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Asymmetric Synthesis of Biaryls by Intramolecular Oxidative Couplings of Cyanocuprate Intermediates.

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tively, and positions Cu4 and Cu5 were no longer occupied.
When crystal 2 was cooled rapidly to -14O'C. occupancy
parameters for Cul, Cu2, C d , and Cu4 of 0.60(1). 0.45(1),
0.36(1), and 0.06(1). respectively, were found. In this case position Cu5 remained unoccupied. The distribution of Cu' in crystal 2 can be considered as a frozen intermediate of the high- and
low-temperature structures of crystal 1.
The arrangement of the Cu' ions (Fig. 2) and their temperature factors at room temperature are indicative of great mobility
within the chain. The Cu' ions change positions by moving
through the shared faces of the coordination tetrahedra to the
unoccupied center of a neighboring tetrahedron. This hypothesis is supported by the specific conductivity in the chain direction of roughly 10- S cm - which is greater than that perpendicular by a Factor of 103.11i1
On cooling. the conductivity
decreases continuously and jumps at - 100 'C. Differential
thermal analysis and differential scanning calorimetry both
show a reversible thermal process at -100(*2)"C. which can
be interpreted as the freezingithawing of the Cu' motion ( A H =
f0.21 k J m o l - ' ; exothermic on cooling).
Fig. 2. Section of the helix of tetrahedra ![Cu,l;]
at room temperature (ORTEP plot at the 50%
probability level: Cu atoms: hatched vibrational ellipsoids. l atoms: outlines of the vibrational ellipsoids.) On slow cooling to - 145 C (crystal I j only
positions Cul. Cu2. and Cu3 are occupied. on rapid
cooling to - 140 C (crystal 2) positions C u l . Cu2,
Cu3. and Cu4 are occupied. The Cu-I distances
range from 2.417(2) to 3.09(1) .& at room temperature and from ?.525(6) to 3.216(8) .& at lower temperatures.
The individual 2[Cu314] chains are chiral. In the crystal the
chains are separated by the tetraphenylphosphonium ions and
arranged in a rod packing parallel to the [loo] direction. A
racemic mixture of chains is required by symmetry (space group
A definite answer to the question of why certain cations lead
to specific types of iodocuprates(1) has not yet been possible. We
can also not explain why tetraphenylphosphonium ions are accompanied by the formation of the unusual helical tetrahedron
chains, whereas anions having the same composition form
[Cu31;] chains with other linkage modes when the cation is
methyltriphenylphosphonium. tetrapropylammonium, or bis(formamidium).[12'
Experinwnial Procedure
A mixture of tetraphenylphosphonium iodide (1.16g. 2.5 mmolj. iodine (1.27 g.
2.5 nimol), and Cu powder (1.27 g. 5 mmolj was heated in anhydrous acetone
(50 mL) under a nitrogen atmosphere until the solution turned pale yellow and was
filtered x hile hot. The cooled colution provided white, needle-shaped crystals with
the composition [(C,Hj),P][Cu,I,]. M.p. 254 ~ 2 5 6 ' C When
the filtrate was allowed to stand for a n extended time or petroleum ether was added. white flakes or
prismatic crystal? formed with the composition [(C,H,),P][CuI,]-A and -B. respectively 1131. M-p. 210 C .
Received: March 24, 1994 [Z6793IE]
German version: Aiigeir. Chon. 1994. 106. 1929
[ l ] A. F. Wells. Sfruc~rural/nor,gnnic C/?wni.\wi,.5th ed.. Clarendon, Oxford. 1984.
p. 191.
[2] H . Hartl. F. Mahdjour-Hassan-Abadi. Anjicir. Ch<wi 1981. Y.3. 804-805:
Airgfw. <'/7ei7?. / i f / . Ed. E i 7 ~ / .19
[3] K. P. Bigalke. A. Hans. H. Hart
Clicni. 1988,363.96-104: H
Hartl. Angaii.. Cl7c2~7?.1987. 99. 9
C/7m?./ n r . Ed. En,q/. 1987. 26.
927-92X: H. Hartl. F. Mahdjour-Hassan-Ab;~di.ihrd. 1984. 96. 359-360 and
[4] H. Hartl. F. Mahdjour-Hassan-Abadi. L. 2 N u ~ n r f o r w hB. 1984. 39. 149-156
[5] S. Aiidersson. S. liigner. J. C'ri.rtulIiijir. Specirusc. Rcs. 1988. I H , 591
[6] G. Henkel. S. Weissgriber. A n p i . Chrn?. 1992. 104, 1382 1383, Angm
C h i . Inr Ed. Eii,?/. 1992. 31. 1368-1369.
[7] A. H. Boerdi,jk. Phi1ip.s He,.Rep. 1952. 7. 303-313.
[8] R. Buckminster-Fuller. S) nwg<~rics,1st ed. (paperback), MacMillan. Neu
York. 1982. p. 510-522.
[Yl C . Zheng. R. Hoffmann. D. R. Nelson. J. A m . Ciiern. Soc. 1990. 112. 3784
3791. and references therein for the helix of tetrahedra.
[lo] Crystal structure data for [(C,H,<j,P] ,"Cu,l,]: .2.1 = 1037.6. orthorhomhic.
Ccw. Crystal 1 . T = - 145 and 20 C (data for 20 C in square brackets). N =
11.559(3) [11.567(6)]. h = 20.917(4) [21.112(7)]. ( ' =22.983(9) [23.?19(6j]A.
I' = 5556.8 [5694.6] A'.
= 2 48 [2.42]
Enrdf-Nonius CAD-4
four-circle diffractomcter,
scans. Mo,, radiation;graphite monochromator, 20 = 40 [45] . 1296 [1791] symmetry-independent reflections. of which 215
14541 had I < 1 u ( / ) :165 11731 refined parameters (Cu5 isotropic. a l l other
atoms anisotropic. no H atoms). iaotropic extinction correction. absorption
correction DIFABS [14]. R = 0.048 [0.054] at uniform weights. Crystal 2:
T = -14O'C. rr=ll.567(2). h=20.930(3), ~ = 2 ? . 9 9 1 ( 3 j A . b'=5566.0.&J.
{ J ' ~ , =
~ ~ 2.48 gcm-'.
Enraf-Nonius CAD-4 four-circle diffractometer. w 2 0
scans, Mo,, ri1diation:graphite monochromator. 20 = 50'. 1829 symmetry-independent reflections. ofwhich 624 had / < 3n(I): 168 relined parameters (Cu4
isotropic, all other atoms anisotropic. no H atoms), isotropic extinction correction, absorption correction DIFABS [14]. R = 0.058 at uniform ueights. Further details of the crystal structure investigation may he obtained from the
Fdchinformationszentruin Karlsruhe. D-76344 Egpnstein-Leopoldshafen
( F R G ) on quoting the depository number CSD-58250.
(111 Direct current o n single crystals. contact by mems of a conducring paste
(Hydrokollack), Cu electrodes.
[12] R . Frydrych, T. Muschter, I. Brudpain. H Hartl. %. Nuturforsclr. B 1989. 45.
679 -6XX.
[I 31 H. Hartl, I. Briidgam, F. Mahdjour-Hassan-Ahadi. Z.!Vu~zrrfor,schB 1985.40,
1032- 1039.
[14] N. Walker. D. Stuart. Acru Cr~,.rrd/cigr.Swr. A 1982, 39, 158-166.
Asymmetric Synthesis of Biaryls by
Intramolecular Oxidative Couplings of
Cyanocuprate Intermediates**
Bruce H. Lipshutz.* Frank Kayser, and Zi-Ping Liu
Dedicated to Professor Manfred Schlosser
O H the occasion o f hi5 6Oih hirthdaj~
The biaryl nucleus is a key subunit associated with many
natural products['] (e.g., steganone, ancistrocladin, etc.) and
forms the basis of several nonracemic reagents (e.g., BINAL-H.
BINAP. etc.) of extraordinary value in synthetic chemistry
(Scheme 1) .'I Owing to the substitution pattern on the ring(s)
or other restraints, hindered rotation about the adjoining C-C
bond gives rise to the stereochemical feature known as atropisomerism. Given the importance of this structural type, there are
Prof. B. H . LipahutL. Dr. F. Kayser. Dr. 2.-P Liu
Department of Chemistry. University of California
Santa Barbara. CA 93106 (USA)
TeIeFax: Int. code + (805)893-4120
[**I This research was supported by the National Science Foundation (CHE-9303883) and the Deutsche Forschungsgemeinschaft (fellowship to F. K.j. We
warmly thank Prof. K. B. Sharpless for a generous gift ofnonraceinic 14b used
in this study.
relatively few chemical methods that directly yield nonracemic b i a r y l ~ . [ ~Some
rely on intermolecular coupling of
while others are based on intramolecular bond formation by the traditional Ullmann coupling.['] Varying levels of generality and stereocontrol are observed. We now describe an experimentally straightforward,
general method. which affords nonracemic biaryls with virtually
complete stereoinduction.
- Anclsfmcladln
\ \ \ P 3
tartaric acid was converted to diol 6 . Consecutive Mitsunobu
reactions of 6 with 1 yielded 7.[121 Treatment of 7 in an
analogous procedure to that used for 3 resulted in formation of
a single binaphthyl derivative 8. Removal of the tether could be
accomplished in a one-pot process. by double benzylic oxidation
with N-bromosuccinimide (NBS) followed by addition of
aqueous KOH. (S)-2,2'-Binaphthol (9) was thus obtained directly. The identity of the product was confirmed by comparison
with authentic
In an identical procedure, linkage of 1 and 10 with tether 6
provided the mixed dibromide 11. Dilithiation,['I cyanocuprate
formation, and oxidation of 11 at 0 ' C afforded the nonracemic
unsymmetrical biaryl 12, again, as a single product (by N M R
Scheme I . Examples of binaphthyl derivatives.
In our approach to the well-known 2,2'-binaphthol system,"]
inexpensive 1 -bromo-2-naphthol (1) was converted to dibromide 3a with lactic acid ester 2 a (R' = Me). Treatment of 3a
with tBuLi['' followed by addition of solubilized CuCN''] presumably led to formation in situ of a higher order cyanocuprate
4a.['] which produced the binaphthyl5a upon exposure to oxygen."'] A 'H N M R analysis (500 MHz) revealed an 83: 17 ratio
12 (68%)
The method applies equally well to 2,2'-C-substituted binaphthyls such as 17. In these cases, the simpler, more readily available nonracemic vicinal diols 14 served as
in the formation of dibromodiethers 15 from 13 (2equiv). Intramolecular biaryl coupling led in each case to a single
diastereomer 16, even though a ten- rather than an eight-membered ring was formed (cf. 16 vs. 8) .[151
Sa (71%)
5b (72%)
2 - 5 : a, R = Me: b. R = P h
0 \\\\R
17 (90%)
of diastereomers (66 % de). With the mandelic acid derivative
3b, 5b was obtained with 80-90% de. To increase the guuche
interaction(s) assumed to be responsible for the induction,"
16a (64%)
16b (73%)
14-16 a, R = Me, b, R = Ph
Removal of the tether in 16b was best effected by catalytic
hydrogenation in HOAc over Pd on charcoal at room temperature. The resulting diol 17 was thus obtained in 90 Yo yield, The
specific rotation of the product compared quite favorably with
the reported
Finally, this method appears well-suited for use in the synthesis of the biaryl portion in several natural products of current
interest, such as van~omycin.~""~
the michellamines,[' 7h1 and the
ellagitannins (e.g., tellimagrandin I1 (20), R = 3,4,5-trihydroxybenzoyl)!'7'1 A step towards target 2011s1
was achieved by subjecting dibroinodiether 18 to cuprate-induced coupling. Biaryl
19 was obtained in 7 7 % yield as the only observable isomer.['"]
In summary, a powerful new method for controlling axial
chirality in numerous biaryl systems has been developed. This
m o
$ - ~ ~ ~
19 (77%)
[ 8 ] P. Knochel. M. C. P. Yeh. S. C. Berk. J. Talbert. 1 Oi.,y. Chern. 1988. 53. 2390
(91 B. H. Lipshutr. S. Sengupta, Org. Reuct. 1992. 41, 325.
[lo] All new compounds gave satisfactory IR. NMR. MS. and HRMS data.
[I I] Further discussion is deferred to the fiill account of this work.
[12] The tether was attached as follows (TBS = trrt-butyldimethylsilyl. Bn =
benryl. DEAD = diethyl arodicarboxylate):
proceeds with oxidation of intramolecularly constructed
cyanocuprates. The aryl bromide precursors are readily available; the nonrxemic tethers are derived from inexpensive members of the "chiral pool"; and the couplings take place, unlike
their intermolecular counterparts,[201at practical temperatures
and are thus expected to be more amenable to scale-up.
Esperinwntal Procedure
16b: Copper cyanide (180 mg, 2.0 mmol) was placed in an oven- and flame-dried
three-necked round-bottom flask (100 mL) equipped with a T-top (for argon'
vacuum). a thermometer adapter fitted with a gas dispersion tube. and a rubber
septum. The flask was once again gently dried with a heat gun under vacuum and
allowed to cool to room temperature under argon. T H F (35 mL) was added, and the
resulting suspension cooled to -78 C. In a round-bottom flask ( 5 0 m L ) . dibromodiether 15b (1.31 g. 2.0 mmol) w'as dissolved in T H F (35 mL). The tlask was
cooled to -78 C, and 4.2 equiv of /err-butyllithium (4.98mL. 8.4 mmol, 1 . 7 in
pentane) added dropwise to give a clear yellow solution. The reaction mixture was
stirred at this temperature for 0.5 h. The dilithium compound was transferred with
a cannula to the flask containing the CuCN suspension. The mixture was warmed
to -40 -C with gentle stirring. A clear yellow solution of the higher order cuprute
was obtained. This was recooled to -78 C. The argon flow was then stopped and
dry oxygen (passed through a trap at -78'C) was bubbled through the re:ict~oii
mixture for 30 min, whereupon the solution turned dark. The mixture w a s allowed
to warm to 0 'C. and the oxygen flow was continued for 1.5 h The reaction was then
quenched with a solution of methanol and concentrated aqueous NaHSO, (2 m L ) .
The mixture was allowed to warm to room temperature and poured into a solution
of 1 0 % N H , in concentrated NH,CI (100mL). After it had been stirred for 0.5 h.
the organic layer was separated. The aqueous phase was extracted three times with
ether. and the combined extracts were subsequently washed with 5 "4,HCI. saturated
NaHCO,. and brine. The oreanic phase was dried over MgSO, and liltered. The
solvent was removed under reduced pressure. Chromatography ofthe crude mixture
on silica gel (hexane:ethyl acetate 90.'10) gave 16b as a white crystalline product
(720mg. 73%). 0.48;I R ( K B r ) . i. = 3030.3020.2835.1455. 1340. 1090. 1070. 1030.
820. 750, 695 c m - ' ; 'H N M R (500 MHz. CDCI,): 6 = 4.35 (s, 2 H . 2 x CHI. 4.5X
= -14.70( c - D.16,
[13] The isolated binaphthol 9 showed a n [z]:'
o f -31 ( c = 0.0125. T H F ) . Thi\
confirms the sense of chiral induction in the cyclization (i.e.. that the (S)isomer
w a s formed). A scale-up of thir reaction has not yet been attempted.
[I41 Diol 14a is commercially avallable. and 14b can he obtained by Sharpless
asymmetric dihydroxylation. cf. G. A. Crispino. K . 3 . Jeong. H. C. Kolb.
Wang. D. Xu. K. B. Sharpless. .1. (IC'lwni.
1993. SX. 31x5.
[I 51 It should he noted that the sense of the asymmetric induction in the synthesis
of 16 is opposite to that observed in that of 8. This observation is in accord with
the conformational requirements o f a n cight- versus a ten-membered ring [ I 11.
[I61 a ) Observed [z]t2,,= 82 (< = 0.056. T H F ) ; ref. [16b][N]:,
= + 86 (c = 1.0.
acetone): b) S. Miyano. M Tobita. H . Hashimoto. Bull. Chcwfr Soc. J p i . 1981.
54. 3522.
[17] a) D.A. Evans, C. J. Dinsonore, E t r c r h r d r o i ~Lerr. 1993, 34, 6029;J. Zhu. R.
Beugelmans. A. Bigot. G P. Sinph. M . Bois-Choussy. h i d 1993. 34. 7401 :
b) G. Bringmann. R. Zagst. M Schiffcr. Y.F. Hallock. J. H . Cardellina. M . R.
Boyd. A n g r w Ch~wi.1993, f0.5. 1242: A n , y r i ~ .Chein h t . Ed. Engl. 1993. 32.
1190. C ) D. E Berry, L. MacKenrie. E. A. Shultis. J. A . Chan. S. M . Heclrt. .I
Or,q C'hoii. 1992. 57. 420.
[lX] K. S. Feldman. S. M Ensel. R. D. Minard. J . A m . Chc,m. Sor. 1994. 116. 1747:
T. D. Nelson. A. I . Meyera. J Or,y. Chrni. 1994, SY, 2577
1191 B. H. Lipshutz, Z. Liu. F. Kayser. Z?.fruhedron L P / / . ,1994. 35. 5567.
[20] B. H.Lipshutz. K . Sieginann. E. Garcia. F. Kciyser, J AM. Che~ii.Sir. 1993.
115. 9276.
7.94(d.2H.JO8.4Hr,Ar-H).8.07(d.2H..l=8.5 H r . A r - H ) : " C N M R ( 5 0 M H z .
CDCIJ 6 =70.5. 87.3.125.X.,127.9.12X.4, 133.0, 136.6. 139.3;El-MS: iii.1; (5'0): 386 (6).281 ( 2 3 ) , 280 (100).279(73).
493 (1.5). 387 (10).325 (15). 298 (22).
276 (IS). 265 (1 I). CI-MS (CH,): ni:: (X).
297 (90). 296 (19). 295 (31), 281 (56).280 (44).267 (99). 197 (loo), 107 (71):
high-resolution EI-MS: C,,H,,02 ( M + 1): calcd: 493.21674,found' 493.21676.
Received: April 14. 1994 [Z6847IE]
German version' .4nxzit. Chpm. 1994. 106. 1962
[ I ] a) G. Bringmann. R. Walter. R. Weirich, A n g m . C'hrrn. 1990. 102. 1006:
Anxeir. Chcni. I w r . Ed. Engl. 1990. 29. 977; b) H:l.
Altenbach in Or,ounrc
Synthesis Highlighlr, Vol. 1 (Ed.: J. Mulzer). VCH. Weinheim, 1991. p. 181.
[2] R. Noyori. Chcm. Ree. 1989, 18. 187: S Inoue. H. P. Takaya. K . Tani, S.
Otsuka. T. Sato. R. Noyori. J Am. Cheni. Soc. 1990, 112, 4897.
[3] D. W.Knight in Coniprehensivc Orgunrc S.vnr/ie.vir, V d . 3 (Ed.: B Trost). Pergamon. New York. 1991, p. 481.
[4] T. D. Nelson, A. I. Meqers, J Org. Chriii 1994. 59. 2655; H. Moorlag, A. 1.
Meyers. Teiruhcdron Lert. 1993. 34, 6989,K. Tomioka. M.Shindo. K. Koga.
illid. 1993. 34, 681 : T. Hayashi. K. Hayashizaki. T Kiyoi. Y. 110, J. Am. Chml.
Soc. 1988, 110. 8153: A. I. Meyers, K. A. Lutomski. rhirl. 1982. 104. X79: M.
Shindo. K. Koga. K. Tomioka. ;hid 1992. 114. 8732:ref. [I a]; A. I . Meyers. M .
Reumann. Terrukedron 1985. 41. 837.
[ 5 ] M. Takahashi. T. Ogikn. K. Okamura, T Da-te, H. Ohmiru. K. Kondo. T.
Iwasaki. J Chcm. Soc. Perkin Trans. / 1993, 1473: S. Miyano, H. Fukushiina.
S. Handa. H . Ito. H. Hashimoto. Bull. Chern. Soc. Jpn. 1988. 61. 3249: S.
Miyano, S.Handa. K . Shimizu. K. Tagami. H. Hashimoto, ihirl. 1984,57, 1943.
[6] C. Rosini, L. Franzini. A. Raffaelli. P. Salvadori. Sw~thesis1992. 503.
[7] Only 1 equiv of tBuLi per aryl bromide unit is needed to effect dihthiation when
performed at 100 -C.
Trehalase Inhibitor Salbostatin, a Novel
Metabolite from Stveptomyces albus,
ATCC 21838
L k z l b Vertesy," Hans-Wolfram Fehlhaber,
and Arno Schulz
Although microbial cultures constitute an enormously rich
source of the most varied secondary metabolites, there have till
now been very few systematic studies of the metabolic products
of any given organism. Usually, only those compounds that
respond to specific biological or biochemical screening tests are
isolated and characterized. So-called chemical screening has recently also come into use,"] but this, too, yields only a random
selection of metabolites.
High performance mutants of Streptomyes alhus,
ATCC21838, are used for production of the polyether antibiotic
salinomycin,[21which is a coccidiostatic. Industrially, feed antibiotics are often not applied in a pure form, but as a dried
[*I Dr. L. Vertesy. Dr. H:W. Fehlhaber
Allgemeine Pharma Forschung der Hoechst AG
D-65926 Frankfurt a m Main (FRG)
Telefax: Int. code + (69)305-16354
Dr. A. Schulz
Forschung Biochemie der AgrEvo, Frankfurt am Main
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asymmetric, cyanocuprate, synthesis, intramolecular, biaryls, couplings, intermediate, oxidative
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