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of the "P nucleus can be anticipated. The "B spectra of
3a, b show a signal at 6=41.9 (61,2=479 Hz), and in addition, a signal at 6= -3.73 in the spectrum of 3b for
[BPh41Q.The 'H N M R spectrum of 3a exhibits a doublet
at 6=7.65 for the olefinic protons, for which the coupling
constant (13JpHI
= 16.7 Hz) is on average 11 Hz greater than
for 2.13]This points to the greater s-character of the boronphosphorus bond in 3. Due to the BN n-bond, the two iPr
groups of the N(iPr)2 unit are inequivalent.
An X-ray structural analysis also confirms the ionic
structure of 3b in the solid state (Fig. la).['] The cation has
approximately DZd symmetry (Fig. lb). The C2BzP rings
are planar (maximum deviations from the best planes
0.008 and 0.019A) and lie perpendicular to each other
(90.9"). The phosphorus atom has distorted tetrahedral
coordination, for which the B-P-B angle inside the ring is
considerably less (93-94") than that between the rings
(1 16-1 19"), but 4-5" larger than in 2,5-dihydro-2,5-bis(diisopropy1amino)- 1H , 1,2,5-pho~phadiboroIe.[~]
The bond
lengths are in good agreement with those of the P-phenyl
substituted C2BzP derivatives,"] although in these compounds the ring is not planar.
Experimental
3a (1,1'-Spirobi[2,5-bis(diisopropylamino)-2,5-dihydro-lH-1,2,5-phosphoniadiborole] chloride): A mixture of 1 (5.16 g, 16.17 mmol) [lo] and P(SiMe,),
(2.02 g, 8.08 mmol) was heated at 140°C for about 5 hours, until no more
Me3SiCI distilled over. The molten reaction mixture gradually solidified. The
crude product was extracted twice with petrol ether then dissolved in
CH2CIZ.After filtering off a yellow, insoluble compound, 3a was obtained at
-30°C as a colorless powder. Yield: 2.9g (5.16 mmol, 64%); m.p. 273°C
(decamp.).-'H NMR (200 MHz, CD2C12): 6 = 1.01 (d, 24H, JHH=6.9 Hz),
l.28(d,24H),3.27(dsept,4H,4JpH%lH ~ ) , 3 . 4 0 ( d s e p t . , 4 H , ~ J ~ , , = 2 . 9 H z ) ,
7.65 (d,4H, ,JpH=16.7 Hz). "C NMR(5O MHz):6=21.38 (s, CH,), 25.28 (s,
CH,),47.13(d,3JpC=6.5 Hz,NCH),60.20(d,3JpC=ll Hz,NCH), 159.3(br.,
BC). MS (DCI (field desorption chemical ionization), CH.,): m / z 562 (3%,
M a ) , 546 (3%, [M-Me-HI"), 519 (6%. [M-iPrI0), 43 (IOOYo, iPr").
+
3b: A solution of 3a (320 mg,0.57 mmol) in CH2C12 (10 mL) was mixed with
Na[BPhl] (340 mg, 0.99 mmol) and the reaction mixture stirred for 1 h. The
insoluble components were filtered off and the solvent removed in a vacuum.
3b was crystallized from a little acetonitrile at -30°C. Yield: 398 mg (0.47
mmol, 83%).
Received: August 10, 1988 [Z 2920 IE]
German version: Angew. Chem. 101 (1989) 219
[I] a) Gmelin, Handbuch der Anorganischen Chemie, Eoruerbindungen. Band
22/4. Erg. 8th edit., Springer, Berlin 1975: b) P. 1. Paetzold, Adu. lnorg.
Chem. 31 (1987) 123; c) D. B. Sowerby in I. Haiduc, D. B. Sowerby
(Eds.): The Chemistry of Inorganic Homo-a n d Heterocycles, Vol. 1. Academic Press, New York 1987, p. 103.
[2] J. R. Wasson in: Gmelin, Handbuch der Anorganischen Chemie, Boruerbindungen Band 19/3, 8th edit., Springer, Berlin 1975, p. 93.
[3] M. Driess, Dissertation, Universitat Heidelberg 1988.
[4] H. Noth, W. Schragle, Z . Naturforsch. B16 (1961) 473.
[5] E. Fluck, J. Svara, B. Neumiiller, H. Riffel, H. Thurn, 2. Anorg. Allg.
Chem. 536 (1986) 129.
[6] J. C. Tehby: Phosphorus-31 NMR Spectroscopy in Stereochemical Analysis (Methods Stereochem. Anal. 8 (1987) 26).
[7] W. Kutzelnigg (Bochum), private communication.
[S] Crystal structure analysis of 3b: space group P2,/n, a = 11.340(3),
b=21.901(6), c=22.638(5) A,p- 104.30(2)", V=5448 A', 2=4.3199 observed reflections (122c,), four-circle diffractometer. MoKn radiation,
w-scan. Non-hydrogen atoms anisotropic, phenyl rings and methyl
H atoms refined with
groups as fixed groups (C-C 1.395 C-H 0.95
common isotropic temperature factors, R ~ 0 . 0 6 7 .Further details of the
crystal structure investigation may be obtained from the Fachinformationszentrum Energie, Physik, Mathematik GmbH, D-7514 EggensteinLeopoldshafen 2 (FRG), on quoting the depository number CSD-53 377,
the names of the authors, and the journal citation.
[9] M. Driess, H. Pritzkow, W. Siebert, Angew. Chem. 99 (1987) 789: Angew.
Chem. fnt. Ed. Engl. 26 (1987) 781.
[lo] M. Hildenbrand, H. Pritzkow, WSiebert, Angew. Chem. 97 (1985) 769;
Angew. Chem. l n t . Ed. Engl. 24 (1985) 759.
A,
2 18
A).
0 VCH Veriagsgesellschoji mbH. D-6940 Weinheim. 1989
LiBH,(NaBH,)/Me,SiCI,
an Unusually Strong and Versatile Reducing Agent**
By Athanassios Giannis* and Konrad Sandhoff
Metal borohydrides MBH4 (M = Li, Na, 1/2Ca, 1/2Zn)
are amongst the most important reducing agents in organic
chemistry.".21 Their reactivity is strongly influenced by the
following factors: a) the solvent,i21b) the metal ion M,i21
and c) the presence of catalysts such as B(OMe)3,131B-methoxy-9-borabicyclononane,[31or h a l i d e ~ lof
~ .cobalt,
~~
nickel, iridium, osmium, copper, platinum and titanium. Despite the variation of these parameters, the range of functional groups that can be reduced by metal borohydrides is
very limited. We now report a method which makes it possible also to reduce amino acids, carboxylic acids, amides,
nitriles, nitroalkenes, and sulfoxides with alkali metal borohydrides in good yields.
We found that the addition of Me3SiC1 makes possible
the reduction of a-amino acids with LiBH, in T H F (Nos.
1-4 in Table 1). When optically pure a-amino acids were
used, optically pure @-aminoalcohols were obtained. This
inspired us to investigate the use of LiBH,/Me,SiCI as a
reducing agent for other functional groups. Thus, simple
carboxylic acids are reduced to alcohols (No. 5), while primary, secondary and tertiary amides (Nos. 6-8) and nitriles (Nos. 10-12) afford the corresponding amines. High
yields were obtained in all cases. Dimethyl sulfoxide was
reduced to dimethyl sulfide (No. 9), the dipeptide derivative Fmoc-L-Phe-L-Ala-OMe (No. 14) gave the corresponding amino alcohol, and N-benzyloxycarbonyl-6-amino-1hexanol was converted into 6-amino-I-hexanol (No. 15).
Similar results were obtained with NaBH, (Nos. 6, 8,9, 11,
12, 14 and 15 in Table 1). Because of its good solubility in
T H F and the milder reaction conditions, LiBHJ6] is, however, the reducing agent of choice.
The strength of this new system is demonstrated by the
smooth reduction of the nitrostyrene derivative (No. 13) on
a preparative scale (100 mmol) to afford the corresponding
amine. Other methods for the reduction of conjugated nitroalkenes, such as LiAIH4 reduction or catalytic hydrogenation, are unsatisfactory; far better results have been
obtained using diborane in the presence of NaBH,"] or
BF, .OEt2.'"
We suggest that in reductions using LiBH4(NaBH4)/
Me3SiC1 in THF, a borane T H F complex is formed [Eq.
(a)] which, with the assistance of excess Me,SiCI, acts as
the reducing agent.
LiBH,
+ Me3SiC1
LiCl
+ Me,SiH + BH3.THF
(4
The addition of Me,SiCI makes it possible to carry out reductions with LiBH4 or NaBH, which are either very slow
o r d o not occur in its absence. The reaction mechanism,
the use of other alkylhalogenosilanes,'9] and the suitability
of the method for other functional groups remain to be investigated.
Typical procedures
Me&H is formed in all reactions. It should therefore be ensured that this
volatile silane (b.p. 10°C) can escape from the reaction vessel.""
-
['I Dr. A. Giannis, Prof. Dr.
[**I
K. Sandhoff
Institut fur Organische Chemie und Biochemie der Universitxt
Gerhard-Domagk-Strasse 1, D-5300 Bonn 1 (FRG)
This work was supported by the Bundesministerium fur Forschung und
Technologie and the Deutsche Forschungsgemeinschaft. We thank Dr.
R. Kirstgen, Dr. S . Hilger and Prof. Dr. W.Steglich for the starting materials for reactions 13 and 14.
0570-0833/89/0202-0218 $ 02.50/0
Angew. Chem. lnt. Ed. Engl. 28 (1989) No. 2
Table 1. Reductions with LiBH,(NaBH,)/Me,SiCI.
No.
Starting material
Product
[a1
Method
PI
1
2
Yield
[W
A
91
A
88
A
94
A
85
Q ,H+ C H 2 0 H
q "H' C 0 0 H
NH2
NH,
MeS-CH20H
3
MeS&COOH
4
/NH2
n-C, 6H33-CH
\
/NH2
n-C,,H,3-CH
\
COOH
CH,OH
5
Ph-COOH
Ph-CH20H
A
92
6
Ph-CO-NH2
Ph-CH2-NH2
A
B
91
a9
7
U e O p H z - C O
I
A
90
NH-Et
Me0
8
HCO-NMe,
Me3N
72 [cl
71
9
Me-SO-Me
Me-S-Me
60
10
Ph-CN
Ph-CH2-NH2
90
11
M e op 2 - C N
B
90
A
3
75 [cl
70
A
91
14
A [dl
B
60
55
15
A
95
a8
Me0
Me0
12
13
Me-CH2-NH2
Me-CN
Meow-No2
M
-
Me0
e
Me0
OMe
o-w
N
H
z
OMe
B
[a] All new compounds gave satisfactory C,H analyses and appropriate spectra. [b] A: LiBH., as reducing agent; B: NaBH4 as
reducing agent. [c] Isolated as the hydrochloride. [d] Purified by flash chromatography (silica gel, chloroform/methanol).
Reaction 1 in Table 1 : A solution of Me3SiCI (8.64 g, 80 mmol) was added
under argon to a solution of LiBH4 (0.87 g, 40 mmol) in T H F (20 mL) over
the course of 2 min. A precipitate of LiCl formed. L-valine (2.34 g, 20 mmol)
was added portionwise to the mixture within 5 min. After stirring for 24 h at
room temperature, 30 mL of MeOH were cautiously added and the volatiles
removed by distillation. The residue was treated with 20% KOH solution and
extracted three times with 50 mL portions of CHZC12.The organic phases
were combined, dried over Na2SO4,and the solvent evaporated to afford Lvalinol which was spectroscopically pure ('H NMR). Yield after Kugelrohr
distillation 1.87 g (91%), [a]g= 14.7 (neat).
Reaction 11 in Table 1: NaBH4 (4.56 g, 120 mmol) was added to a solution of
Me3SiCl (26.04 g, 240 mmol) in THF (100 mL) and the mixture refluxed for
3 h under argon. A solution of 3,4-dimethoxybenzylcyanide(10 g, 56.4 mmol)
in THF (50 mL) was then added over the course of 10 min. The solution was
refluxed for a further 10 h. After cooling, 100 mL MeOH were cautiously
added and the volatiles removed in vacuo. The residue was taken up in dilute
HCI and washed with ether. The aqueous solution was treated with excess
dilute NaOH and then repeatedly extracted with CH2C12.The organic extracts were combined, dried over Na2S0,, and the solvent evaporated to afford 2-(3,4-dimethoxyphenyl)ethylamine(pure by 'H NMR). Yield after kugelrohr distillation 9.16 g (90%).
+
Angew. Chem. I n t . Ed. Engl. 28 (1989) No. 2
Received: September 26, 1988 [ Z 2977 IE]
German version: Angew. Chem. I01 (1989) 220
CAS Registry numbers:
PhCN, 100-47-0; MeCN, 75-05-8; Me2S, 75-18-3; CITMS, 75-77-4; LiBH,,
16949-15-8; NaBH4, 16940-66-2: Me2S0, 67-68-5: Me3N, 75-50-3; EtNH2,
75-04-7; PhC02H, 65-85-0; PhCONH2, 55-21-0; Me2NCH0, 68-12-2;
PhCHzOH, 100-51-6; PhCHzNHz, 100-46-9; Me," HCI, 593-81-7;
EtNHZ. HCI, 557-66-4; HO(CH&NHZ, 4048-33-3; HO(CHZ)~NHCO~CHZP~,
17996-12-2; CH,(CH~)ISCH(NH~)CO~H,
21 87-07-7; (L)-~-P~CH(NH~)COZH,
72-18-4;(s)-i-PrCH(NH,)CH,OH, 2026-48-4; 3,4-(Me0)&H3CH2CN, 93- 17-4;
(L)-MeS(CHZ),CH(NH2)COzH,63-68-3; CH3(CH2)&H(NHZ)CH2OH,2335696-9; (s)-MeS(CHz)2CH(NH2)CH20H, 2899-37-8; 3,4-(Me0)zC6H3(CHz)2NH2,
120-20-7;
3,4-(Me0)2C6H3CHzCONHEt,
1 18474-93-4;
2,3,4(Me0)2C6Hz(CH2)zNH2,
3937-16-4; 3,4-(MeO)2C6H3(CH2)2NHEt, 39792-999; (E)-2,3,4-(Me0)3C6HZCH=CHNOz,118474-94-5; methyl [N-(Y H-fluorenq-ylmethyloxycarbonyI)phenylalanyl]alanine,1 18474-95-6; 9 H-fluoren-q-ylmethyl 1-( l-hydroxy-2-propylamino)-3-phenyl-2-propylcarbamate,
1 1847496-7; (L)-Proline, 147-85-3; (L)-Prolinol, 23356-96-9.
[I] A. Hajos in: Houben- Weyl-Muller, Merhoden der organischen Chemie,
Band I V / l d , Thieme, Stuttgart 1981, p. I .
0 VCH Verlagsgesellschaji mbH, 0-6940 Weinheirn. 1989
0570-0833/89/0202-0219 .$ 02.5010
2 19
[2] E. R. H. Walker, Chem. SUC.Rev. 5 (1976) 23.
[3]H. C. Brown, S. Narasimhan, J . Org. Chem. 49 (1984)3891.
[4]T.Sato, S. Suzuki, Y . Suzuki, Y. Miyaji, Z. Imai, Tetrahedron Lett. 1969.
455s.
[S] S . W. Heinzman, B. Ganem, J . Am. Chern. SOC.104 (1982)6801.
[6] Obtainable from Aldrich or easily prepared according to H. C . Brown,
Y . M. Choi, S. Narasimhan, Inorg. Chem. 20 (1981)4456.
[7] M. S . Mourad, R. S. Varma, G. W. Kabalka, Synth. Cummun. 14 (1984)
1099.
[S]R. S. Varma, G. W. Kabalka, Synth. Cummun. 15 (1985)843.
[9]Using NaBH4/Me2SiCIZ, we were able to reduce benzyl cyanide to 2phenylethylamine in 86% yield.
[lo] 0. W. Steward, 0. R. Pierce, J. Am. Chem. SUC.83 (1961)1916.
stirring the resulting mixture for 45 minutes. With lipase P,
on the other hand, the 3,6-di-O-acetyI derivatives 4a and
4 b were obtained in 92% and 75% yield, respectively.
LCC
2
la, b
3a. b
P
1a.b
Enzymatic Synthesis
of Selectively Protected Glycals**
+
2
4a, b
By E. Wolfgang HoNa*
Glycals and their esters are versatile chiral building
blocks.[’I They can be obtained in good yields from the
corresponding saturated carbohydrates;[’] however, because of their overfunctionalization with hydroxyl groups
and because of the absence of strategically valuable functional groups such as C=C and C=O bonds, these are in
many cases unsuitable for direct conversion into the target
molecules. The directed chemical linkage or transformation of glycals such as la and lb at the hydroxyl groups
usually requires tedious, multistep protection and deprotection procedures. Regioselective acetylations of D-glucal
la and D-galactal lb and deacetylations of the triacetates
5c, 5d have so far never been reported.[31This prompted us
to investigate lipase-catalyzed acetyl transfer reactions [Eq.
(a)-( c)].[~]
+ y R‘COOR”
+Gly(OCOR’),(OH), + x R’COOH
+Gly(OH),(OCOR’), + yR”0H
+ yR’COOCH=CH2
+Gly(OH),(OCOR‘),
Gly(OCOR’),+,
Gly(OH),
+y
Gly(OH),+,
+xH~O
+ yCH3CHO
In the present communication we report some novel, efficient and facile enzymatic syntheses of partially protected
as well as fully hydroxyl-differentiated glucals and galactals.
Of primary interest was the realization of enzymatic
transacetylations in nonaqueous organic media. Reversible
transesterifications [Eq. (b)], however, generally result in
unsatisfactory conversions. This problem can be overcome
by using vinyl esters[51[Eq. (c)]. An especially suitable reagent for irreversible enzymatic acetyl transfer is the inexpensive vinyl acetate 2. For carrying out the reactions the
glycals are either stirred with the enzyme in pure 2 at room
temperature or are previously taken up in small amounts
of a cosolvent and finally treated with 2 and the lipase
(Table 1). The enzymes employed are commercially available lipases from Candida cylindracea (LCC) and Pseudomonas fluorescens (P).[“’ Especially suitable for the selective acetylation of the primary hydroxyl groups of la and
lb are the Candida lipases (Scheme 1, Table 1). Thus, the
reaction of la in 2/ethyl acetate in presence of the lipase
O F afforded, in 24 hours, 6-O-acetyl-~-glucal3a in 90%
yield. The galactal derivative 3b was obtained by dissolving lb in a little water, addition of 2 and lipase S-VII, and
1’1 Dr. E. W. Holla
Hoechst Aktiengesellschaft
Postfach 800320,D-6230 Frankfurt am Main 80 (FRG)
[**II am grateful to Frau A. Weber for carrying out some of the preparative
work.
220
0 VCH Verlagsgesellschaji mbH, D-6940 Weinheim. 1989
Scheme 1. Lipase-catalyzed acetylations and deacetylations.
Table 1. Enzymatic acetyl transfer reactions with o-glucal la, D-galactal lb
and 3,4,6-tri-0-aCetyI-D-gluCal5c.
Starting
Cpd.
Enzyme [6][a]
Reaction
conditions [b]
Product
Isolated
Yield [Yo] [c]
la
lb
la
OF,0.4 g
2 [d], 24 h
S-VII, 0.8 g
P, 0.25 g
P, 1.0 g
P, 1.0 g
2 [el, 45 min
2 [d], 48 h
2 [el, 20 h
buffer [g],5-7 h
3a
3b
4a
4b
6c
90
93
92
75 14
90
(a)
(b)
(c)
Ib
5c
[a] The quoted amounts of enzyme refer to 1.Og of starting compound; the
enzymes can be used several times. [b]All reactions at room temperature. [c]
After flash chromatography. [d] 20-25 vo!-% ethyl acetate. [el 1-4 vol-Yo water, 2 g of powdered molecular sieve 4 A. [fl Approx. 10% of regioisorner
found. [gI 10 mL 0.25 M potassium phosphate buffer, p H = 7 .
After completion of the reactions the insoluble enzymes
can be recovered by membrane filtration and used again in
further transformation^.[^^
Especially interesting with regard to the regiochemistry
is the deacetylation of tri-0-acetyl-D-glucal 5c. The lipaseP-catalyzed ester cleavage in weakly buffered solution
without pH-control affords 4,6-di-O-acetyl-~-glucal6c in
90% yield. In the case of the tri-0-acetyl-D-galactal 5d, on
the other hand, the formation of a complex mixture of 6d
and several di- and monoacetates is observed.
For the synthesis of completely hydroxyl-differentiated
glycals we investigated the enzymatic transfer of benzoyl
and chloroacetyl groupsLs1by using vinyl esters 7 and 9 ,
respectively (Scheme 2, Table 2). Lipase AY-20 and, contrary to expectation, lipase P are suitable for the selective
benzoylation of the 6-hydroxy groups of la and lb with 7.
With tetrahydrofuran or water as cosolvent, the monobenzoates 8a,b are obtained in about 70% yield.[’] Regioselective chioroacetylation of 3a,b and 8a,b with 9/lipase P
and acetylation of 8a,b with 2Aipase P gave the completely differentiated glycals lOa,b, lla,b, and 12a,b in good
yields.“”’
0570-0833/89/0202-0220 $ 02.50/0
Angew. Chem. Int. Ed. Engl. 28 (1989) Nu. 2