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Novel Strategies for the Construction of Complex Polycyclic Ether Frameworks. Stereocontrolled Synthesis of the FGHIJ Ring System of Brevetoxin A

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C0M M U N I C ATIONS
2-deoxy-~-ribose,tri-0-acetyl-D-glucal, and D-mannose, respectively. The successful execution of the designed strategy
for reaching 2 is described below.
Syntheses of key intermediates 6 and 7 are briefly summarized in Scheme 2. Thus, 2-deoxy-~-ribosewas converted
Me
Novel Strategies for the Construction of Complex
Polycyclic Ether Frameworks.
Stereocontrolled Synthesis of the
FGHIJ Ring System of Brevetoxin A**
CHO
1: brevetoxin A
By K . C. Nicolaou,* C. A . Veale, C.-K. Hwang, J. Hutchinson,
C. K C. Prasad and W. W. Ogilvie
OSi t BuPh,
Dedicated to Professor Hans Jurgen Bestmann
on the occasion of his 65th birthday
Recent reports from these laboratories described new synthetic technologies and strategies for the construction of the
In this
ABCD"] and E['I ring systems of brevetoxin A (l).[31
communication we describe an efficient and stereocontrolled
synthesis of the FGHIJ ring framework (2) of this novel
neurotoxin.
An attractive retrosynthetic analysis of brevetoxin A (1)
with a high degree of convergency is shown in Scheme 1.
Thus initial disconnection of the indicated strategic bonds of
1 (dotted lines) leads to the appropriately functionalized intermediate 2 containing the FGHIJ ring framework of the
target molecule. Further disconnection of the G ring of the
newly generated intermediate 2 as shown leads to compounds 3 and 4 as potential precursors. In order to ensure a
high yielding formation of the 8-membered ring system in 3,
an additional ring was temporarily installed in its pregenitor
( 5 ) (to decrease number of rotations and facilitate ring closure). Finally, disconnection of 6,7, and 4 led to enantiomerically pure precursors of the correct stereogenicity, namely
2
n
H
F
e
u
0
M
e
+U E
2
OCHZPh
tBuPh,
PPh, IG
OH
PhAo
r w
OHCHoH
H
H3
4n
a
U
H
EtS
"'OCOtBu
7
5
U
2-deoxy-D-ribose
1
U
I I tri-0-acetyl-o-glucal I
I
Scheme 1. Retrosynthetic analysis of brevetoxin A (1)
K. C. Nicolaou, C. A. Veale, C.-K. Hwang, J. Hutchinson,
C. V. C. Prasdd, W.W. Ogilvie
Department of Chemistry
Research Institute of Scripps Clinic,
10666N. Torrey Pines Road
La Jolla. CA 92037 (USA)
and
Department of Chemistry
University of California San Diego
Ld Jolld, CA 92093 (USA)
This work was financially supported by the National Institutes of Health
(USA). the National Science Foundation (USA), Merck Sharp and
Dohme (USA) and Hoffmann LaRoche (USA) and was partially carried
out at the University of Pennsylvania. Abbreviations used: mCPBA =
mera-chloroperbenzoic acid. PDC = pyridinium dichromate, CSA =
camphorsulfonic acid, HMPA = hexamethylphosphoric acid triamide,
Tf = trifluormethanesulfonate, TBAF = tetrabutylammonium fluoride,
DIBAH = diisobutylaluminum hydride, DBU = diazabicyclo[5,4,0]undec-7-ene, py = pyridine, DET = diethyltartrate, 9-BBN = 9-horabicyclo[3,3,l]nonane.
Angew. Chem. Inr. Ed. Engi. 30 (1991) No. 3
into olefin 9 (65 % overall yield) by a Wittig reaction followed
by sequential and selective protection involving 1,3-benzylidene formation and silylation. Subsequent ozonolysis-reduction led to alcohol 10, which was then converted into
phosphonium salt 6 via iodide 11 by standard chemistry
(68 % overall yield). For the synthesis of 7, tri-0-acetyl-D-glucal (Scheme 2) was converted into 12 by methods previously
described from these laboratoriesc41 followed by selective
monosilylation. Epoxidation with mCPBA gave the a-epoxide 13 as a single product (75 %), which was transformed into
epoxyketone 14 by PDC treatment (86%). Reductive opening of 14 to 15 (88%) occurred smoothly upon treatment
with NaI, whilst transformations 15 -+ 16 -+ 17 18 -+ 7
0 VCH Verlagsgeseilschafl mbH, W-6940 Weinheim, 1991
-+
0570-0833/9ll0303-0299 S 3.50
+ .25/0
299
H
,C02Me
...u
IOVOH
a
H
___)r
HO
OHCGO,
F
OH
2-deoxy-o-ribose
"
19: R = SitBuMe2
20:R=H
'C
>
.
Jc
d
OSitBuMe:,
11: x = I@
6: XnPPhl 1'
25
10
ec
Ace
tri-0-acetyl-o-glucal
Ih
26
12
'"OR
21: R = COtBu, X = SEt
R = COtBu, X = H
G22
L-)23:R=H,X=H
L 2 4 : R = S02CH3,X = H
lg
'
'
15: X = O , R = H
16: X = (SEt),, R = H
17: X = (SEt)2, R = OCOtBU
C
27: R H, X = OH
G28:R =H ,X=OC OIB ~
=29:
R = SitBuMe,, X = OCOIBu
I L30:
R = SitBuMe,, X = OH
L 3 1 : R = SitBuMe,, X = OS02CH3
3 2 R = SitBuMe,, X = I
3: R = SitBuMe,, X = $Ph3 lQ
13:R' =OH, R2 = H
w R 1 = R2 = 0
"
m
__t
EtS
''-ocornu
"'OCOIBU
18
Scheme 2. Preparation of key intermediates 6 and 7. Reagents and conditions:
a ) l : 1.1 equiv of Ph,PCHCOOMe, THF, 8 0 ° C 4 h , 100%; 2 : 1.5 equiv of
PhCH(OMe),, 0.1 equiv of CSA, CH,CI,, 25"C, 12 h, 65%; b) 1.1 equiv of
IBuMe,SiOTf, 1.5 equiv of 2,6-lutidine, CH,CI,, 0% 30 min, 100% c) 0,,
CH,CI,, -78"C,2h, then3.5equivofNaBH4,MeOH,0"C,2h,90%;d)1.4
equiv of I,, 1.4 equiv of PPh,, 1.4 equiv of imidazole, CHJN, 25°C. 30 min,
84Oh;e)l.l equivofPPh3.CH,CN,80"C,48h,90%;f)l:seeref.[4];2: 1.5
equiv of tBuMe,SiCI, 2.0equiv ofimidazole, DMF, 0 ° C 1 h, 94%; g) 1.2 equiv
ofmCPBA,CH,CI,,0-25"C, 12 h,75%;h)2.0equivofPDC,CH,CI,,25"C,
6 h, 86 %; i) 5.0 equiv of NaI, 0.5 equiv of NaOAc, 5.0 equiv of HOAc, acetone,
2 5 °C 1 h, 88 %; j) 4.0equiv of EtSH, 2.5 equiv of BF,,OEt,, CH,CI,, - 4 0 T ,
1 h, 74%; k) 1.5 equiv of (CH,),CCOCI, Et,N, CH,CI,, 25°C 18 h, 84%;
I) 1.5 equiv of TBAF, THE 0°C. 3 h, 95%; m) 5.0 equiv of SO,.py, 5.0 equiv
of Et,N, DMSO, CH,CI,, 0°C. 1 h, 75%.
proceeded uneventfully affording the requisite aldehyde (7)
in high overall yield.
The coupling of intermediates 6 and 7 and elaboration of
the resulting product to compound 3 is summarized in
Scheme 3. Generation of the phosphorane from 6 followed
by reaction with aldehyde 7 gave selectively the cis olefin 19
(75 %), which was converted into hydroxydithioketal20 and
then ~yclized[~]
by the action of AgClO, to afford oxocene
derivative 21 (74%). Desulfurization of 21 (95 YO)followed
by standard manipulations led to methanesulfonate 24 in
high overall yield. Base-induced elimination converted 24
into a mixture of 25 and 26 (84%, 25:26 ca 4.6:l). The
undesired isomer 25 was isomerized to the desired enol ether
300
0 VCH Vedagsgeselischafl mbH.
W-6940 Weinheim. 1991
Scheme 3. Synthesis of key intermediate 3. Reagents and conditions: a) 0.9
equiv of nBuLi, THE -78°C. 1 h, then 4.0 equiv of HMPA, 1.0 equiv of 7,
-78-25"C, 18 h, 75%; b) 1.5 equiv of TBAF, T H E 25"C, 12 h, 98%; c)4.0
equiv of AgCIO,, 5.0 equiv of NaHCO,, 4 A molecular sieves, silica gel,
CH,NO,, 2 5 °C 4 h, 74 %; d) 4.0 equiv of Ph,SnH, 0.1 equiv of AIBN, toluene,
llO"C, 2 h, 95%; e) 2.5 equiv of DIBAH, CH,CI,. -78"C, 1 h, 85%; f) 1.5
equivofCH,SO,CI, 3.0equivofEt3N,CH,CI,. O"C, 1 h;g) S.OequivofDBU,
DMF, 145"C, 2 h; 84% from 23(25:26 = 4.6:l); h) 1.0equivof KOrBu, DM1h;
SO,THF,5O0C,3h,60%;1) 1: 1.1 equivofmCPBA,THF,H2O,0-25"C,
2 : lO.OequivofNaBH,.MeOH, 0 ° C 1 h;3:excessNa104,EtOH, H20,25"C.
1 h; 4: 3.0 equiv of NaBH,, MeOH, O"C, 1 h, 85% from 26; j) 1.1 equiv of
(CH,),CCOCI,py, - 2O-O0C,4 h, 82Y0;k) 1.5equivoftBuMe2SiCI,5.0equiv
ofimidazole,DMF,25"C, 12 h,97%;1)2.7equivofDIBAH,CH,CI,, -78°C.
1 h, 98%: m) 1.4 equiv of CH,SO,CI, 3.0 equiv of Et,N, CH,CI,, O"C, 1 h;
n) 10 equiv of NaI, acetone, 56°C. 2 h, 84% from 30; o ) 1.0 equiv of I,, 1.0
equiv of PPh,, CH,CN, 6 0 T , 48 h, 92%.
26 (60 YO)under basic conditions. Transformation of 26 to 27
(85 O h overall yield) required three steps: mCPBA epoxidation of the enol ether in the presence of H,O leading to a
hydroxy lactol, NaBH, reduction forming a triol, and
NaIO, cleavage of the 1,2-diol system. Compound 27 was
converted into phosphonium salt 3 by conventional methods
via intermediates 2 S 3 2 as summarized in Scheme 3 (77%
overall yield).
Scheme 4 outlines the construction of the key intermediate
4 from D-mannose. This synthesis was based on synthetic
technology for the regio- and stereoselective synthesis of
cyclic ethers from hydroxy epoxides previously described
from these laboratoriesr6]and appliedt7]to the construction
of brevetoxin B intermediates. The highlights of this sequence were the two ring forming reactions 49 -+ 50 (CSA,
80 O h ) and 59 -+ 60 (CSA, 80 O h ) .
+
0570-083319ijO303-0300$3.50 2510
Angew. Chem. Inr. Ed. Engl. 30 (1991) No. 3
D-
33: R = SitBuPh,
mannose
bC
34: R = H
47: X = 0, R = SiEt,
48: X CH,, R = SiEt:,
1 - 4 9 : X = CH2, R = H
d
L
__t
C 51: R
S
"5
I OCH,Ph
P
-
OCH2Ph
P - x.H
RO
H
ee
tBuMe2Si
53: x = 0
54: X = E-CHCOOMe
55: X = E-CHCH20H
= Sit BuMe,
H
I
t BuMe,Si
52
62: R =SitBuMe,
63: R = H
c
E
__t
__t
=H
37: R = COOMe
38: R = CH,OH
39: R = CH,0SitBuPh2
c
RO"'
50: R
'
40: R' = R, = H
41: A' = CH,Ph, R2 H
42: R' = CH2Ph, R2 = SiEt,
43:X=O
44:X =€-CHCOOMe
45: X =€-CHCH,OH
'rn
46
35: x = 0
C 36: X =E-CHCOOMe
-
56
1-
bb
H
H
H
60: X = E-CHCOOMe
cc c 6 1 : X = 0
RO
OHC
H
57: X = 0, R = SitBuMe,
58: X =E-CHCOOMe, R = SitBuMe2
59: X = E-CHCOOMe, R = H
c
H
64: X = 0, R = SitBuMe,
99 L 6 5 : x = (SEt),, R = SitBuMe,
hh
66: X = (SEt),, R = H
H
4
E
Scheme 4. Reagents and conditions: a) see ref. [7]; b) 1.5 equiv of TBAF, TH E 25°C. 2 h, 95%; c) 1.5 equiv of (COCI),, 2.0 equiv of DMSO, 5.0 equiv of Et,N.
CH,CI,, -78'C, 1 h; d) 1.2 equiv of Ph,PCHCOOMe, CH,CI,, 2 S T , 18 h, 90% from 34;e) 2.0 equiv of L-selectride,2.5 equiv of tBuOH, THF, -78°C. 1 h. then
3 equiv of NaOH. 3 equiv of H,O,, 0% 1 h; f) 2.5 equiv of DIBAH, CH,CI,. -78"C, 1 h, 78% from 36; g) 1.1 equiv of lBuPh,SiCl, 3.0 equiv ofimidazole, DMF.
0-25°C. 2 h. 95%; h) 0.1 equiv of CSA, MeOH, 2 5 T , 4 h, 90%; i) 1.04 equiv of nBu,SnO, MeOH, 65°C. 1 h, then 1.2 equiv of CsF, 1.2 eqiv of PhCH,Br, DMF,
25°C. 18 h. 87%: j) 1.2 equiv of Et,SiCI, 2.0 equiv of imidazole, DMF, 2 5 °C 12 h, 96%; k)excess 0,. CH,CI,, -78°C. then 1.5 equiv of Ph,P; I) 1.1 equiv of
Ph,PCHCOOMe, benzene, 25% 12 h, 78% from 42; m) 2.5 equiv of DIBAH, CH,CI,, -78°C 1 h, 96%; n) 0.075 equiv of ( +)-DET, 0.05 equiv ofTi(iOPr),, 1.3
- 2OCC,48h,92%; 0)S.OequivofSO,.py, 5.0equivofEt3N,CH,CI,, DMSO,O"C, 1 h;p) lSequivofPh,PCH,Br,
equiv oftBuOOH.4Rmolecularsieves,CHZCI,,
1.4equivofNaN(TMS),,THF,O0C,
1 h,76YVfrom46;q)1.1equivofTBAETHF, - 20-O"C.3 h,92%,r)0.1 equivofCSA. CH,CI,,O"C,2 h,80%;s) 1.5equiv
of tBuMe,SiCI, 3.0 equiv of imidazole, DMF, 25°C. 12 h, 99%; t ) 2.0 equiv of 9-BBN, THF, 0°C. 2 h, then excess NaOH, excess H,O,, O T , 1 h, 92%; u) 1.5 equiv
(COCI),, 2.0 equiv of DMSO, 5.0 equiv of Et,N, CH,Cl,, -78 "C, 1 h; v) 1.0 equiv of Ph,PCHCOOMe, benzene, 2 5 °C 12 h, 86% from 52, w) 2.5 equiv of DIBAH,
CH,CI,, - 78° C 1 h,96%;x) 0.075equivof( +)-DET,O.O5equivofTi(iOPr),, 1.3equivofrBuOOH,4 .&molecularsieves,CH,CI,, - 20°C. 12 h,92%;y) 5.0equiv
of SO,.py. 5.0 equiv of Et,N, DMSO, CH,Cl,. 0 ° C 2 h; z) 1.5 equiv of Ph,PCHCOOMe, benzene, 2 S T , 12 h, 78% from 56; aa) 1.03 equiv of TBAF, THE 0°C.
3 h, 87%; bb) 0.2 equiv of CSA, CH,Cl,. 0-25"C. 80%; cc) excess 0,, CH,CI,, -78"C, then 1.5 equiv of Ph,P, 25"C, 3 h; dd) 4.0 equiv of NaBH,, MeOH. 0 ° C
96% from 60;ee) 1.5 equiv of iBuMe,SiCI. 3.0 equiv of imidazole, DMF. 0°C. 1 h, 93%; ff) 1.5 equiv of (COCI),, 2.0 equiv of DMSO, 5.0 equiv of Et,N. CH,CI,,
-78"C, 1 h, 93%; gg) 5.0 equiv of EtSH, 3.0 equiv of Zn(OTf),, CH,CI,, 25'C. 5 h; hh) 0.01 equiv of CSA, MeOH, 0 ° C 83% from 64;ii) 4.0 equiv of SO,.py, 4.0
equiv of Et,N, DMSO, CH,CI,, O T , 1 h, 92%.
Scheme 5 outlines the synthesis of the targeted intennediate 2 starting with the coupling of 3 and 4 (nBuLi, HMPA)
to afford predominantly the cis olefin 6718](&:trans ca 3 : 1,
Angen. Chem. In[. Ed. Engl. 30 (1991) No. 3
0 VCH
88 % total yield).fg]Desilylation of both oxygens in 67 followed by selective monosilylation with Hunessiun'sr'ol more
robust and UV-active protecting group gave 69 via diol 68
Verlagsgesellschafi mbH. W-6940 Weinheim. 1991
0S70-0S33f9lf0303-0301$3.50+ .2S/0
301
1
.
OR2
67: R'
= SifBuMe2, R2 = SitBuPh,
R'
69: R'
t
G68:
L
t
H, R2 = H
H, R2 = SitBuPhp
OSif BuPh,
70: X = SEt, R' t R2 = CHPh
71: X = S02Et, R' I R2 = CHPh
72: X = Me, R' = R2 = CHPh
73: X = Me, R' D R2 = H
74: X = Me, R' = H, R2 = COt6u
'
L
L
t 6uCOO
OSif6uPh2
=76:
75: R D H
R D SitBuMe2
(72 % overall from 67). Cyclizationrslof hydroxy dithioketal
69 induced by AgCIO, led to 70 in 87 % yield. Application of
previously described technology[51allowed us to replace the
ethylthio group in 70 with a methyl group with retention of
stereochemistry to give 72 via intermediate 71 (mCPBA oxidation, followed by treatment with AIMe,, 94% overall
yield). The benzylidene protecting group was then removed
by exposure to Zn(OTf),.EtSH followed by selective monopivaloate formation to give sequentially 73 (90%) and 74
(86%). At this juncture the double bond in ring G, which
assisted in its high-yield formation, was to be hydrogenated
to reach the desired goal. To do this it was found necessary
to block temporarily and selectively the double bond of the
F ring, a task that became possible by utilizing the directing
effect of the homoallylic hydroxyl group. Thus, 74 reacted
smoothly with stoichiometric amounts of mCPBA to furnish
epoxide 75" (75 %), which was then protected as the silyl
ether 76 (82 %). Diimide reduction of 76 proceeded smoothly
to afford the saturated system 77 (83 %) and deoxygenation
by the method of Sharpless[''] (WCI,-nBuLi) led to the desired compound 78 in excellent yield (92%). Finally, the
required chain extention and conversion into the phosphonium salt proceeded with standard chemistry and through intermediates 79 (95 %), 80 (83 %), 81 (73 %), and 82 (75 %) to
afford the targeted FGHIJ ring framework 2 (80 % from 82).
Similar chemistry was carried out with intermediates carrying a one-carbon substituent on ring J. An X-ray crystallographic analysis of the crystalline compound 74a (Fig. I),
related to 74 (Scheme 2), was performed[l3I (see ORTEP
drawing, Fig. 1 ) and confirmed the stereochemical assignments shown in all structures.
tBuCOO
t6uCOO
OSitBuPh,
77
74a
OSit BuPh,
m
d?t
L78: R = CH2OOCtBu
79: R t CH2OH
82: R P CH#Ip&
L 2: R = CH2CH2PPh3 1'
Fig. 1. Structural formula and ORTEP drawing of 74a
Scheme 5. Synthesis of 2. Reagents and conditions: a) 0.97 equiv of nBuLi,
T H E -78-0"C, 20min, then4,0equivofHMPA,O,Sequivof4, -78-25°C.
3 h, 88%; b) 3.0 equiv of TBAF, THF, 25°C. 3 h; c) 1.02 equiv of BuPh,SiCI,
3.0 equiv of imidazole, DMF, 0"C, 3 h, 72% from 67; d) 8.0 equiv of AgCIO,,
10 equiv of NaHCO,, 3 8, molecular sieves, silicagel, CH,NO,, 25°C. 3 h.
87%; e) 2.0equiv ofmCPBA, 3.0 equiv ofNaHCO,, CH,CI,, 0°C; f) 3.0equiv
of AIMe,, CH,CI,. -78"C, 30 min, 94% from 70; g) 5.0 equiv of EtSH, 10
equiv of NaHCO,. 3.0 equiv of Zn(OTf),, CH,CI,, 25°C. 5 h, 90%; h) 1.05
equiv of (CH,),CCOCI, py, O'C, 12 h, 86%; i) 1.0 equiv of mCPBA, CH,CI,,
0 ° C 3 h, 75%; j) lSequivoffBuMe,SiOTf, 3.0equivof2,6-lutidine, CH,CI,,
O T , 20 min, 82%; k) 10 equiv of KO,CN = NCO,K, 20 equiv of HOAc, py.
O'C. 18 h, 83%; I) 1Oequiv of WCI,, 20 equiv ofn-BuLi, THF, - 78-25"6,4 h,
92%; m) 3.0 equiv of DIBAH, CH,CI,, - 7 8 ° C 20 min, 95%; n) 5.0 equiv of
SO,.py, 5.0 equiv of Et,N, DMSO, CH,CI,, 0 ° C 2 h , then 3.0 equiv of
Ph,PCH,Br, 2.0 equiv of NaN(TMS),, THF, 0°C. 1 h, 83 %; 0) 1.2 equiv of
9-BBN, THF, 0% 2 h, then excess NaOH, excess H,O,, O"C, 1 h. 73 %; p) 2.0
equiv ofCH,SO,Cl, 5.0 equiv of Et,N, CH,CI,, 0°C. 20 min. then 10 equiv of
Nal, acetone, S O T , 12 h, 75%; q) 10 equiv of PPh,, CH,CN, 60°C 24 h.
80%.
302
0 VCH
Verlagsgesellschurft mbH, W-6940 Weinheim, 1991
The described chemistry provides practical and efficient
access to the advanced intermediate 2 and related compounds representing the FGHIJ ring assembly of brevetoxin
A (1). The complexity of the systems and the high yields in
which they are obtained demonstrates the power of new
synthetic technology and strategies developed in this program for the construction of complex polycyclic frameworks
containing medium-size cyclic ethers. Studies towards the
total synthesis of brevetoxin A (1) are continuing.
0S?0-0833/91/0303-0302$3.50+ .25/0
Received: October 4, 1990 [Z 4226 IE]
German version: Angew. Chem. 103 (1990) 304
Angew. Chem. Int. Ed. Engl. 30 (1991) No. 3
[l] K. C. Nicolaou, D. G. McGarry, P. K. Sommers, J. Am. Chem. Soc. 112
(1 990) 3696.
[21 K. C. Nicolaou. C. V. C . Prasad, W. W. Ogilvie, J. Am. Chem. Soc. 112
(1990) 4998.
[3] Y. Shimizu, H. N. Chou, H. Bando, G. Van Duyne, J. Clardy, J. Am. Chem.
SOC.108 (1986) 514. See also: M. Pawlak, M. S. Tempesta, J. Golik, M. G .
Zagorski. M. S . Lee, K. Nakanishi, T. Iwashita, M. L. Gross, K. B. Tomer,
J. Am. Chem. Soc. 109 (1987) 1144.
141 K. C . Nicolaou, C.-K. Hwang, B. E. Marron, S . A. DeFrees, E. A. Couladouros, Y. Abe, P. J. Carroll, J. P. Snyder, J Am. Chem. Soc. 112 (1990)
3040.
151 K. C. Nicolaou, M. E. Duggan, C.-K. Hwang, J. Am. Chem. Soc. 108
(1986) 2468.
[6] K . C. Nicolaou, C. V. C. Prasad, P. K. Somers, C.-K. Hwang, J. Am.
Chem. SO<.111 (1989) 5330.
[7] K. C. Nicolaou, C.-K. Hwang, M. E. Duggan, J. Am. Chem. Soc. 111
(1989) 6682.
[8] All new compounds exhibited satisfactory. spectral
and analytical. and/or
_
exact mass data. Yields refer to spectroscopically and chromatographically homogeneous materials. Selected physical properties of compounds 67.
72. and 82: 67: oil; R, = 0.5 (20% ether in petroleum ether); IR (neat)
= 3080, 3040, 2980, 2940, 2880, 1480, 1440, 1260, 1100, 840, 710,
680cm-';'H NMR (500 MHz. CDCI,) 6 =7.7-7.2 (m, 20H, aromatic),
5.7-5.9 (m. 4H. olefinic), 5.39 (s. 1 H, benzylic), 4.72 (d, J = 12.5Hz, 1 H,
benzylic). 4.58 (d. J = 12.6 Hz, 1 H, benzylic), 4.33 (d, J = 8.3 Hz, 1 H,
Intermediates in Nitrogenase Models:
N,H, and N,H, as q2-CoordinatedLigands **
By Sabine Vogel. Annette Barth, Gotffried Huttner,*
Thomas Klein, Laszlo Zsolnai, and Reinhard Kremer
Dedicated to Professor Dieter Sellmann
on the occasion of his 50th brithday
Dinitrogen ligands of the type N,H, are important intermediates in all models which attempt to explain the activity
of nitrogenase.['] The hydrazido(1-) ligand, N2H,e, plays a
key role. Only in one case recently was it possible to stabilize
this ligand on a organometallic complex fragment.['] Organo(m 2 1) of the parent compound
derivatives R,N,H(,-,,
N2H,, however, have been known as ligands for some
time.I3l We report here the synthesis and properties of
[(tripod)Co(q2-N,H,)]@ (tripod = CH,C(CH,PPh,),), 1, the
first non-organometallic N,H, complex. The protonation of
1 led to [(tripod)Co(q2-N,H4)]'@,2. The q2-coordinationof
the N2H4ligand, which is as important in the interpretation
of nitrogenase activity, could be proven for the first time by
CHO).4.13im,2H.CHO),3.95-3.6(m,8H,CHO),3.55(t,J=10.4Hz.the X-ray structure analysis of this complex.
1 H. CHO). 3.41 (m.I H, CHO). 3.15 (m, 2H, CHO), 2.88 (dd. J = 6.0.
In the presence of tripod, [Co(BF,), .6H,O] reacted with
4.2 Hz. 1 H, CH,), 2.78 (m, 1H, CH,), 2.67 (m, 4H, CH,), 2.48 (m, 2H,
N2H4aq to cation 1 (Fig. I), which precipitated as the dark
CH,). 2.26 (m. 2H. CH,), 2.01 (m. 1 H, CH,), 1.87 (m, 2H. CH,), 1.74(t,
green, air-sensitive BPh, salt. The analytically pure, crysJ = 12.7 Hz. 1H. CH,). 1.7 (series of multiplets, 4H, CH,), 1.31 (t,
J = 7 . 1 Hz. 3H, CH,), 1.25 (t, J = 7 . 1 Hz, 3H, CH,), 1.10 (s, 9H, fBu),
talline salt l-(BPh,). 2THF has a magnetic moment of
0.89 ( s . 9 H , IBu), 0.08 (s, 3H, CH,Si), 0.04 (s, 3H, CH,Si); MS: mi;
1.8 lB,
corresponding to a low spin d 7 configuration at C O ~ ~ .
(intensity) 1135 (24), 1106 (64), 1074 (100). 942 (33), 662 (90); HRMS
Figure 1 shows the results of the X-ray structure analysis of
Calcd forC6,H,,0,S,Si,: ( M + H)@:1135.564, found: 1135.560. 72: oil;
this salt.
R, = 0.35 (30% ether in petroleum ether); [ E ] ~+ 186" (c = 0.34, CDCI,);
IR (neat)<,,, = 3090.3040,2950,2885.1600,1460,1430.1400,1105,1070,
The coordination geometry of cobalt lies between the two
940.740.710cm-'; 'H NMR(500 MHz,CDC1,)6 =7.91-7.22(m,20H,
extremes of square pyramid and trigonal bipyramid. The
aromatic), 5.83 (dd, J = 10.0. 6.6Hz, I H , olefinic). 5.77 (dd, J = 10.9,
best description of the geometry of 1 is as an ideal tetrahe6.2 Hz. 1 H. olefinic), 5.69 (m. 2H, olefinic), 5.41 (s, 1 H, benzylic), 4.72 (d.
dron around the cobalt atom, where the N,H, unit, as a
J=12.6Hz,1H,benzylic),4.61(d,J=12.6Hz,lH,benzylic),4.36(t,
J =7.4 Hz, 1 H , CHO), 4.17 (dd, J = 9.4, 3.8 Hz, 1 H, CHO), 4.00 (d.
whole, occupies one tetrahedral site.[41
J = 5.7 Hz. 1 H, CHO), 3.90 (m, 1 H. CHO), 3.86 (dt, J = 10.6, 4.4 Hz,
The only moderate quality of the crystals[51did not permit
1H,CHO),3.80(dd,J=9.3,4.4Hz,1H,CHO),3.76(t,J=8.4Hz,1H,
the
crystallographic location of the hydrogen atoms attached
CHO). 3.70-3.58 (series of multiplets, 5H, CHO), 3.18 (m. l H , CHO).
to nitrogen. The identification of the ligand as an N,H, unit
3.15(dd,J=9.6,2.5Hz,1H,CHO),3.06(m,1H,CHO),2.74(m,2H.
is, however, unambiguous: in the IR spectrum three NH
CH,CH=CH), 2.37 (dd.J= 14.2, 7.0 Hz, IH,CH,),2.25 (m, 3H. CH,),
2.11 (dd, J = 12.0, 4.3 Hz, l H , CH,), 1.88 (bs, 2H, CH,), 1.71 (t,
stretching frequencies are observed (d = 3290, 3217,
J = 11.9 Hz. 1 H, CH,), 1.61 (m, 3H, CH,), 1.44 (dd, J = 11.3, 11.3 Hz,
3130 cm-') as expected for N,H,; these bands do not ap1H. CH,). 1.21 (s, 3H, CH,), 1.04 (s, 9H, IBu); I3C NMR (125 MHz,
pear
when deuterated reagents are used for the synthesis.
CDCI,) 139.23, 138.76, 137.66, L35.52, 134.06, 131.83, 129.46, 128.91,
The magnetism of 1 mentioned above corresponds to one
128.91, 128.23. 128.17, 128.09, 127.55, 127.11, 127.06, 126.14, 124.10,
101.61, 85.92, 82.30, 82.14, 81.04, 77.67, 77.58, 76.84, 72.99, 72.33, 72.39,
unpaired electron per cobalt atom. This only allows the for72.26. 70.30. 69.76, 63.73, 62.65, 44.57, 35.70, 32.98, 32.64, 30.24, 29.85,
mulation of 1 as [(tripod)Co(N,H,)]@, where x = 2n + 1 .
28.69, 26.86. 19.20, 16.80; MS m/z (intensity) 913 ( M + H, 40), 856 (55),
Furthermore, the structure of 1 points to the existence of the
808 (52). 748 (loo), 688 (49), 627 (45), 464 (62); HRMS Calcd for
N2H, unit: the N-N distance of 138.4(14)pm lies in the
( M + H)@: 913.471, found: 913.469; Anal. Calcd for
C,,H,,O,Si:
C , 73.68; H, 7.45, found: C , 73.88; H, 7.63. 82: oil;
C,,H,,O,Si:
range observed for the N-N bond lengths of q2-organoR , = 0.6 (30% ether in petroleum ether); [ E ] +
~ 108" (c = 0.19, CHCI,);
hydrazido ligands in R,N,H(, - ,,,,.I3]
IR (neat) tmSx
3080, 3040, 2940, 2880, 1600, 1440, 1390, 1100, 840,
Similarly the different Co-N distances (Fig. 1 ) reflect the
710cm-I; 'H NMR (500MHz, CDCI,) 6=7.66-7.22 (m, 15H,
familiar pattern[31 of the q'-coordinated R,,,N,Ho ),- liaromatic), 5.71 (dd, J = 10.8, 5.4 Hz, 1 H, olefinic), 5.62 (m, 1 H, olefinic),
4.71 (d. J = 12.6 Hz, 1 H, benzylic). 4.61 (d, J = 12.6 Hz, 1H, benzylic,
gands. The shorter metal-N distance agrees with those for
4.46 (m. 1 H. CHO), 3.90 (d, J = 2.7Hz, 1 H, CHO), 3.86 (dt,
the nitrogen atoms which carry only one substituent (H or
J = 10.4, 4.7Hz. 1 H, CHO), 3.79 (dd, J = 9.4, 4.1 Hz, 1 H, CHO), 3.72
R).[,' The same pattern is also observed for [(tripod)Co(q2(m, 1 H. CHO), 3.68 (t, J = 6.0 Hz, 2H, CH,OSi), 3.56 (m, 1 H, CHO),
NHNMe,][BPh,] . 1.5THF: Co-NNMe2= 205(2), Co-N,, =
3.31 (m. 3H,CH0,CHz),3.15(m, 3H,CHO,CH,), 3.05(m, l H , CHO),
196(2) pm.I7l
2.68(m. 1 H,CH,CH=CH), 2.4-1.4(seriesofmultiplets, 19H,CH,), 1.21
<,Ax
(s, 3H. CH,). 1.04 (s, 9H, tBuSi), 0.89(s, 9H, tBuSi),0.09 (s, 3H, CH,Si),
0.04 (s. 3H. CH,Si); MS m/r (intensity) 1065 ( M + H, 5). 809 (7), 199
(100); HRMS Calcd for C,,H,,O,Si,I:
( M + H)": 1065.459, found
1065.463.
This mixture was taken through the next two steps, at which point the cis
isomer 69 was separated chromatographically.
a) S . Hanessian, P. Lavallee, Can. J. Chem. 53 (1975) 2975. b) S . Hanessian. P. Lavallee, Cun. J. Chem. 55 (1977) 562.
The structure of thisepoxide was tentatively assigned on the basis of NMR
studies.
K. B. Sharpless, M. A. Umbreit, M. T. Nieh, T. C . Flood, J. Am. Chem.
Soc. 94 (1972) 6538.
This X-ray crystallographic analysis was carried out by Dr. Patrick
C a r r d of the University of Pennsylvania. Details are published elsewhere.
Angew. Chem. hi.Ed. Engl. 30 (1991) No. 3
0 VCH
[*] Prof. Dr. G. Huttner, Dipl.-Chem. S. Vogel, Dipl.-Chem. A. Barth,
Dipl.-Chem. T. Klein, Dr. L. Zsolnai
Anorganisch-chemisches Institut der Universitat
Im Neuenheimer Feld 270, W-6900 Heidelberg (FRG)
Dr. R. Kremer ['I
Max-Planck-Institut fur Festkorperforschung
Heisenbergstrasse 1, W-7000 Stuttgart 80 (FRG)
['I Magnetic measurements
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
Verlugsgesellschufi mbH. W-6940 Weinheim, 1991
0570-0833/91/0303-0303S 3.50
+ .25/0
303
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