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Nonclassical Stabilization of Planar Allenes Low Rotational Barriers for Allene Double Bonds.

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R. A . Hougliten. C. Pinilla. S E . Bloiidelle. J. R. Appel. C. T. Dooley, J. H.
Cuervo ,Yufure. 1991.354.84-86. For other trypsin assays. see: B. F. Erlanger,
N.Kokowsky. W. Cohen. A w h . Biochefii. B I O I / J ~1961,
L . S . 95. 271 -278. H . F.
Gaertner. A. J. Puigserver. Ei?:j,inr M i c r o h . T ~ i ~ h n n1992,
l.
14, 150 155.
[7] T. Carell, J. Rebek. Jr.. unpublished results.
[ 8 ] M. Laskobcski. Jr., 1. Kato. Afin. Rcr. Bioclirw?. 1980. 49, 593-626.
191 Both compounds w,ere fully characterized. A detailed description of their synthesis and chnracteri.Gdtion will be described elsewhere. Compound 3 *as reacted first with :%"-Boc-Lys-OMe and Ile-OiBu (at poaitions 4 and 5 ) . and the
compound in which A ' = Lys and A' = Ile was isolated through chromdtography. Subsequent debenzylation and reaction o f the rewlting dicdrboxylic
acid b i i t h Pro-OtBu and Val-OrBu (at positions 2 and 7) gave four compounds
from ahich the two isomers ( A ' = Lys. A2 = Ile. B1 = Val. B' = Pro and
A ' = Lys. A' = Ile. Bl = Pro. BZ = Val) wcre obtained inditwdually by chromatography. Deprotection with trilluoroacetic acid and purification by recersed-phase preparative HPLC gave 4 and 5 as white powders. All analytical
data (NMR, COSY. NOE, MS) are 111 agreement w i t h the proposed structures.
lnitial experiments indicate that 4 i, a specific trypsin inhibitor: 4 does not
inhibit the activity o f thrombin. a related serine prolease. to any noticeable
extent.
I
;
o-n
Nonclassical Stabilization of Planar Allenes: Low
Rotational Barriers for Allene Double Bonds**
Dirk Steiner, Heinz-Jurgen Winkler, Sigrid Woeadlo,
Stefan Fau, Werner Massa, Gernot Frenking,
and Armin Berndt*
According to MP2i4-31G calculations of Schleyer et al.,r'l the
orthogonal allene I, is 11.6 kcalinol-' higher in energy than the
planar allene 1 , ,which is misleadingly described by the classical
formula 1;. Polarization of the C-C double bonds adjacent to
the boron atoms leads to the stabilization of the negative charge
in the 2x-electron arene diboriranide"' (resonance structure 1:).
The positive charge of the formal vinyl cation can, however.
only be stabilized through C-B hyperconjugation with the
strained C-B o bond^^"^^ of the three-membered ring after
I
2p
I
2,
2;;
rotation around the polarized double bond. Optimum stabilization is achieved in planar 1;. These nonclassical interactions in 1,
are adequately described by 3c-2e bonds.I2] We report here on
the classical orthogonal allenes 2,, which are related to 1 and
have remarkably low barriers to rotation around C-C double
bonds. This can be explained by the formation of planar, nonclassical allenes 2, in the transition state, which are stabilized as
described above; the 2x-electron arene diboriranide in 1 has
now been replaced by the 2x-electron arene homodiboriranide14] in 2.
Dur
I
-
H
H
- 2ooc
3
.)
Me,Sn-CGC-Ar
a
a
Dur
H
'b
;
I
H'
lBuLi
0-n
H
1;
\
H
1P
\H
[*] Prof. Dr. A. Berndt. Dipl.-Cheni. D. Steiner. DipLChem. H:J.
S. WoEadlo. S. Fau. Prof. Dr. W Massa. Prol. Dr. G . Frenking
R = CH,
Winkler,
H3C
I**]
8-Dur
c ~ ' P'CH Vcrlu,o~~~~s't~ll.vr/ioft
inhH. 0.69451 IViZiihPvn, 19Y4
\8-Dur
H,C-I
C
,H3
This work was supported by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischeii Industne.
2064
H,C-Li
H3C
\
Fachbereich Chemie der Universitit
D-35032 Marburg (FRG)
Telefax. Int. code +(6421) 28 89 17
1
9
/
DM
W
'
Ar
(
0570-0(333:94:_7020-2064
X /U.OO+ .25$
Dur
Angciv. Chem. In!. E d Engl. 1994. 33. No. 26
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The methyleneborane 3 (Dur = 2,3,5,6-tetramethylphenyl,
Ar = 3.5-di-tevt-b~tylphenyl)[~]
added to alkyne 4 at -20 "C to
forrn 5. which isomerized at - 10 "C to 6.j5]Rearrangement of 6
at 25 . C gave the allene 2 a . The aryl group, which was linked to
an allene C atom in 6, is now bound to the C atom between both
B atoms in 2a. The allene 2a could be transformed by tinjlithium
exchange with tBuLi to the lithium compound 7. which gave the
allenes 2 b and 2c on treatment with chlorotrimethylsilane
(X = Cl) and methyl iodide (X = I), respectively. The 1.1-diborylallene 9 was prepared for the purpose of comparison from 2c
via 8 by treatment with methyllithium and then methyl iodide.
The structures of 2a-c, 5, 6, and 9 were deduced from their
NMR spectra (Table 1); those o f 2 a and 2c were confirmed by
crystal structure analysis (Fig. 1 , Table 2)
The signal at 6 = 85 in the "B NMR spectrum of 9 lies in the
region associated with boron atoms that are not in conjugation
Table 1. Selected physical data for compounds 2 a - c . 5. 6. and 9
o c 4 3
LJl
bC27
C61
2a: yellow crystals. m.p. 128'C. yield 60%. - ' H N M R (500MHz, [DJtoluene,
-40 C): d = 0.15. 0.34 ( 2 x br.s. 2 x 9 H . Si(CH,),). 0.35 (br.s* 9 H . Sn(CH,),),
1 . 1 4 ( s , I X H . C ( C H , ) , ) . 2 . 0 6 . 2 . 1 8 . 2 . 2 6 . 2 . 5 2 ( 4 ~s . 4 x bH.o-andni-CH,).6.83
(s. 2 H . p H ( D u r ) ) . 7.16 (d. 2 H . o-H(Ar)). 7.19 (t. 1 H . p-H(Ar)j; " C N M R
(75 MHr. CDCI,. 25 C): 6 = - 3.5 (q. 3C. Sn(CH,),), 0.7. 1.4 ( 2 x br.q. 2 x 3C.
Si(CH,),). 1 9 4 , 19.5. 19.6, 20.4 ( 4 x q, 4 x 2C. o- and n - C H J , 31.1 (4. 6 C ,
C(CHl)3).14.3 (s. 2C. C(CH,),). 70.1 (s. 1 C. CSi?). 81.1 (s, 1 C. sp3.CB2), 92.2 (s.
1 C. sp'-CB,). 117.3 (d. 1 C . p-C(Ar)). 122.9 (d, 2 C , o-C(Ar)), 130.7 (d. 2C. p c43
U D u r ) ) . 132.6.11?.8.133.6.133.8(4~s , 4 x 2C.o-andf,i-C(Dur)), 141.6(s.lC.
r-C(Ar)). 142.7 (hr.s. 2 C , i-C(Dur)). 149.1 (s. 2C. nr-C(Ar)j. 199.7 (s. 1 C.
C=C=CI. " B N M R ( 9 6 ~C ~D C~ I ., . ~c):
~ 6 = 63.
Zb: yellow crystals. m.p. 1 3 7 ' T . yield 81 %.
'H NMR (500MHz. CDCI,,
-40 C ) . d = - 0.23. 0.38 ( 2 x s, 2 x 9 H , sp'-CSi(CH,),). 0.06 (s, 9 H . sp3CSi(CH,),). 1.04 (s. 18H. C(CH,),). 1.74, 2.06, 2.25. 2.41 ( 4 x s, 4 x 6H. 0- and
n-CH.,).
6 75 (d. ? H . o-H(Ar)j. 6.89 (m, 3H,p-H(Ar) andp-H(Dur)j; 13CNMR
(I00MH7. C'DCI,. -30
d = 0 . 6 . 1 . 5 ( 2 ~q . 2 x 3C.spz-CS~(CH,),),2.4(q,
bC27
3 C . s ~ ~ - C S I ( C . H , 19.8,
) ~ ) . 20.0. 21.2 (3 x q. total 8C. O- and m-CH,). 31.0 (4. 6 C ,
C(CH,j,). 14.3 (s. ? C . C'(CH,j,). 70.2 ( 5 . 1C, CSi,). 77.6 (s. 1 C. sp'-CB,). 96.5
Fig.
1
.
Crystal
structures
of
2a
(top) and 2c (bottom)
(br.s. I C. \p'-CB,), 116.6 (d. 1 C. p-C(Ar)), 124.3 (d, 2C. o-C(Ar)), 130.5 (d. 2C.
p-C(Dur)). 132.7,132.9. 1 3 3 . 6 , 1 3 3 . 8 ( 4 ~s . 4 x 2C,o-andrri-C(Dur)).142.4(s,lC.
i-C(Ar)). 142.9 (s. 2 C . i-C(Dur)), 148.0 (s. 2C. m-C(Ar)). 198.4 (s. 1 C. C=C=C);
" B N M R (96 MHz. CDCI,. 25 C): 6 = 67.
Table 2. Important distances [pm] and angles [ ] in the crystal structures o f 2 a and
2c.
2 c : yellow crystals, m p. 157 C . yield 63%.
' H N M R (400MHz. CD,CI,.
- 100 C) ij = 0.04. 0.26 (2 x s. 2 x 9 H , SI(CH,),). 1.04 (s, 38H. C(CH,),), 1.29
2a
2c
2a
2c [a]
(~.3H.B,C'CH,).1.75,2.11,2.25,?.40(4~
s,4x 6H.o-andm-CH,).6.84(~.2H.
p-H(Dur)). 6.91 (d. 7 H . o-H(Ar)). 7.03 (t. 1 H, p-H(Arj). ' , C N M R (75 MHz,
CDCI,. 25 'C). 6 = l . l (6C. Si(CH,j,j, 19.5. 19.9 (8C, o- and m-CH,), 31.2 (6C.
C1-BI
156.3(10)
160.2(12)
B1-Cl-Sn
105.3(4)
107.2(7)
c(cH,),).Y 7(1~.~,~~~,),34.5(2~.~(~~,),),52.9(1~,~~'-~~,),70.7(1~.
Cl-B2
156.9(10)
162.8(12)
B2-C1-Sn
104.5(4j
110.3(7)
CSi,), 97 4 (1 C. sp'-CB,). 117.7 (1 C, p-C(Ar)). 122.6 ( 2 C . o-C(Ar)), 130.7 (2C.
C2-B1
157.8(10)
151.7(13)
Sn-Cl-C30
100.4(4)
108 8(7j
p-C(Dur)). 133.8.133.4 ( 2 x 4C. o- and m-C(Dur)), 143.4 ( 2 C . r-C(Dur)), 147.3
C2-B2
155.9(10)
153.1(12)
Cl-BI-BZ-C2 159.7(4)
157 3 9 )
( l C , i-C(Ar)), 149.8 ( 2 C . m-C(Ar)). 200.0 (1C. C=C=C); "BNMR (96MHr.
B1-B2
208.5(12)
211.1(14)
CDCI,. 25 Cj. 6 =74.
C2-C3
131.6(30)
136 3(11)
~ 3 . ~ 4 i31.3(10)
13i.x(ii)
5 : " C N M R (125 MHr. CDCI,, -40 C): 6 = - 9.9 (3C. Sn(CH,),), 2.6, 2.3 (je
3C, Si(CH,),). 28.7 (1C. CSi,), 55.7 ('J(Sn,I3C) = 62.8 Hz, l C , CB,). 167.8
[a] C 5 instead of Sn.
(lJ(Sn.''C) = 183.6 Hr. 1 C. C=CSn(CH,),), 179.6 (1 C, C'=CSn(CH,j,j; the other signals could no1 be assigned due to the overlap with signals from the starting
material and product 6 .
~
~
6 ' , C N M R ( 1 0 0 MHr.CDC1,. -20'C).6 = - 6.1 (q,3C,Sn(CH,j,),0.4(q,6C,
with TI donors: due to mutual steric hindrance, the boryl subSi(CH,),). 19.5. 19.7. 20.7. 21.0 ( 4 x q, 4 x 2 C , o- and m-CH,). 31.1 (4, 6C.
stituents are twisted in such a way that the empty p orbitals of
C(CH,),). 34 4 (s. 2 C . C'(CH,),). 78.0 (br.s, 'J(Sn,13C = 46.5 Hz. 1 C. CB,), 78.9
(5. lC.CS1~1.99.1(s. l C . C = C B ) . 119.4(d, IC,p-C(Ar)),123.4(d,2C,o-C(Ar)), the boron atoms cannot interact with the TI electrons of the
allene. The signal at 6 =74 in the IlB N M R spectrum of 2c
12X.9 (br.s. I C'. i-C(Dur)). 128.8 (d. 1 C,p-C(Dur)). 132.1. 132.3. 133.0 (3 x s. total
of XC. u- and n-C(Dur)). 135.8 (d. 1 C.p-C(Durj). 141.6 (s. 1 C. i-C(Ar)). 142.9 (d.
indicates TI delocalization as shown in 2b;this is also reflected in
2C. o-C(Dur1). 148.3 (br.s. 1C. r-C(Dur)). 149.1 (s. 2 C , m-C(Ar)), 211.5 (s. 1 C.
the
relatively long C2-C3 bond and in the shortened C2-B1
C=C=C)
and C2-B2 bonds with respect to 2a (see Table 2). The TI delo-
9 - yellow crystal\. m.p. 179-C. yield 7 3 % . 'H N M R (300 MHr. CDCI,, 25 C):
calization corresponding to 26 is less important in 2a because
h = 0 . 2 5 ( ~ 18H.Si(CH,),).0.91
.
( s , 3 H . H,CBj. 1.12(s. lXH.C(CH,),). 1.55, 1.77.
1 79. 1.97 (4 x 8 . total 30H. CH,(Dur) and ArC(CH,),). 6.38, 6.55 (2 x s. 2 x 1 H.
C - Sn hyperconjugation reduces the electron deficiency at the
p-H(Dur)l. 6.82 (d. 2H. o-H(Ar)). 6.94 (t, 1 H, y-H(Arj): "CNMR (75 MHz,
boron atoms. This results in a long C1 -Sn bond (224 compared
CDCI,.25 Cl:d=1.2(q.6C.Si(CH,),),13.9(q,1C,H,CB),18.8,18.9.19.6.21.1
with 212-214 pm for the Sn-CH, bonds), small B-C-Sn and
( 4 x q. 4 x 3C.o- and ns-CH,), 28.1 (4, 2C. ArC(CH,),). 31.3 (q. 6 C . C(CH,),j,
Sn-C-C(ary1) angles, short C1-B1 and CI-B2 bonds, and
34.6 (s. 2 C . C'(CH3)3).40.1 (5. 1 C. ArC(CH,j,). 72.6 (s. 1 C. CSi,). 91.2 (br.s. 1 C.
CB,). 118.1 (d. 1 C. ,f-C(Ar)),121.5 (d. 2 C , o-C(Ar)), 129.3. 129.4 (2 x d, 2 x 1 C.
shielding of the boron atoms (6("B) = 63). The geminal
p-C(Dur)). 130.3.130.8.131.7.132.0(4~ s.4x 2C.o-andm-C(Dur)).147.7(~.2C. triniethylsilyl groups in 2a-c give rise to two signals in the
ni-C(Ar)). 147 8. 149.3 (2 x brs. 2 x 1 C. i-C(Dur)). 149.8 (s, 1 C. ;-C(Arj), 212.6 (s,
'H NMR spectrum only below 300,263, and 173 K, respective1 C, C=C=C). " B N M R (96MHz. CDCI,. 2 5 ° C ) : 6 = 85.
~
ly. These signals broaden at higher temperatures and coalesce at
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315, 273. and 183 K, respectively. The activation energies for
exchange were calculated to be 14.5 (2a). 12.6 (Zb), and 8.6
(2 c) kcal mol ' , as determined by the temperature of coalescence and the difference in the chemical shifts at slow exchange.
The low barriers (rotation around the C-C double bond of
an allene usually requires 46-47 kcalmol-t[71)and their dependence on the substituent at C1 can be explained when one assumes that exchange takes place by rotation around the C-CB,
bond. The transition-state conformations are therefore planar
allenes 2,. Their negative charge is stabilized by n-x delocalization towards homodiboriranides 2b, and their positive charge
through ~ - delocalization
x
of the C(sp2)-B o bonds of the
homodiboriranide rings as shown in 2,. The Me,Sn and Me+
substituents in 2a and 2b lower the electron deficiency of the
boron atoms through C-Sn and C-Si hyperconjugation. The x
delocalization as shown in 2bas well as the subsequent 0 delocalization as shown in 2, are therefore less important. The energies of the transition-state conformations of 2a and 2b are thus
higher than that of 2 c .
Our explanation for the low exchange barriers is supported by
MP2/6-31G* calculations[*' for the model allene 2u: The nonclassical planar allene 2u, is only 6.2 kcalmol-' (MP2/631G* + ZPELsl)higher in energy than the classical orthogonal
H
I
2u.a
I
H
*UP
H
2u,. This difference in energy is consistent with the exchange
barrier of 8.6 kcalmol-' determined for 2c. The strong homoaromatic x delocalization in the transition state 2 up is reflected
in a short calculated B . . . B distance of 185.7 pm (2u,:
198.2 pm);["l the strong C-B hyperconjugation results in a
short bond length for the polarized C-CB, bond (130.9 pm).
which is even shorter than the weakly polarized C-CB, bond of
2u, (132.0 pm). Similarly, a very short B-B bond (147.2 p m ;
158.7 pm in 1,) and a slightly shorter C-CB2 bond (129.7 pm:
130.9 pm in 1,) have been calculated for 1,.['] The influence of'
the silyl substituents on the rotational barrier is low: the energy
difference between the orthogonal and planar forms of allene 2 u
without silyl groups is 9.1 kcalmol-I (MP2/6-31G* + ZPE"]).
The energy difference between the orthogonal and planar
allenes is approximately 37 kcalmol- less for 2c than for alkylsubstituted allenes (46-47 kcalmol-'['I). Replacement of the
homoaromaticity in 2 by the aromaticity in the diboriranide 1
should further stabilize the planar form and give rise to allenes
with planar ground states. However, calculations at the MP21
6-31 G* level show that the structure 1, is not a minimum on the
potential hypersurface. The Hesse matrix has a negative eigenvalue, which indicates that 1, is a transition state. A geometrical
optimization without symmetry constraints gives the minimum
energy structure 10. which is 23.7 kcalmol-' more stable than
1, at the MP2/6-31G* level.
Thus, planar allenes are just as unlikely to be prepared by this
route as the analogous orthogonal alkenes with the basic unit
H
1,
\
10
H
H
I
11
\
3u
H
11. The latter is 25.6 kcalmol-' (MP2/6-31G*) higher in energy
than the corresponding methyleneborane 3 u . [ ~ .'1
'
Received: May 27, I994 [Z 6975 IE]
German version: A N , ~ C L~I h. l v I 7 .1994. 106, 2172
[l] K. Krogh-Jespersen. D. Cremer. 0 . Poppinger, J. A. Pople. P. von R. Schleyer.
.I.
Chandrasekhar, J AN?. Chein. Sor. 1979. 101. 4843-4851. According to
MP?:6-31G* calculations. 1, is 16.1 kcalrnol-l more stable than 1,. which is
a transition state (i=1) at the MP2:6-31G* level.
[2] A. Berndt. AirgL,w Cl7em 1993. 103, 1034-1058: An,yew. Chrm. I n f . Ed. Enx/.
1993.32,985-1009: R. wehrmann. H. Meyer. A. Berndt. ibid. 1985. 97, 7797x1 and 1985. 25. 7x8-790.
[3] A. Hofner. B. Ziegler. W. Massa, A. Berndt, Angew. C'/7w. 1989, 101. 1x8190: .4ngru~.Chem. Ini. Ed. Enngl. 1989, 28. 186-187.
[4] P. Willershausen. C. Kybart, N. Stamatis, W. Massa. M . Buhl. P. von R.
Schleyer, A . Beriidt. An,Trw. Cliiwi. 1992. 104. 127X-12XO: . 4 n g w . Chen?. I i i i .
€0. E17g/. 1992. 31. 1238- 1240.
[5] The structure of 6 (Me,% group linked to the carbon atom adjacent to the
dicoordinated boron atom) follows clearly from the small ' ' C , "'Sn coupling
constant of 46.5 Hr and the shielding of the C atom in the C - B double bond
(d("C) = 78). which IS characteristic of stannylmethyleneboranes (the correipoiiding compound with M e & instead of the aryl group shows values of
ii("C) =75.3 and '/("C. ""Sn) = 66 Hz 121.
[6] Crqstal structure analysis: yello~.crystals of Z a . 0.5 { I - C ~ Hand
, ~ Zc were
measured on a four-circle diffractometer (CAD4 Enraf-Nonius) at - 80 "C and
at room temperature (2c) with Cu,, radiation ( 2 =154.178 pm). 2 a :
C,-H,,B,Si,Sn
0.5 C,H,,. crystal diinenGona 0.3 x 0.25 x 0.2 mm3. monoclinic, space group P2,:n. 2 = 4. u =1326.5(1). h = 947.4(1). ( ' =
4207.0(4)pm, [1=91.99(1). V = 5283.9x10-"'mm3. priird=1.104gcm-';
7220 measured reflections up to 20 = 1 1 0 ( ( o scans). of which 6609 were independent. 4877 reflections uith f, > b(4,).after Lorentr and polarization
correction. here used for further calculations, no absorption correction
( 1 1 = 4.479 mm-'1. The structure was solved with direct methods and rcfined
wilh full matrix against the 6)
data. The H atoms were included in the calculation riding on their bonding partners. partially oncalculated positions and with
common isotropic temperature factor, refined in groups. For the rest of the
atoms. anisotropic temperature factors were used. R = 0.062. W R = 0.040
( M = 1 ''u'(f0)). maximum residual electron density 0.66 e k ' .
2c:
C,,H,,B,SiI. crystal dimensions 0.4 x 0.3 x 0.15 inm. monoclinic. space group
P2,;n. Z = 4, u = 1399.3(3). h = 2001 6(4). L' = 1666.7(3) pm, [j = 95.80(3)
V = 4644.0 x 10.'" m'. pLrlCd
= 0.9X2 gcm-'; 4353 measured reflections up to
20 = 94 ( ( ( 1 scans). of which 4166 were independent. 4165 rellections, after
Lorentz and polarization correction. were used for further calculations: the
structure was solved and refined as for Za. The refinement against the f: data
(SHELXL-93)was complicated by disorder in the ti,rr-butyl groups at C32 and
C34: a "split atom model" description led to a w R 2 = 0.225. Corresponding t o
a conventional R = 0.076 for 1759 reflections with I > ?a(/). and a iimximum
residual electron density of 0.27 c A'. Further details of the crystal structure investigation may be obtained from the Fachinformationszentrum
Karlsruhe, D-76344 Eggenstein-Leopoldshafen. on quoting the depository
number CSD-58377.
[7] The rotational barrier for the C - C double bond in 1.3-dimethyl- and 1.3-diiivr-butylallene were determined to be 46. I7 and 46.9 1 kcal mol- I . respectivcly: W. R. Roth. G. Ruf. P. W. Ford. C h m Bur. 1974. 107. 48 52.
[XI The calculations were performed with the programs Gaussian 92 [9a] and
TURBOMOLE [9b]. The geometries uere optimized at the HF16-31G* and
MP2,6-31G* levels. The equillibrium structures were calculated as minima
( i = 0) or transition states ( r = I ) at the HF:6-31G* level. Thezero-point vibration corrections (ZPE) were scaled with a factorof0.89at the HF.6-31G* Ierel.
~
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a) Gaussian 92. Revision A : M. J. Frisch. G. W Trucks, M. Head-Gordon.
P. M. W. Gill. M. W. Wong. J. B. Foresman. H. B. Schlegel, K. Raghavachari,
M A . Robb, J. S. Binkley. C. Gonzalez. R. Martin, D. J. Fox, D. J. DeFrees, J.
Baker. J. J. P. Stewart. J. A. Pople. Gaussian Inc., Pittsburgh, PA, 1992; b)
TURBOMOLE: R. Ahlrichs. M. Blr. M. Haser. H. Horn. C. Kolmel. Chem.
P/7? 5 . Lcjtt. 1989. 162. 165-169.
The ring foldingangle at the B--B diagoiial is 32.3'in 2u, and 31.3- in 2u,; the
barriers LO ring inversion of the folded four-membered ring are calculated as
4.5 kcalinol-' for 2u, and 5.5 kcalmol-I for 2u, and thus are significantly
smaller than for a homodiboriranide without strong C- B hyperconjugation
(7.9 kc;ilinol-' [4]).
P. H M. Budrelaar. K. Krogh-Jespersen, T. Clark, P. von R. Schleyer, J Am.
C't~eni.Sot. 1985. 107. 2173-2179.
b
bso3R
BocNH
1
3
R'
BocNHb s d ; N B u 4
BocNH
5
I
Synthesis of Sulfonamido-Pseudopeptides:
New Chiral Unnatural Oligomers
Cesare Gennari,* Barbara Salom, Donatella Potenza,
and Anthony Williams
Although many research groups have devoted their efforts
during the past two decades to the replacement of the scissile
peptide bond with mimetic groups,"] relatively little is known
about pseudopeptides characterized by the presence of the sulfonamide bond.[21This modification creates a peptide bond surrogate with significant changes in polarity, H-bonding capability. and acid-base character (RSO,NHR', pK, = 20-11).
Furthermore, the sulfonamide bond should show enhanced
metabolic stability and structural similarity to the tetrahedral
transition state involved in the amide bond enzymatic hydrolysis.[' 'I This makes sulfonainidopeptides promising candidates
in the development of protease inhibitors and new
The
oligomers and the polymers should also be interesting molecular
scaffolds. with specific pseudopeptide backbone conformations
based on the hydrogen-bonding network.
Unfortunately a-aminosulfonamides are known to be unstable and to immediately decompose by fragmentati~n.'~]
We
have synthesized chiral vinylogous aminosulfonic acids (ramino-x,/i-unsaturated) from natural a-amino acids, developed
a straightforward protection -deprotection -coupling chemistry for the sulfonamide bond, and synthesized sulfonamidopseudopeptides by an iterative process (Scheme 1).
N-Boc a-aminoaldehydes 1 (Boc = revt-butoxycarbonyl)
were obtained from naturally occurring a-amino
Wittig-Horner reaction with methyl- o r ethyldiethylphosphoryl
methanesulfonate 2 (R = Me, Et[6.7a1)and nBuLi at -78°C
gave the corresponding a$-unsaturated sulfonates 3 in good
yield (75-85 ?") and complete E stereoselectivity.["] Cleavage
of the methyl (ethyl) ester was effected by treatment of sulfonates 3 with nBu,NI in refluxing acetone (100 % ) . I 7 *. 81 This
deprotection offers several advantages over related reactions
leading to different sulfonate salts (e.g., N a + , N H f ,
NHEt:)" h - d l : a) the nBu4N+ salts 4 are easily handleable and
soluble in organic solvents; b) they are the most suitable starting
material for the next step. The activation step required an extensive search for appropriate reagents and conditions. After
screening several different methods, we found that SO,Cl,/PPh,
in dichloroniethane ['I gives the corresponding sulfonyl chlo('1
Prof. Dr. C. Geniiari. B. Salom, D r D. Potenra. Dr. A. Williams
Dipartimento di Chimica Organica e Industriale
Univerhiti di Milano
Centru CNR per lo Studio delle Sostanre Organiche Naturali
via G. Venezian 21. 20133 Milano ( I t ~ l y )
Telefax' I n i . codc + (2) 236-4369
t
I
Scheme 1 . Synthesis of sulfonamido-pseudo pep tide^ from N-Boc a-aminoaldrhydes. a) (EtO),PO-CH,SO,R 2. nBuLi, THF, -78 'C. 30min. 7 5 85%. b)
Bu,NI, acetone, reflux, 10- 16 h, 100%. c ) SO,CI,, Ph,P. CH,CI:. 3 A molccular
sieves. 0 + 25 C , 3 h, 85-90%. d) CH,CI,. DBU, cat. DMAP. 25 C . 1811.
55-65"h. e) 3 M HCI in MeOH, 0 + 25'C. 3 h, 100%.
rides 5 cleanly and in high yield (85-90 %) as stable compounds
which can be purified by chromatography, while other protocols (e.g., triphosgene/cat. dimethylformamide (DMF);
CH,CI, ,I9] PC1,/CHC1,['O1) were less efficient. The sulfonyl
chlorides 5 were coupled with the amine salts 6 (CH2C12/1&diazabicyclo[5.4.0]undec-7-ene(DBU)/cat. 4-dimethylaminopyridine (DMAP)) to give the dimers 7. Although the coupling
step is unoptimized and needs further improvement. the dimers
7 were obtained in a reasonable yield (55-65'6). Amine hydrochlorides 6 were prepared from N-Boc derivatives 3 by treatment with 3 M HC1 in MeOH (room temperature, 3 h) followed
by solvent removal (100%). The process can be further iterated
to give trimers (e.g., 9. 60%) and tetramers (e.g.. 10. 6 0 % ;
R = Et, R' = Me, R 2 = iPr, R3 = CH,Ph, R4 = CH,CHMe,).
The stereochemical integrity was checked a) by a-methoxy-atrifluoromethyl(pheny1)acetic acid (MTPA) derivatization [ ''1 of
hydrochlorides 6 and N M R analysis ('H, I3C, '9F),1121
and b) by
I3C N M R analysis of dimers 7.[l3] The sulfonamide bond is
formed from the sulfonyl chloride and the amine by a nucleophilic substitution at the four-coordinate ~ulfur.['~'I
The alternative sequence involving an elimination-addition reaction via
an achiral unsaturated ~ u l f e n e , [ ' ~is~not
' likely to occur as it
would lead to a mixture of two diastereomeric d i m e r ~ . ~ ' ~ ]
Similar activation and coupling chemistry proved effective
also for the synthesis of sulfonamido-pseudopeptides based on
/$aminosulfonamides, which, unlike r-aminosulfonamides, are
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