Stereoselective Grignard additions to N-formyl hydrazone: A concise synthesis of NoxafilR side chain and a synthesis of Noxafil R

Article abstract of DOI:10.1016/j.tetlet.2004.09.028

Addition of ethyl Grignard reagent to the formyl hydrazone 11 via in situ silylation provided the corresponding formyl hydrazine with excellent diastereoselectivity in favor of the desired S,S-diastereoisomer 6. Treatment of 6 with the phenyl carbamate 13 efficiently provided the O-benzyl protected Noxafil, which was deprotected to provide Noxafil^R.

Full text of DOI:10.1016/j.tetlet.2004.09.028

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8249–8251
Stereoselective Grignard additions to N-formyl hydrazone:
a concise synthesis of Noxafil side chain and
a synthesis of Noxafil
R
R
a,
b
b
Anil K. Saksena, Viyyoor M. Girijavallabhan, Haiyan Wang, Raymond G. Lovey,
b
*
c
Frank Guenter, Ingrid Mergelsberg and Mohinder S. Puar
c
b
a
5
Schering-Plough Research Institute, 2015, Galloping Hill Road, Kenilworth, NJ 07033, USA
3, Beverley Road, Upper Montclair, NJ 07043, USA
b
c
Werthenstein Chemie AG, CH-6105 Schachen, Switzerland
Received 18 June 2004; accepted 2 September 2004
Available online 25 September 2004
Abstract—Addition of ethyl Grignard reagent to the formyl hydrazone 11 via in situ silylation provided the corresponding formyl
hydrazine with excellent diastereoselectivity in favor of the desired S,S-diastereoisomer 6. Treatment of 6 with the phenyl carbamate
R
3 efficiently provided the O-benzyl protected Noxafil, which was deprotected to provide Noxafil .
1
ꢀ
2004 Elsevier Ltd. All rights reserved.
R
Noxafil is a novel 2,2,4-trisubstituted tetrahydrofuran
based antifungal agent, which has successfully under-
gone phase III clinical trials. It has shown improved
therapeutic potential over existing drugs against a vari-
ety of invasive fungal infections in normal and immuno-
compromised patients refractory to or intolerant of
now describe below the successful outcome of these
experiments.
Stereoselective addition of EtMgBr to the aldhydrazone
11 would constitute the most direct route to 6. Examples
of such Grignard additions to C@N are not too com-
1
3,4
standard therapy.
mon and no examples could be found for additions
to formyl hydrazones. Jager and co-workers have
described additions of Grignard reagents to lactalde-
hyde derived benzyl imine 7 in a stereoselective manner
O
H
5
Me
to favor the S,S-diastereoisomer 8 (Scheme 2).
F
N
N
N
N
S
S
O
4
O
N
R
2
OH
N
Me
The chiral (S)-N,N-tetramethyleneacetamide 1 was pre-
pared from ethyl (S)-lactate according to Terashima and
N
N
F
NoxafilR
6,7
co-workers. Treatment of 1 with Red-Al provided the
8
(
S)-2-benzyloxy propanal 10 in 94% yield. Formyl
hydrazine reacted quite readily with 10 providing the
formyl hydrazone 11 as a low melting crystalline solid
R
A major improvement in the synthesis of Noxafil
would be an efficient synthesis of the S,S-hydroxy side
chain in the form of the N-formyl hydrazine intermedi-
ate 6. The existing route to this key intermediate is a
9
in >80% yield. Reaction of 11 with EtMgBr (4equiv;
ꢁC to rt) gave a mixture of the desired S,S-diastereo-
0
isomer 6 and its S,R-diastereoisomer 12 with excellent
diastereoselectivity (6:12, 94:6) in 55% yield (Scheme 3).
2
protracted low yielding sequence as shown in Scheme 1.
The main inefficiency in the above sequence lay in the
necessity to obtain the pure S,S-enantiomer 5 via crystal-
lization from the dibenzoyl-D-tartaric acid salt. A more
direct route to the formyl hydrazine 6 was desired. We
In order to improve yields and diastereoselectivity, the
hydrazone 11 was silylated in situ before addition of
the Grignard reagent. Silylation was also expected to
block deprotonation site thereby reducing the amount
of Grignard reagent. A dramatic improvement in dia-
stereoselectivity was observed. The yields were slightly
*
Corresponding author. E-mail: anilsaksena@cs.com
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.028

8250
A. K. Saksena et al. / Tetrahedron Letters 45 (2004) 8249–8251
O
O
OH
Me
Me
Me
Me
Me Brosylation
ZnBH4
N
EtMgBr
OBn
OBn
OBn
1
2
3
NH2
Me
NH.CHO
Me
OBs
HN
HN
Me
Me (i) NH .NH
Me
EtCHO
Me
2
2
~
50%
OBn
(ii) DBTA salt
OBn
OBn
4
5
6
Scheme 1.
Bn
H
Bn
Bn
N
HN
HN
Me
i
BuMgBr (4 equiv.)
EtOEt
Me
CHMe2
Me
CHMe2
+
OBn
(70% yield)
OBn
OBn
7
8
(>95:5)
9
Scheme 2.
NH.CHO
H
O
O
N
Me
Me
Me
NH2NH.CHO
NH.CHO
N
Red-Al
H
OBn
OBn
OBn
1
10
11
NH.CHO
Me
HN
HN
EtMgBr (4 equiv.)
EtOEt
Me
Me
Me
+
OBn
OBn
(
55% yield)
6
(96:4)
12
Scheme 3.
improved but the minimum EtMgBr required remained
the same. Ethyl magnesium bromide was also found to
be better than ethyl magnesium chloride in terms of dia-
stereoselectivity (Table 1).
Table 1.
Conditions
6:12
Yield
%)
(
(a) 11 + BSA (1.2equiv) + EtMgBr (4equiv)
(b) 11 + BSA (2.0equiv) + EtMgBr (4equiv)
99.4:0.6
99.8:0.2
95:5
57
1
0,11
62.3
53
The formyl hydrazine 6 obtained according to (b)
was subjected to treatment with the phenyl carbamate
(
(
c) 11 + BSA (0equiv) + EtMgCl (4equiv)
d) 11 + BSA (2.0equiv) + EtMgCl (4equiv)
98:2
59
1
3 to provide the O-benzyl protected Noxafil 14 in
O
H
HN NH.CHO
F
O
N
N
N
OPh
Me
CHMe
2
R
+
O
N
OBn
N
N
F
6
1
3
7
8
10 11
13 14
O
1
H
3
5
19
18
20
7
N
Me
2
6
F
O
N
N
N
OR
3'
1'
1
4
N
Me 21
1
6
O
22
2
3
6
'
N
N
F
N
5'
3"
14 R = Bn
Noxafil R = H
R
5"
Scheme 4.

A. K. Saksena et al. / Tetrahedron Letters 45 (2004) 8249–8251
the product was extracted with Et
8251
8
5% yield. Its deprotection with Pd/C and HCOOH fur-
2
O. The organic phase
R
25
D
2 4
was washed with brine, dried over Na SO , and evapo-
nished pure Noxafil mp 164–165ꢁC, ½aꢀ ꢁ 29 (c 1.00,
1
2,13
rated to dryness in vacuo to provide a residue, which was
purified on a silica gel column (20% EtOAc/n-hexane) to
provide formyl hydrazine 6 (2.52g; 62.3% yield) as a
colorless oil.
CHCl3)
(Scheme 4).
Acknowledgements
1
1. The diastereoisomeric ratio was determined by treating a
small aliquot of the product with phenyl isocyanate
to provide a phenyl urea derivative and determining
HPLC on a reverse phase C18 (100A, 3.9 · 300mm)
We would like to thank Dr. Birendra Pramanik for high
resolution mass spectral data.
2
column using MeOH–H O (66:34) containing 0.1%
References and notes
TFA, against authentic 6 and 12 provided by Dr. D. R.
2
Andrews et al. Retention time 6 9.3min; retention time 12
8.0min.
1
2
3
. Everett, N. Antifungal Drug Discovery and Development,
Fifth International Summit, March 28–29, 2001; Princeton,
NJ, U.S.A. Drugs, 2001, 4, 652–655.
. Andrews, D. R.; Gala, D.; Gostelli, J.; Guenter, F.;
Leong, W.; Mergelsberg, I. U.S. Patent 5,625,064, April
12. (ꢁ)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-Difluorophenyl)-tetrahydro-
5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-
2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxypropyl]-3H-1,2,4-
R
triazol-3-one, (Noxafil ): A solution of the phenyl carba-
2
9, 1997.
mate 13 (4g; 6mmol) in toluene (150mL) was treated with
the formyl hydrazine (1.56g; 6.6mmol) and DBU (0.1g;
0.66mmol). The mixture was stirred at 80ꢁC (bath temp)
and then overnight at 100–110ꢁC (bath temp). Toluene
was evaporated off in vacuo and the residue was purified
by chromatography on silica gel (80% EtOAc/n-hexane) to
provide 14 as a foamy solid (4.03g; 85% yield). It was
dissolved in formic acid (70mL) and treated with 5%Pd/C
(8g) at 20ꢁC. The resulting mixture was stirred at 20ꢁC for
15h, then heated to 35–40ꢁC and stirred for an additional
24h. The mixture was cooled to 20ꢁC and filtered through
Celite washing the filter cake with ꢂ40mL formic acid and
then with two 35mL portions of MeOH. The filtrate and
washings were combined and concentrated in vacuo at
. Addition of carbon nucleophiles to aldehyde tosylhydra-
zones of aromatic and heteroaromatic compounds leading
upto alkylative reduction or alkylative fragmentation were
observed. See: Chandrasekhar, S.; Venkat Reddy, M.;
Srinivasa Reddy, K.; Ramarao, C. Tetrahedron Lett. 2000,
4
1, 2667–2670.
4
. See also, alkylative elimination of a,b-epoxy tosylhydra-
zones: Chandrasekhar, S.; Takhi, M.; Yadav, J. S.
Tetrahedron Lett. 1995, 36, 307–310.
. Franz, T.; Hein, M.; Veith, U.; Jager, V.; Peters, E.-M.;
Peters, K.; von Schnering, H. G. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1298–1301.
5
6
. Kobayashi, Y.; Takase, M.; Ito, Y.; Terashima, S. Bull.
Chem. Soc. Jpn. 1989, 62, 3038–3040.
65ꢁC to a residue, which was chromatographed on silica
R
) to provide Noxafil (3/44g;
7
. Yields refer to isolated products and have not been
optimized. All new compounds were characterized by
PMR, CMR, and high resolution mass spectra. When
necessary diff NOE, COSY, and NOESY spectra were
obtained. Elemental analysis were obtained for crystalline
compounds only. Selected spectral data is given here.
. Preparation of (S)-2-benzyloxy propanal 10: Benzyloxy
amide 1 (10g, 42.8mmol) was dissolved in toluene (40mL)
and the stirred solution cooled in ice–MeOH bath. To this
solution was slowly added Red-Al (3.4M in toluene;
gel (5% MeOH/CH
84% yield) as a crystalline solid (from acetonitrile), mp
2
Cl
2
164–165ꢁC.
13. Noxafil : H NMR (DMSO-d
R
1
6
, d, ppm) 2.15 (dd, J = 13,
8Hz, 2H
(multiplet, 3H), 3.75 (multiplet, 4H
a
), 2.40 (multiplet, J = 13, 8, 2Hz, 2H ), 2.55
b
a
), 6.80 (dd, J = 9, 2Hz,
0
0
8
2H, 7,7 H), 6.94 (dd, J = 9, 2Hz, 2H, 8,8 H), 3.15
0
0
(multiplet, 4H, 10,10 H), 3.32 (multiplet, 4H, 11,11 H),
0
7.10 (dd, J = 9, 2Hz, 2H, 13,13 H), 7.50 (dd, J = 9, 2Hz,
0
2H, 14, 14 H), 8.34 (s, 16H), 3.79 (multiplet, 18H), 1.70
(multiplet, 2H, 19H), 0.74 (triplet, J = 7Hz, 3H, 20H),
4.18 (multiplet, 21H), 4.65 (d, J = 5Hz, 21-OH), 1.12
8
.5mL, 29mmol). After stirring for 5h the solution was
quenched with acetone (5mL) and 2N HCl (70mL) was
added. The product was extracted with EtOAc and the
EtOAc phase was washed with water and saturated NaCl.
After drying over Na SO , the solvent was evaporated in
(doublet, J = 7Hz, 3H, 22H), 4.57 (d, J = 15Hz, 23H
4.62 (d, J = 15Hz, 23H
a
),
), 6.95 (multiplet, J = 8, 8, 2Hz,
0
b
0
0
00
3 H), 7.28 (multiplet, 2H, 5 ,6 H), 7.78 (s, 3 H), 8.32 (s,
5 H).
2
4
0
0
vacuo to obtain 10 as a thick oil (6.6g; 94% yield).
. Preparation of formyl hydrazone 11: N-Formyl hydrazine
1
3
3
9
C NMR (DMSO-d
6
, d, ppm) 83.2 ( JCF=4Hz, C-1), 37.5
4
( J = 3Hz, C-2), 38.3 (C-3), 69.8 (C-4), 68.6 (C-5), 152.1
(
2.63g; 43.4mmol) was dissolved in methanol and mixed
CF
0
0
with (S)-2-benzyloxy propanal 10 (6g; 36.5mmol). The
resulting solution was stirred overnight. Methanol was
evaporated in vacuo and the residue was redissolved in
(C-6), 114.9 (C-7, -7 ), 117.5 (C-8, -8 ), 125.4 (C-9), 49.5*
0
0
(C-10, -10 ), 48.2* (C-11, -11 ), 149.7 (C-12), 115.6 (C-13,
0
0
13 ), 122.7 (C-14, -14 ), 145.3 (C-15), 135.0 (C-16), 152.0
(C-17), 57.7 (C-18), 26.1 (C-19), 10.5 (C-20), 70.7 (C-21),
16.4 (C-22), 55.1 ( JCF = 3Hz, C-23), 126.1 ( JCF = 13Hz,
Et O. The precipitate was removed by filtration and the
2
4
2
filtrate evaporated in vacuo to provide a residue, which
was purified on a silica gel column (20% EtOAc/n-hexane)
to obtain the formyl hydrazone 11 as a waxy solid (6.02g;
4
0
3
J
0
CF = 4Hz, C-1 ), 161.8 (JCF = 246Hz, JCF = 12Hz, C-
2
2 ), 104.4 ( JCF = 26, 27Hz, C-3 ), 158.6 (JCF = 247Hz,
0
3
0
2
= 13Hz, C-4 ), 110.9 ( J = 21Hz,
4
8
0. Preparation of formyl hydrazine 6: Formyl hydrazone 11
0% yield).
J
J
CF
00
= 3Hz,
C-5 ), 128.4 ( JCF = 10, 6Hz, C-6 ), 150.4 (C-3 ), 144.9
FC
0
CF
3
0
1
0
0
*
(
(
(
4g; 19.4mmol) was dissolved in anhydrous diethyl ether
400mL) and treated with bis(trimethylsilyl) acetamide
BSA) (7.89g; 38.8mmol). The solution was stirred at
(C-5 ). Assignments interchangeable.
MS (EI) 700 (M+), 698 (Mꢁ2), 685 (Mꢁ15), 655 (Mꢁ45),
618 (Mꢁ82), 600 (Mꢁ100), 425, 423, 422, 399, 328, 302,
301, 278, 262, 229, 195, 141, 127.
room temperature for 45min and then cooled (ice-bath)
for 15min. EtMgBr (3M in Et O; 25.86mL; 77.6mmol)
was added and the solution stirred overnight at room
temperature. The reaction was quenched with water and
2
Elemental analysis: found: C, 63.38; H, 5.95; N, 16.03; F,
5.68; calcd for C H F N O : C, 63.43; H, 6.00; N, 16.00;
F, 5.43.
3
7
42
2
8
4