Total synthesis and stereochemical assignment of the quinquecyclopropane-containing cholesteryl ester transfer protein inhibitor U-106305

Full text of DOI:10.1021/ja961399n

J. Am. Chem. Soc. 1996, 118, 7863-7864
Total Synthesis and Stereochemical Assignment of
7863
the Quinquecyclopropane-Containing Cholesteryl
Ester Transfer Protein Inhibitor U-106305
Figure 1.
Anthony G. M. Barrett,* Dieter Hamprecht,
Andrew J. P. White, and David J. Williams
Department of Chemistry, Imperial College of Science
Technology and Medicine, London, SW7 2AY, U.K.
ReceiVed April 29, 1996
Recently, Upjohn scientists have reported the isolation of the
unusual metabolite U-106305 (1) from the fermentation broth
of Streptomyces sp. UC 11136.1 The compound is structurally
remarkable being graced with six cyclopropane rings, five of
which are contiguous. U-106305 (1) is a potent in Vitro inhibitor
of the cholesteryl ester transfer protein (CETP) reaction, thus
being of potential application in the prevention of arterioscle-
rosis.2 Extensive NMR studies of the fatty amide side chain
were consistent with the assignment of all of the alkene units
as trans and all of the cyclopropane rings trans-disubstituted.
However, the authors did not determine the absolute stereo-
chemistry of any chiral center. In consequence there are 64
possible stereoisomeric structures for this exquisite natural
product.
Figure 2.
Scheme 1. Synthesis of the Quinquecyclopropane 9a
U-106305 (1) shows a striking similarity to the potent
antifungal agent FR-900848 (2) which was isolated from the
fermentation broth of StreptoVerticillium ferVens.3 The full
structure and absolute stereochemistry of FR-900848 (2) were
recently determined by our group.4 Additionally, we have
recently reported the total synthesis of FR-900848 (2) thereby
confirming its relative and absolute stereochemistry.5 Since all
the cyclopropane units of FR-900848 (2) are located on the same
face of an all-anti carbon backbone, it appears reasonable to
assume that the same (or similar) enzyme is involved in the
biosynthesis of each cyclopropane entity. The Upjohn group
have shown that all six cyclopropane methylene carbons of
a
(
a) 10, 4 Å molecular sieves, Zn(CH
2
I)
2
‚DME, CH
2
Cl
Cl , or DMSO,
PdCHCO Me, 75-
, hexanes, -78 °C, 96-97%. Reactions
2
, -40f25
°
2
8
C, 83-91%. (b) Dess-Martin periodinane, pyridine, CH
5 °C; PPh
1%. (c) DIBAL-H, CH
described by a single letter were carried out in a one-pot sense without
isolation of intermediates.
2
2
3
, ca. 10 °C; Ph
Cl
3
PdCHCO
2
2
Et or Ph
3
2
2
47 using pre-formed Zn(CH2I)2‚DME and the chiral dioxaboro-
lane 10 gave 5 in excellent yields. This synthesis is significantly
easier than the literature synthesis via the resolution of trans-
1,2-cyclopropanedicarboxylic acid and subsequent reduction.
The enantiomeric purity of 5 was variable being 74% and 89%
1
U-106305 (1) are biosynthetically derived from methionine.
8
Finally, it should be noted that the organisms producing both
U-106305 (1) and FR-900848 (2) are related. In consequence
of all these factors, we considered that both U-106305 (1) and
FR-900848 (2) should be isostructural and that the absolute
stereochemistry of U-106305 should be represented as stereo-
isomer 3. Herein we report the first total synthesis of U-106305
9
ee respectively using 1.10 and 2.10 equiv of 10. Dess-Martin
1
0
oxidation of the diol 5 (81% ee) proceeded smoothly and the
resultant volatile dialdehyde was directly converted into the
diester 6 [96%, (E,E):(E,Z) ) 28:1] by olefination with
Ph3PdCHCO2Et. Much to our delight, fractional recrystalli-
zation of 6 was especially efficient in enriching the material in
the required enantiomer. Thus recrystallization from Et2O:petrol
(3), which establishes this structural hypothesis to be correct.
The synthesis additionally underscores the versatility of Charette
6
asymmetric cyclopropanation in the synthesis of ter- and
quinquecyclopropane arrays.
We have synthesized 3, using a bi-directional approach to
assemble the C2-symmetrical quinquecyclopropane unit 9 using
(
7) Cowie, J. S.; Landor, P. D.; Landor, S. R. J. Chem. Soc., Perkin
Trans. 1 1973, 720-724.
5
(8) Inouye, Y.; Sugita, T.; Walborsky, H. M. Tetrahedron 1964, 20,
1695-1699. Inamasu, S.; Horiike, M.; Inouye, Y. Bull. Chem. Soc. Jpn.
methodology as for FR-900848 (2) (Scheme 1). Charette
6
cyclopropanation of the readily available 2(E)-butene-1,4-diol
1
969, 42, 1393-1398.
(9) Optical purities determined by the specific rotation of the corre-
(1) Kuo, M. S.; Zielinski, R. J.; Cialdella, J. I.; Marschke, C. K.; Dupuis,
sponding diacetates of 5: Schlosser, M.; Fouquet, G. Chem. Ber. 1974,
107, 1162-1170.
M. J.; Li, G. P.; Kloosterman, D. A.; Spilman, C. H.; Marshall, V. P. J.
Am. Chem. Soc. 1995, 117, 10629-10634.
(10) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
(
2) For a recent review see: Yalpani, M. Chem. Ind. 1996, 85-89.
(
3) Yoshida, M.; Ezaki, M.; Hashimoto, M.; Yamashita, M.; Shigematsu,
(11) Crystal data for 9: C17H26O2, M ) 262.4, monoclinic, space group
N.; Okuhara, M.; Kohsaka, M.; Horikoshi, K. J. Antibiot. 1990, 18, 748-
P21, a ) 5.221(1) Å, b ) 8.912(1) Å, c ) 16.514(1) Å, â ) 98.03(1)°, V
3
-3
-1
7
54.
) 760.9(1) Å , Z ) 2, Dc ) 1.15 g cm , µ(Cu KR) ) 5.7 cm , F(000)
) 288. A clear platy ribbon of dimensions 0.80 × 0.23 × 0.02 mm was
used. Data were measured on a Siemens P4/RA diffractometer with Cu
KR radiation (graphite monochromator) using ω-scans. The structure was
solved by direct methods and the non-hydrogen atoms were refined
(
4) 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,
1
143-1144. Barrett, A. G. M.; Doubleday, W. W.; Kasdorf, K.; Tustin, G.
2
J. J. Org. Chem. 1996, 61, 3280-3288.
anisotropically using full-matrix least squares based on F to give R1 )
(
5) Barrett, A. G. M.; Kasdorf, K. J. Chem. Soc., Chem. Commun. 1996,
0.042, wR2 ) 0.112 for 1231 independent observed reflections [|Fo| >
4σ(|Fo|), 2θ e 125°] and 180 parameters.
3
25-326.
(6) Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651-
(12) B u¨ chel, K. H.; Conte, A. Chem. Ber. 1967, 100, 1248-1251.
(13) Obtained by heating 2-chloro-N-isobutylacetamide and triphen-
ylphosphine to 150 °C.
2
1
652. Charette, A. B.; Prescott, S.; Brochu, C. J. Org. Chem. 1995, 60,
081-1083.
S0002-7863(96)01399-6 CCC: $12.00 © 1996 American Chemical Society

7864 J. Am. Chem. Soc., Vol. 118, No. 33, 1996
Communications to the Editor
Scheme 2. Assembly of U-106305 3a
a
(
a) TBSCl, imidazole, CH
P(O)CH CHdCHCO
‚DME, CH Cl
, -50f25 °C, 72%. (e) N-(phenylsulfenyl)succinimide,12 PBu
g) TBAF, THF, 25 °C; DMSO, pyridine, 25 °C; Dess-Martin periodinane, 25 °C; PPh
2
Cl
2
, 25 °C, 75% calcd at 78% conversion. (b) Dess-Martin periodinane, pyridine, DMSO, 25 °C; PPh
Cl , hexanes, -78 °C, 95%. (d) 10, 4 Å molecular sieves,
, C , 25 °C, 91%. (f) Raney nickel, THF, 25 °C, 44%.
, ca. 15 °C; Cl Ph
1%. Reactions described by a single letter were carried out in a one-pot sense without isolation of intermediates.
3
, 25 °C;
(
E)-(MeO)
Zn(CH I)
2
2
2
Me, NaH, DBU, 25 °C, 88%. (c) DIBAL-H, CH
2
2
2
2
2
2
3
6 6
H
-
+
i
13
(
3
3
2 2
P -CH CONHCH Pr, DBU, 25 °C,
9
Diol 9 was desymmetrized by silylation which gave the mono-
TBS ether 11 (58%) in addition to unreacted starting material
9
(22%) and the di-TBS ether (19%) both of which were
recycled. Dess-Martin oxidation, Wadsworth-Emmons ho-
mologation, and DIBAL-H reduction, gave the dienol 12.
Charette cyclopropanation of 12 proceeded with excellent
stereoselectivity to give the hexacyclopropane 13. Deoxygen-
ation of alcohol 13 was achieved via conversion14 into the
phenyl sulfide 14 and Raney nickel mediated desulfurization.
A comparable strategy was employed in our recent synthesis
5
of FR-900848 (2). Much to our relief, desulfurization pro-
ceeded readily to provide 15, albeit in modest yield (44%). The
synthesis of U-106305 (3) was completed by desilylation,
oxidation to the aldehyde, and Wittig olefination to introduce
the unsaturated isobutylamide. All these reactions proceeded
effectively in a one-pot procedure to give 3 in 91% yield as a
crystalline solid. The synthetic material was identical in all
respects with an authentic sample of U-106305. All these
results clearly establish the full structure and stereochemistry
of U-106305 (3). Further studies on related multiple cyclopro-
pane systems will be reported in due course.
Figure 3. X-ray structure of the quinquecyclopropane 9. The X-ray
structure of 9 shows the molecule to have an extended geometry with
four of the five cyclopropyl rings oriented to give an approximately
uniform helix. The H-C-C-H torsional geometries about the C(3)-
C(4), C(6)-C(7), and C(9)-C(10) bonds are all gauche with angular
rotations of -61, -60 and -50°, respectively. This sequence is broken
by a reversal of the sign of rotation (+50°) about the bond [C(12)-
1
5
1
1
C(13)] linking the fourth and fifth cyclopropyl ring.
Acknowledgment. We thank Glaxo Group Research Ltd. for the
most generous endowment (to A.G.M.B.), the Wolfson Foundation for
establishing the Wolfson Centre for Organic Chemistry in Medical
Science at Imperial College, the Engineering and Physical Science
Research Council, Myco Pharmaceutical Inc. for support of our research
on antifungal agents, G.D. Searle & Company for generous unrestricted
support, Dr. M. S. Kuo for a sample of U-106305, and the EPSRC
National Chiroptical Spectroscopy Facility for CD spectra on natural
and synthetic U-106305.
ether gave first the racemic (E,E)-diester 6 (17%) and subse-
quently enantiomerically pure (E,E)-diester 6 (75%). The
structures of both enantiomerically pure and racemic forms of
(
E,E)-diester 6 were confirmed by X-ray crystallography.
Reduction of 6 provided the bis(allylic alcohol) 7 which was
6
doubly cyclopropanated, again using Charette methodology,
to produce the corresponding tercyclopropanedimethanol. Sub-
sequent one-pot oxidation-Wittig olefination followed by
DIBAL-H reduction gave the dienediol 8 in 70% yield from 7.
Supporting Information Available: Tables of X-ray data for
1
13
compound 9 and H NMR, C NMR, CD, and chiral HPLC results
for 3 and authentic U-106305 (12 pages). See any current masthead
page for ordering and Internet access instructions.
6
Double Charette cyclopropanation of diene 8 afforded the
quinquecyclopropane 9. It should be noted that all the isolated
intermediates in the sequence from 6 to 9 are crystalline
compounds, thus facilitating the removal of any traces of
undesired stereoisomers formed in the cyclopropanation reac-
tions. The structure of the quinquecyclopropane 9 was con-
firmed by X-ray analysis and is shown in Figure 3.
JA961399N
(
14) Walker, K. A. M. Tetrahedron Lett. 1977, 4475-4478.
1 13
(
15) By H NMR, C NMR, [R]D, CD, UV, chiral HPLC, mp, and mixed
mp.