 Hz), 1.53 (s, 1H), 1.22-1.11
(m, 2H), 0.89 (s, 9H), 0.76-0.61 (m, 2H), 0.60-0.45 (m, 6H), 0.28-
0.12 (m, 2H), 0.12-0.05, (m, 4H), 0.04 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 138.9, 132.0, 128.6, 126.7, 66.8, 63.7, 26.1, 23.1, 20.7, 19.6,
18.8, 18.53, 18.46, 18.33, 18.27 (2C), 12.6, 8.4, 8.2, 8.0, -5.00, -5.03;
MS (CI, NH3) m/e 406 (M + NH4)+, 388, 371, 257, 239, 213; exact
mass (CI, NH3) calcd for C24H44NO2Si (M + NH4)+ 406.3141, found
406.3126. Anal. Calcd for C24H40O2Si: C, 74.16; H, 10.37%.
Found: C, 73.89; H, 10.39.
10%) as a light yellow oil. Alcohol 31: [R]31 ) -120.7° (c 1.00,
D
CHCl3); Rf 0.35 (20:80 EtOAc/petrol); IR (film) 3334 (br), 3065, 2997,
2953, 2931, 2887, 2858, 1466, 1410, 1389, 1363 cm-1; 1H NMR (270

11036 J. Am. Chem. Soc., Vol. 118, No. 45, 1996
Barrett and Kasdorf
(1R,3S,4R,6S,7S,9R,10S,12R)-1-[[(tert-Butyldimethylsilyl)oxy]-
methyl]-12-{2-[(1S,2R)-2-(hydroxymethyl)cyclopropyl]-1(E)-ethen-
1-yl}quatercyclopropane (35). The following procedure is a modi-
fication of that reported by Charette and co-workers.19b CH2I2 (0.43
mL, 5.4 mmol) was added dropwise to a stirred solution of Et2Zn (2.7
mL, 1.0 M in hexanes, 2.7 mmol) and DME (0.28 mL, 2.7 mmol) in
CH2Cl2 (10 mL) at -15 °C. After 15 min, the solution was added to
a stirred solution of (E,E)-diene 34 (0.210 g, 0.540 mmol) and
dioxaborolane 15 (0.354 g, 0.594 mmol) in CH2Cl2 (10 mL) at -40
°C. The reaction mixture was maintained at -40 °C for 7 days and
quenched by the slow addition of saturated NH4Cl solution (5 mL).
The mixture was allowed to warm to room temperature and extracted
with CH2Cl2 (5 × 50 mL). The combined organic layers were dried
and concentrated. Chromatography on silica (10:90 to 15:85 to 20:80
EtOAc/petrol) provided alkene 35 (0.197 g, 90%) as a colorless oil:
EtOH (10 mL) was added, and the mixture was stirred at -60 °C for
2 days. The reaction mixture was filtered through Celite using absolute
EtOH, and the filtrate was concentrated to half-volume. NH4F (0.278
g, 7.48 mmol) was added to the resulting solution, and the mixture
was heated to 65 °C for 26 h. The reaction mixture was allowed to
cool, silica was added, and the mixture was concentrated. Chroma-
tography on silica (10:90 to 15:85 to 20:80 EtOAc/petrol) provided
alcohol 3 (50.0 mg, 49%) as a light yellow oil: [R]27 ) -224.3° (c
D
1.00, CHCl3); Rf 0.30 (20/80 EtOAc/petrol); IR (film) 3342 (br), 3065,
1
2998, 2952, 2926, 2868, 1453, 1073, 1025, 954 cm-1; H NMR (500
MHz, CDCl3) δ 5.00 (app t, 2H, J ) 3.7 Hz), 3.44-3.36 (m, 2H),
1.56 (s, 1H), 1.31-1.19 (m, 1H), 1.03 (d, 3H, J ) 6.0 Hz), 1.01-0.96
(m, 1H), 0.89-0.79 (m, 1H), 0.78-0.74 (m, 1H), 0.72-0.65 (m, 2H),
0.59-0.51 (m, 4H), 0.49-0.44 (m, 1 H), 0.40-0.37 (m, 1H), 0.34
(dd, 2H, J ) 7.3, 6.6 Hz), 0.29-0.24, (m, 2H), 0.13-0.02 (m, 4H);
13C NMR (125 MHz, CDCl3) δ 131.2, 130.6, 67.0, 22.5, 21.9, 20.1,
19.8, 18.61 (2C), 18.55, 18.5, 18.3, 18.1, 14.93, 14.90, 11.6, 8.3 (2C),
7.8; MS (CI, NH3) m/e 290 (M + NH4)+, 273, 255, 213, 199, 187;
exact mass (CI, NH3) calcd for C19H32NO (M + NH4)+ 290.2484, found
290.2475. Anal. Calcd for C19H28O: C, 83.77; H, 10.36. Found: C,
83.88, H, 10.25.
(1R,3S,4R,6S,7S,9R,10S,12R)-1-[5-Methoxy-5-oxo-1,3(E,E)-pen-
tadien-1-yl]-12-{2-[(1R,2R)-2-methylcyclopropyl]-1(E)-ethen-1-yl}-
quatercyclopropane (38). Following the procedure described for the
preparation of (E,E)-ester 32, alcohol 3 (60.0 mg, 0.220 mmol) was
treated with a mixture of PCC (95.2 mg, 0.440 mmol), NaOAc (36.1
mg, 0.440 mmol), and silica (0.1 g), followed by a mixture of NaH
(26.4 mg, 60% dispension in oil, 0.660 mmol) and (E)-MeO2-
CCHdCHCH2P(O)(OMe)2 (0.137 g, 0.660 mmol) to provide, after
chromatography on silica (1:99 to 2:98 to 3.5:96.5 EtOAc/hexane),
(E,E)-ester 38 (37.3 mg, 48%) as a faintly yellow oil and (E,Z)-ester
39 (11.6 mg, 15%) as a yellow oil. (E,Z)-Ester 39: 1H NMR (270
MHz, CDCl3) δ 7.76 (ddd, 1H, J ) 15.4, 11.7, 1.0 Hz), 6.00 (app t,
1H, J ) 11.3 Hz), 5.84 (d, 1H, J ) 15.4 Hz), 5.18 (app t, 1H, J ) 10.6
Hz), 5.03-4.99 (m, 2H), 3.76 (s, 3H), 2.08-1.90 (m, 1H), 1.72-1.58
(m, 1H), 1.20-1.24 (m, 1H), 1.04 (d, 3H, J ) 6.0 Hz), 1.02-0.95 (m,
1H), 0.84-0.78 (m, 2H), 0.68-0.40 (m, 8H), 0.40-0.34 (m, 2H), 0.12-
0.04 (m, 4H). The (E,Z)-ester 39 was isomerized directly without
further characterization.
[R]27 ) -171.5° (c 1.02, CHCl3); Rf 0.30 (20:80 EtOAc/petrol); IR
D
(film) 3343 (br), 3066, 2998, 2953, 2931, 2887, 2858, 1466, 1254 cm-1
;
1H NMR (270 MHz, CDCl3) δ 5.05 (app t, 2H, J ) 3.3 Hz), 3.51-
3.37 (m, 4H), 1.55 (s, 1H), 1.29-1.21 (m, 2H), 1.12-0.99 (m, 2H),
0.89 (s, 9H), 0.79-0.62 (m, 2H), 0.61-0.49 (m, 6H), 0.39-0.33 (m,
2H), 0.27-0.14, (m, 2H), 0.13-0.05 (m, 4H), 0.04 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 132.0, 129.4, 66.8, 66.6, 26.1, 22.8, 22.0, 20.1,
19.60, 19.57, 18.7, 18.52, 18.46, 18.3, 18.2 (2C), 11.6, 11.5, 8.4, 8.2,
7.9, -5.00, -5.03; MS (CI, NH3) m/e 420 (M + NH4)+, 401, 385,
362, 271, 253; exact mass (CI, NH3) calcd for C25H46NO2Si (M +
NH4)+ 420.3298, found 420.3285. Anal. Calcd for C25H42O2Si: C,
74.56; H, 10.51. Found: C, 74.53; H, 10.81.
(1R,3S,4R,6S,7S,9R,10S,12R,16S,18R)-1-[[(tert-Butyldimethylsi-
lyl)oxy]methyl]-18-(hydroxymethyl)sextacyclopropane (37). Fol-
lowing the procedure described for the preparation of quatercyclopro-
pane 30, (E,E)-diene 34 (25.7 mg, 0.0661 mmol) was treated with a
mixture of CH2I2 (32 mL, 0.40 mmol), Et2Zn (20 mL, 0.20 mmol),
and DME (21 mL, 0.20 mmol) in the presence of dioxaborolane 15
(43.3 mg, 0.0727 mmol) to give, after chromatography on silica (10:
90 to 15:85 to 20:80 EtOAc/petrol), alkene 35 (2.9 mg, 11%) as a
colorless oil and sextacyclopropane 37 (23.1 mg, 84%) as a colorless
oil: 1H NMR (270 MHz, CDCl3) δ 3.49-3.36 (m, 4H), 1.57 (br s,
1H), 0.88 (s, 9H), 0.88-0.77 (m, 2H), 0.75-0.60 (m, 2H), 0.54-0.40,
(m, 6H), 0.30-0.04 (m, 14H), 0.04 (s, 6H).
(1R,3S,4R,6S,7S,9R,10S,12R)-1-[[(tert-Butyldimethylsilyl)oxy]-
methyl]-12-{2-[(1S,2R)-2-[(phenylthio)methyl]cyclopropyl]-1(E)-
ethen-1-yl}quatercyclopropane (36). The following procedure is a
modification of that reported by Walker.26 N-(Phenylthio)succinimide
(24) (0.141 g, 0.680 mmol) was added to a stirred solution of n-Bu3P
(0.17 mL, 0.68 mmol) in PhH (2.0 mL). After 10 min, a dark purple
solution was obtained, and half of the solution was added to a stirred
solution of alcohol 35 (54.8 mg, 0.136 mmol) in PhH (3.0 mL). After
30 min, the remaining reagent solution was added to the reaction
solution. After 1 h, the reaction mixture was diluted with Et2O (10
mL) and washed with H2O (3 × 10 mL). The organic layer was dried
and concentrated. Chromatography on silica (petrol to 2:98 EtOAc/
petrol) provided sulfide 36 (60.1 mg, 89%) as a faintly yellow oil:
Following the procedure described for the isomerization of (E,Z)-
diester 28, (E,Z)-ester 39 (11.6 mg, 0.0329 mmol) was treated with a
mixture of n-BuLi (13 µL, 1.8 M in hexanes, 0.024 mmol), thiophenol
(2.1 µL, 0.024 mmol), and Ti(O-i-Pr)4 (5.5 mg, 0.024 mmol) to give,
after chromatography on silica (1:99 to 2:98 to 3.5:96.5 EtOAc/hexane),
(E,E)-ester 38 (5.9 mg, 51%, 56% total from 3) as a faintly yellow oil:
[R]24 ) -339.2° (c 0.84, CHCl3); Rf 0.26 (5:95 EtOAc/petrol); IR
D
(film) 3066, 2997, 2951, 2928, 2867, 1718, 1634, 1434, 1302, 1262,
1
1239, 1146, 952 cm-1; H NMR (500 MHz, CDCl3) δ 7.21 (ddd, 1H,
J ) 15.3, 11.2, 0.5 Hz), 6.18 (dd, 1H, J ) 15.0, 11.2 Hz), 5.73 (d, 1H,
J ) 15.3 Hz), 5.62 (dd, 1H, J ) 15.0, 9.5 Hz), 5.01 (app t, 2H, J )
3.7 Hz), 3.72 (s, 3H), 1.26-1.23 (m, 2H), 1.03 (d, 3H, J ) 6.0 Hz),
1.01-0.97 (m, 2H), 0.78-0.75 (m, 1H), 0.69-0.66 (m, 1H), 0.64-
0.53 (m, 6H), 0.48-0.44 (m, 1 H), 0.40-0.37 (m, 1H), 0.36-0.33 (m,
2H), 0.12-0.02 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 168.0, 148.5,
145.3, 131.2, 130.6, 125.5, 117.4, 51.4, 24.3, 22.5, 21.9, 21.8, 20.1,
19.0, 18.6, 18.5, 18.3, 18.1, 14.93, 14.90, 13.7, 11.6, 7.8 (2C); MS
(CI, NH3) m/e 353 (M + H)+, 321, 293, 259, 237, 199; exact mass
(CI, NH3) calcd for C24H33O2 (M + H)+ 353.2481, found 353.2508.
Anal. Calcd for C24H32O2: C, 81.77; H, 9.15. Found: C, 81.89; H,
9.25.
(1R,3S,4R,6S,7S,9R,10S,12R)-1-[5-Hydroxy-5-oxo-1,3(E,E)-pen-
tadien-1-yl]-12-{2-[(1R,2R)-2-methylcyclopropyl]-1(E)-ethen-1-yl}-
quatercyclopropane (2). The following procedure is a modification
of that reported by Laganis and Chenard.35 Potassium trimethylsil-
anolate (0.117 g, 0.908 mmol) was added to a stirred solution of (E,E)-
ester 38 (16.0 mg, 0.0454 mmol) in CH2Cl2 (5.0 mL), and the reaction
mixture was evaporated to dryness by flushing with N2. CH2Cl2 (5.0
mL) was added, and the reaction mixture was again evaporated to
dryness. The reaction mixture was dissolved in H2O (20 mL), treated
with 10% HCl (5 mL), and extracted with EtOAc (5 × 30 mL). The
combined organic layers were dried and concentrated. Chromatography
on silica (20:80 to 35:65 to 50:50 EtOAc/petrol) provided acid 2 (13.0
[R]30 ) -131.8° (c 1.00, CHCl3); Rf 0.16 (2:98 EtOAc/petrol); IR
D
(film) 3065, 2997, 2954, 2929, 2888, 2856, 1471, 1439, 1253 cm-1
;
1H NMR (270 MHz, CDCl3) δ 7.38-7.33 (m, 2H), 7.30-7.23 (m,
2H), 7.20-7.15 (m, 1H), 5.00-4.98 (m, 2H), 3.46 (ABXdd, 1H, J )
10.8, 6.1 Hz), 3.40 (ABXdd, 1H, J ) 10.8, 6.3 Hz), 3.00 (ABXdd,
1H, J ) 12.9, 6.4 Hz), 2.76 (ABXdd, 1H, J ) 12.9, 7.3 Hz), 1.27-
1.20 (m, 2H), 1.05-0.98 (m, 2H), 0.89 (s, 9H), 0.78-0.64 (m, 2H),
0.63-0.48 (m, 6H), 0.37-0.32 (m, 2H), 0.28-0.15, (m, 2H), 0.13-
0.05 (m, 4H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 136.8, 132.0,
129.8, 129.4, 128.9, 126.1, 66.8, 38.9, 26.1, 22.4, 22.0, 20.1 (2C), 19.6,
18.7, 18.53, 18.47, 18.3 (3C), 14.2, 11.6, 8.4, 8.2, 7.9, -5.0; MS (CI,
NH3) m/e 512 (M + NH4)+, 385, 363, 297, 253; exact mass (CI, NH3)
calcd for C31H50NOSSi (M + NH4)+ 512.3382, found 512.3359. Anal.
Calcd for C31H46OSSi: C, 75.24; H, 9.37. Found: C, 74.96; H, 9.47.
(1R,3S,4R,6S,7S,9R,10S,12R)-1-(Hydroxymethyl)-12-{2-[(1R,2R)-
2-methylcyclopropyl]-1(E)-ethen-1-yl}quatercyclopropane (3). W-2
Raney nickel (9.25 g, 50% in H2O) was washed with H2O (3 × 10
mL) and absolute EtOH (3 × 10 mL) and suspended in absolute EtOH
(40 mL). The mixture was sonicated for 2 h, and cooled to -60 °C
with stirring. A solution of sulfide 36 (0.185 g, 0.374 mmol) in absolute

Pentacyclopropane Antifungal Agent FR-900848
J. Am. Chem. Soc., Vol. 118, No. 45, 1996 11037
mg, 85%) as a gummy, off-white solid: [R]24 ) -352.7° (c 0.45,
as an off-white solid: [R]20 ) -167.0° (c 0.40, DMSO-d6); Rf 0.21
D
D
CHCl3); Rf 0.30 (50:50 EtOAc/petrol); IR (film) 3065, 2998, 2953,
2927, 2866, 2656 (br), 2565 (br), 1684, 1628, 1417, 1304, 1276, 1160,
999, 950, 882 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.28 (dd, 1H, J )
15.2, 11.2 Hz), 6.22 (dd, 1H, J ) 14.9, 11.2 Hz), 5.73 (d, 1H, J )
15.2 Hz), 5.67 (dd, 1H, J ) 14.9, 9.6 Hz), 5.01 (app t, 2H, J ) 3.7
Hz), 1.31-1.27 (m, 2H), 1.03 (d, 3H, J ) 6.0 Hz), 1.01-0.96 (m,
2H), 0.89-0.86 (m, 1H), 0.78-0.74 (m, 1H), 0.69-0.53 (m, 6H), 0.48-
0.44 (m, 1 H), 0.40-0.38 (m, 1H), 0.36-0.33 (m, 2H), 0.13-0.03 (m,
4H); 1H NMR (500 MHz, CD3OD) δ 4.98 (dd, 2H, J ) 5.1, 2.5); 13C
NMR (125 MHz, CDCl3) δ 172.4, 149.9, 147.4, 131.2, 130.6, 125.4,
116.8, 24.6, 22.6, 21.96, 21.92, 20.2, 19.0, 18.6, 18.5, 18.4, 18.1, 14.9
(2C), 13.9, 11.6, 7.8 (2C); MS (CI, NH3) m/e 356 (M + NH4)+, 339,
321, 293, 283, 262, 245; exact mass (CI, NH3) calcd for C23H31O2 (M
+ H)+ 339.2324, found 339.2326.
(1R,3S,4R,6S,7S,9R,10S,12R)-1-[5-[(5′-deoxy-5,6-dihydrouridin-
5′-yl)amino]-5-oxo-1,3(E,E)-pentadien-1-yl]-12-{2-[(1R,2R)-2-meth-
ylcyclopropyl]-1(E)-ethen-1-yl}quatercyclopropane (1). The fol-
lowing procedure is a modification of that reported by Cabre and
Palomo.36 Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (8.4 mg, 0.033
mmol) was added to a stirred solution of acid 2 (10 mg, 0.030 mmol)
and Et3N (4.7 µL, 0.033 mmol) in DMA (0.20 mL). After 3 h, Et3N
(6.4 µL, 0.044 mmol) and amine 4037 (11 mg, 0.044 mmol) were added.
Additional Et3N (11 µL, 0.075 mmol) and amine 40 (7.3 mg, 0.030
mmol) were added after 18 h. After 24 h, the reaction mixture was
diluted with H2O (5 mL), 10% HCl was added until pH 1 was reached,
and the aqueous layer was extracted with EtOAc (10 × 10 mL). The
combined organic layers were washed with saturated NaHCO3 solution
(50 mL), dried, and concentrated. The residue was triturated with
EtOAc, and the triturant was concentrated and further triturated with
Et2O. The process was repeated using 70:30 Et2O/hexane, 50:50 Et2O/
hexane, 30:70 Et2O/hexane, and hexane. The solution obtained was
concentrated, and chromatography on silica (20:80 to 35:65 to 50:50
EtOAc/petrol) provided recovered acid 2 (1.0 mg, 10%) as a gummy,
off-white solid. The residues from each trituration were combined,
and the resulting semipure amide 1 was chromatographed on octadecyl-
functionalized silica (40:60 to 35:65 to 30:70 to 25:75 to 20:80 H2O/
MeOH) and triturated with hexane to provide amide 1 (10 mg, 69%)
(10:90 MeOH/CHCl3); HPLC retention time 6.36 min (15:85 10% acetic
acid/MeOH); IR (CHCl3) 3339 (br), 3268 (br), 3068, 3020, 2951, 2927,
2870, 2850, 1718, 1685, 1657, 1621, 1547, 1485, 1452, 1425, 1375,
1352, 1336, 1315, 1275, 1167, 1128, 1097, 1072, 1032, 993, 957, 930,
887, 864, 854 cm-1; UV (MeOH) λmax (log ꢀ) 281 nm (4.49); 1H NMR
(500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.03 (t, 1H, J ) 5.9 Hz), 6.92
(dd, 1H, J ) 15.0, 11.2 Hz), 6.19 (dd, 1H, J ) 15.0, 11.2 Hz), 5.87 (d,
1H, J ) 15.0 Hz), 5.64 (d, 1H, J ) 5.9 Hz), 5.65 - 5.60 (m, 1H), 5.16
(d, 1H, J ) 4.8 Hz), 5.06 (d, 1H, J ) 4.1 Hz), 4.95 (dd, 2H, J ) 5.3,
2.6 Hz), 3.93-3.91 (m, 1H), 3.74-3.73 (m, 1H), 3.68-3.65 (m, 1H),
3.50-3.28 (m, 3H), 3.21-3.18 (m, 1H), 2.49 (m, 2H), 1.25-1.22 (m,
2H), 0.98 (d, 3H, J ) 6.0 Hz), 1.00-0.94 (m, 1H), 0.84-0.83 (m,
1H), 0.73-0.70 (m, 1H), 0.65-0.61 (m, 1H), 0.60-0.48 (m, 6H), 0.43-
0.39 (m, 1 H), 0.36-0.30 (m, 3H), 0.11-0.09 (m, 2H), 0.08-0.02 (m,
2H); 13C NMR (125 MHz, DMSO-d6) δ 170.3, 165.6, 153.1, 145.7,
139.4, 130.6, 130.3, 125.5, 121.5, 87.6, 81.2, 71.2, 70.0, 41.0, 36.0,
30.8, 23.3, 22.0, 21.2, 21.0, 19.6, 18.3 (2C), 18.0, 17.8, 17.6, 14.4,
14.1, 12.9, 11.1, 7.63, 7.61; MS (FAB) m/e 566 (M + H)+, 506, 484,
452, 437, 413; exact mass (FAB) calcd for C32H44N3O6 (M + H)+
566.3230, found 566.3222.
Acknowledgment. We thank Fujisawa for generous donation
of samples and spectroscopic data for FR-900848 (1), Dr. G.
Tustin and Ms. A. Daumens for preparing amine 40,37 the
EPSRC National Chiroptical Spectroscopy Facility for CD
spectra, Glaxo Group Research Ltd. for a most generous
endowment (to A.G.M.B.), the Wolfson Foundation for estab-
lishing the Wolfson Centre for Organic Chemistry in Medical
Science at Imperial College, the Engineering and Physical
Science Research Council, ChemGenics Pharmaceutical Inc. for
support of our research on antifungal agents, G.D. Searle &
Co. for generous unrestricted support, and the Overseas Research
Students Program for fellowship support (to K.K.).
JA960964J