Synthesis of (-)-isonitrin B

Article abstract of DOI:10.1021/ja981700v

The first enantioselective synthesis of (-)-isonitrin B (2), the parent of a small family of isonitrile antibiotics having compact but highly functionalized (and highly reactive) cyclopentane rings, is described. They key in this synthesis is the cyclization of 5b to 4b, by way of the intermediate alkylidene carbene.

Full text of DOI:10.1021/ja981700v

VOLUME 120, NUMBER 51
DECEMBER 30, 1998
© Copyright 1998 by the
American Chemical Society
Synthesis of (-)-Isonitrin B
Douglass F. Taber,* Han Yu, Christopher D. Incarvito,# and Arnold L. Rheingold#
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Delaware,
Newark, Delaware 19716
ReceiVed May 18, 1998
Abstract: The first enantioselective synthesis of (-)-isonitrin B (2), the parent of a small family of isonitrile
antibiotics having compact but highly functionalized (and highly reactive) cyclopentane rings, is described.
They key in this synthesis is the cyclization of 5b to 4b, by way of the intermediate alkylidene carbene.
Introduction
The conventional approach to the assembly of highly func-
tionalized ring systems has been to first construct the ring(s)
and then to elaborate the functional groups. We proposed to
invert this strategy (eq 2), by first preparing the fully oxygenated
ketone 5 and then cyclizing it to 4. The essential question was
Isonitrin A (1), isonitrin B (2), and trichoviridin (also called
isonitrin C) (3) are three representatives of a small family of
isonitrile antibiotics1 having compact but highly functionalized
(and highly reactive) cyclopentane rings (eq 1). Compared with
isonitrin B (2), isonitrin A (1) has an extra epoxide outside the
cyclopentane ring, while trichoviridin (3) has an extra epoxide
in the ring. The current rapid rise in bacterial infections that do
whether the generation and cyclization of the alkylidene carbene4
from this highly functionalized substrate could proceed smoothly
to form the strained bicyclic product 4. The key to this analysis
is the observation that intramolecular C-H insertion of an
alkylidene carbene proceeds with retention of absolute config-
uration.5
not respond to antibiotic therapy makes it urgent that leads such
as these be pursued. Although isonitrin B was first described
more than 15 years ago, only one synthesis, by Baldwin of the
racemate, has been reported.2 Baldwin also accomplished the
conversion of isonitrin B (2) to isonitrin A (1) and to tricho-
viridin (3).3 We now report the first enantioselective synthesis
of (-)-isonitrin B (2), the parent member of this family of
antibiotics.
(2) For the correction of the structure of isonitrin B and the only previous
(racemic) synthesis, see: Baldwin, J. E.; Aldous, D. J.; Chan, C.; Harwood,
L. M.; O’Neil, I. A.; Peach, J. M. Synlett 1989, 9.
(3) For the conversion of isonitrin B to isonitrin A, see: (a) Baldwin, J.
E.; O’Neil, I. A. Synlett 1990, 603. For the conversion of an intermediate
in the isonitrin B synthesis to trichoviridin, see: (b) Baldwin, J. E.; O’Neil,
I.; Russell, A. T. Synlett 1991, 551. (c) Baldwin, J. E.; Adlington, R. M.;
O’Neil, I. A.; Russell, A. T.; Smith, M. L. J. Chem. Soc., Chem. Commun.
1996, 41.
# X-ray crystallography.
(1) For isolation and physiological activity, see: (a) Fujiwara, A.; Okuda,
T.; Masuda, S.; Shiomi, Y.; Miyamoto, C.; Sekine, Y.; Tazoe, M.; Fujiware,
M. Agric. Biol. Chem. 1982, 46, 1803. (b) Okuda, T.; Fujiwara, A., Fujiwara,
M. Agric. Biol. Chem. 1982, 46, 1811.
10.1021/ja981700v CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/04/1998

13286 J. Am. Chem. Soc., Vol. 120, No. 51, 1998
Taber et al.
Scheme 1
Scheme 2
Generation of Alkylidene Carbenes from r-Heterosub-
stituted Ketones. Before our investigation of the preparation
and cyclization of the alkylidene carbene derived from ketone
5, we first addressed the simple question of whether an
R-heterosubstituted ketone (6a-6c, Scheme 1) would participate
efficiently in 1,5 C-H insertion.6
Several reagents have been used to convert ketones into the
corresponding alkylidene carbenes.4 In our hands, the most
efficient protocol has been our modification7 of the Ohira
procedure.8 Treatment of a DME solution of trimethylsilyldi-
azomethane with n-BuLi at -60 °C resulted in a suspension
that was allowed to warm until just homogeneous. This solution
of trimethylsilyldiazomethyllithium was chilled again to -40
°C before addition of ketones 6a-6c. Under these conditions,
insertion proceeded to give exclusively 7a-7c.
First-Generation Approach. Construction and Cyclization
of the Acetonide-Protected Ketone 4a. In our first retrosyn-
thetic analysis of (-)-isonitrin B (eq 3), the key intermediate
was projected to be the acetonide-protected cyclopentene 4a,
which would be prepared from ketone 5a by alkylidene carbene
insertion. The cyclization precursor, ketone 5a, was to be
prepared from the racemic alcohol 8 over several steps.
Figure 1. ORTEP of the 4-bromophenylurethane of 11b. Thermal
ellipsoids at 30% probability and the hydrogen atoms, with the exception
of those on chiral carbon atoms, are omitted for clarity.
dihydroxylation10 and protection led to the acetonide 10.
Hydrogenation11 gave a pair of diastereomers, 11a and 11b,
which were readily separable on silica gel. The relative
configuration of 11b was established by X-ray analysis of the
derived 4-bromophenylurethane (Figure 1).12 Mitsunobu inver-
sion13 of 11b to 11a proceeded smoothly. Threo-selective
epoxidation (mCPBA) of 11a gave the desired epoxide 12 as
the expected major diastereomer.14 We expected that the
alkylidene carbene derived from 12 would insert both into the
We started (Scheme 2) our synthesis from alkyne 9.9 Coupling
with trans 1-bromo-1-propene followed by enantioselective
(4) For reviews of cyclopentene construction by intramolecular C-H
insertion of an alkylidene carbene, see: (a) Taber, D. F. Methods of Organic
Chemistry; Helmchen, G., Ed.; Georg Thieme Verlag: Stuttgart, New York,
1995; Vol. E21, p 1127. (b) Kirmse, W. Angew. Chem., Int. Ed. Engl. 1997,
36, 1164.
(5) (a) Gilbert, J. C.; Giamalva, D. H.; Baze, M. E. J. Org. Chem. 1985,
50, 2557. (b) Ohira, S.; Moritani, M.; Ida, T.; Yamato, M. J. Chem. Soc.,
Chem. Commun. 1993, 1299.
(6) After this phase of the work was completed, Ohira reported the facile
cyclization of an R-hetero ketone: Ohira, S.; Sawamoto, T.; Yamato, M.
Tetrahedron Lett. 1995, 36, 1537.
(7) Taber, D. F., Meagley, R. P. Tetrahedron Lett. 1994, 35, 8405.
(8) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun.
1995, 36, 1537.
(10) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.; Kwong, H.; Morikawa, K.; Wang, Z.; Xu, D.; Zhang,
X. J. Org. Chem. 1992, 57, 2768. The crude diol from this procedure had
an ee of 73%. A single crystallization raised the ee to 92%. The latter
material was used in this synthesis. The assignment of the absolute
configuration of the diol was based on literature precedent.
(11) (a) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226. (b)
Brown, C. A.; Ahuja, V. K. J. Chem. Soc., Chem. Commun. 1973, 553.
(12) Crystal data for the 4-bromophenylurethane of 11b: C24H28BrNO5,
P212121, a ) 8.1279(3), b ) 13.3495(5), and c ) 22.1776(8) Å, V )
2406.35(15) Å3, Z ) 4, T ) 203 K; R(F) ) 4.77%, R(wF2) ) 9.46%.
(13) (a) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(b) Caine, D.; Kotian, P. L. J. Org. Chem. 1993, 57, 6587.
(14) Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B. Tetrahedron
Lett. 1979, 4733.
(9) Takano, S.; Sugihara, T.; Ogasawara, K. Synlett 1991, 279.

Synthesis of (-)-Isonitrin B
J. Am. Chem. Soc., Vol. 120, No. 51, 1998 13287
Scheme 3
Scheme 4
target methine group and the benzylic methylene group,15 so
the benzyl protecting group was replaced with a tert-butyldi-
methylsilyl group to give alcohol 12a, which was oxidized to
ketone 5a.
With the results of the model study of the cyclization of the
R-heterosubstituted ketones in hand, we were ready to attempt
the cyclization of ketone 5a (Scheme 3). The key question was
whether the alkylidene carbene C-H insertion reaction would
still be competent when there was an epoxide between the
ketone and the target C-H bond. There were two concerns:
the additional ring strain and the deactivation of the target C-H
by the electron-withdrawing oxirane. In the event, we were
delighted to observe that treatment of the ketone 5a with the
anion of (trimethylsilyl)diazomethane in DME gave the aceto-
nide-protected cyclopentene 4a. Removal of the silyl protecting
group gave the primary alcohol 13.
Alcohol 13 proved to be unstable, as had been expected. Since
we would need to remove the acetonide group from the fragile
cyclopentadiene monoepoxide at the end of the synthesis, we
attempted this deprotection at the stage of alcohol 13. Unfor-
tunately, none of the deprotected triol 14 could be found.
Second-Generation Approach. Synthesis of (-)-Isonitrin
B. It was clear from the investigation in the acetonide series
that we would have a greater chance of success if we were to
prepare the tris-silylated ketone 5b (eq 4). We proposed to
synthesize ketone 5b from the dibromide 15.
by addition of the aldehyde gave the coupling product 17 as an
inseparable pair of diastereomers. Fortunately, hydrogenation11
gave the corresponding Z-alkenes as a pair of diastereomers (18a
and 18b) that were readily separable on silica gel.
The relative configuration of the correct intermediate 18b was
established by chemical and spectroscopic correlation with
alcohol 11a, the structure of which had been secured by X-ray
crystallography. The alcohol 18b was recycled to the 1:1 mixture
of 18a and 18b by Dess-Martin oxidation19 followed by NaBH4
reduction. The expected threo-selective epoxidation of 18a14
then gave the two diastereomeric epoxides 19a and 19b in a
1:3 ratio favoring the desired epoxide 19b. Epoxide 19b was
oxidized efficiently to the cyclization precursor, ketone 5b.
As before, treatment of the ketone 5b with the anion of
(trimethylsilyl)diazomethane in DME gave clean conversion to
the cyclized product 4b (Scheme 5). Selective deprotection of
the primary silyl group of 4b under the neutral conditions of
HF/pyridine20 gave the acid-sensitive cyclopentadiene mono-
epoxide 19, which was converted to the aldehyde 20 by Dess-
Martin oxidation19 and was further oxidized to the acid with
sodium chlorite.21 Treatment of the acid with NaH and (PhO)2P-
(O)N3 gave the acyl azide.22 Thermolysis of the acyl azide gave
the unstable isocyanate. Employment of the literature reagent
(LiEt3BH)22 for the conversion of this isocyanate to formamide
21 gave only over-reduction. Fortunately, NaBH4 in t-BuOH/
water reduced the isocyanate cleanly to the formamide 21. We
found that it was crucial to use tert-butyl alcohol as the solvent
in this reduction, as use of ethanol led to substantial amounts
of the derived urethane. The formamide 21 was the expected
The construction of the required cyclization precursor 5b
(Scheme 4) began with (E)-1,1-dibromo-trans-1,3-pentadiene
(16), which was available in one step16 from crotonaldehyde.
Sharpless asymmetric dihydroxylation10 of 16 followed by
protection with tert-butyldimethylsilyl chloride resulted in
dibromide 15. The key to this approach would be the ability to
separate the diastereomers resulting from the addition of the
lithium acetylide derived from 15 to OdCH-CH2-OTBS.17
In the event, exposure of 15 to 3 equiv of n-BuLi18 followed
1
mixture of four geometric isomers on the H NMR time scale
(rt).
Dehydration of the formamide 222a gave the intermediate bis-
silyloxy isonitrile. We were concerned about our ability to
(19) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(20) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992,
114, 9434.
(15) In fact, the alkylidene carbene derived from 12 inserted into both
positions to give a 1:1 ratio of the desired cyclopentene and the byproduct
dihydrofuran.
(16) Wrobel, J. E.; Ganem, B. J. Org. Chem. 1983, 48, 3761.
(17) Carreira, E. M.; Hastings, C. A.; Shepard, M. S.; Yerkey, L. A.;
Millward, D. B. J. Am. Chem. Soc. 1994, 116, 6622.
(21) Isobe, M.; Ichikawa, Y.; Bai, D.; Masaki, H.; Goto, T. Tetrahedron
1987, 43, 4767.
(22) Chenera, B.; Chung, C.; Hart, D. J.; Lai, C. J. Org. Chem. 1992,
57, 2018.
(18) Villieras, J.; Perriot, P.; Normant, J. F. Synthesis 1979, 502.

13288 J. Am. Chem. Soc., Vol. 120, No. 51, 1998
Taber et al.
Scheme 5
To a solution of diol (1.1 g, 4.2 mmol) in DMF (22 mL) were added
imidazole (3.0 g, 42.3 mmol), DMAP (321 mg, 2.6 mmol), and tert-
butyldimethylsilyl chloride (3.3 g, 21.9 mmol). The mixture maintained
at reflux (bath ) 80 °C) for 3 h and then was quenched with 20 mL of
water at room temperature. EtOAc (2 × 20 mL) was added, and the
layers were separated. The combined organic extract was dried
(Na2SO4) and concentrated. The residue was chromatographed to afford
dibromide 15 (1.88 g, 3.85 mmol, 91% yield) as a clear oil, TLC Rf
(100% petroleum ether) ) 0.38; 1H NMR δ 6.39 (d, J ) 8.6 Hz, 1H),
4.18 (m, 1H), 3.75 (m, 1H), 1.11 (d, J ) 6.3 Hz, 3H), 1.11 (m, 18H),
0.03 (m, 12H); 13C NMR δ down 138.8, 76.7, 71.0, 25.9, 25.8, 25.7,
18.4, -4.5, -4.6, -4.7, -4.8; up 89.8, 18.1; IR (cm-1) 2928, 2858,
1616, 1472, 1362, 1255, 1108; FAB MS (m/z) 57 (23), 73 (85), 75
(22), 147 (100), 159 (68), 189 (24); FAB HRMS calcd for Br2C17H36O2-
Si2Na 509.0556, found 509.0518; [R]D -7.0 (c 2.1, CHCl3). Anal. Calcd
for Br2C17H36O2Si2: C, 41.80; H, 7.43. Found: C, 41.87; H, 7.69.
deprotect this to the very sensitive natural product. Fortunately,
the combination of TBAF in THF buffered with solid NH4Cl
recently developed in our laboratory23 effected smooth desily-
lation to give the natural product isonitrin B (2). The synthetic
2 exhibited identical properties to those reported for the
natural substance (1H NMR, GC-MS, IR; [R]D ) -92.2° (lit.
) -89.9).24
We have completed the first synthesis of the natural enan-
tiomer of (-)-isonitrin B (2), confirming the assigned absolute
configuration. Isonitrile 23, a similar intermediate to that in the
trichoviridin synthesis of Baldwin, should be convertible to
trichoviridin (3) in four steps following his procedures.
Conclusion
(2R,5S,6S)-1,5,6-(Tris-tert-butyldimethylsiloxy)hept-3-yn-2-ol and
(2S,5S,6S)-1,5,6-(Tris-tert-butyldimethylsiloxy)hept-3-yn-2-ol (17).
n-BuLi (3.5 mL of 2.21 M in hexane, 7.6 mmol) was added dropwise
at -78 °C to a solution of dibromide 15 (1.2 g, 2.5 mmol) in 16 mL
of THF. After 5 min of stirring at -78 °C, the mixture was allowed to
warm to -35 °C for 20 min. The siloxy aldehyde (0.87 g, 5.0 mmol)
in 1.0 mL of THF was added to the above mixture at 0 °C at once.
After 5 min of stirring at 0 °C, the mixture was quenched by the addition
of 20 mL of water and extracted with EtOAc (3 × 20 mL). The
combined organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to give alkyne 17 (1.1 g, 2.1 mmol, 84%
yield) as a pale yellow oil: TLC Rf (10% MTBE/petroleum ether) )
It is encouraging that the strained bicyclic skeleton of 2 can
be formed directly by alkylidene carbene insertion. The approach
outlined here should pave the way for the construction of other
members of this family of isonitrile antibiotics.
Experimental Section25
(3S,4S)-(E)-1,1-Dibromo-3,4-(tert-butyldimethylsiloxy)pentene
(15). To a flask containing AD-mix-R (37.1 g) in tert-butyl alcohol
(130 mL) and water (130 mL) at room temperature was added
methanesulfonamide (2.5 g, 26.5 mmol). The mixture was cooled to 0
°C, then (E)-1,1-dibromo-trans-1,3-pentadiene (5) (6.0 g, 26.5 mmol)
was added at once, and the heterogeneous slurry was stirred vigorously
at 0 °C for 24 h. Solid sodium sulfite (40 g) was added at 0 °C, and
the mixture was allowed to warm to room temperature and stirred for
1 h. The mixture was extracted with EtOAc (3 × 100 mL), and the
layers were separated. The combined organic extract was dried
(Na2SO4) and concentrated. The residue was chromatographed to give
the diol (4.7 g, 18.0 mmol, 68% yield) as a pale yellow oil: ee ) 73%
(HPLC column Chiralcel OD; injection amount 30 µL; sample
concentration 2 mg of diol/1 mL of mobile phase solvent; mobile phase
hexane/2-propanol (95/5 v/v); flow rate 1 mL/min). This was further
crystallized from 95% EtOH (20 mg/8 mL) to give a white crystalline
compound: ee ) 92%, TLC Rf (40% MTBE/petroleum ether) ) 0.28;
1H NMR δ 6.49 (d, J ) 8.5 Hz, 1H), 4.11 (t, J ) 7.5 Hz, 1H), 3.82
(bs, 1H), 3.74 (m, 1H), 3.45 (bs, 1H), 1.23 (d, J ) 6.4 Hz, 3H); 13C
NMR δ down 137.4, 76.7, 69.8, 18.7; up 93.2; IR (cm-1) 3361, 2976,
2931, 1618, 1375, 1264, 1134, 1055; FAB MS (m/z) 55 (51), 105 (31),
107 (35), 135 (100), 137 (88), 215 (38); FAB HRMS calcd for
Br2C5H8O2Na 282.8789, found 282.8768; [R]D -8.8 (c 2.0, CHCl3).
1
0.60; H NMR δ 4.39 (m, 1H), 4.19 (m, 1H), 3.72 (m, 2H), 3.58 (m,
1H), 1.16 (d, J ) 4.8 Hz, 1H), 1.16 (d, J ) 6.1 Hz, 3H), 0.88 (m, 27
H), 0.06 (m, 18 H); 13C NMR δ down 71.4, 68.2, 63.2, 25.8, 19.0,
-4.5, -4.6, -4.7, -5.3; up 85.0, 83.0, 67.0, 18.3, 18.2, 18.1; IR (cm-1
)
3454, 2957, 2859, 1743, 1362, 1257, 1119; MS (m/z) 73 (98), 75 (38),
115 (33), 147 (68), 150 (25), 159 (100), 313 (73); HRMS calcd for
C25H54O4Si3 502.3305, found 502.3330; [R]D -7.7 (c 0.9, CHCl3).
(2R,5S,6S)-1,5,6-(tert-Butyldimethylsiloxy)hept-3-en-2-ol (18a) and
(2S,5S,6S)-1,5,6-(tert-butyldimethylsiloxy)hept-3-en-2-ol (18b). So-
dium borohydride (215 mg, 5.7 mmol) was added to a suspension of
Ni(OAc)2‚4H2O (900 mg, 3.6 mmol) in 7 mL of ethanol at 0 °C. The
black suspension was vacuun/refilled for three times. Then, 2 mL of
ethylenediamine and the alkyne 17 (1.14 g, 2.27 mmol) in 1.5 mL of
ethanol were added sequentially. The black suspension was stirred
vigorously under an atmosphere of hydrogen at room temperature for
48 h. The reaction mixture was filtered through a pad of Celite, and
the filtrate was concentrated in vacuo. The residue was chromatographed
to give the desired alkene 18a (444 mg, 0.88 mmol) and its diastereomer
18b (440 mg, 0.87 mmol, 77% combined yield of 18a and 18b), as
clear pale yellow oils.
(23) Taber, D. F.; Kanai, K. Tetrahedron 1998, 54, 11767.
(24) The 1H and 13C NMR spectra were recorded in CD2Cl2, as reported
in conjuction with the original isolation. Isonitrin B (2) is not stable to
CDCl3.
(25) For general experimental procedures, see: Taber, D. F.; Houze, J.
B. J. Org. Chem. 1994, 59, 4004.
For 18a: TLC Rf (1:4:6 toluene:CH2Cl2:petroleum ether) ) 0.44;
1H NMR δ 5.46 (m, 2H), 4.45 (m, 1H), 4.38 (m, 1H), 3.73 (m, 1H),
3.60 (m, 1H), 3.41 (m, 1H), 2.69 (d, J ) 3.0 Hz, 1H), 1.04 (d, J ) 6.2
Hz, 3H), 0.85 (m, 27 H), 0.03 (m, 18 H); 13C NMR δ down 133.2,

Synthesis of (-)-Isonitrin B
J. Am. Chem. Soc., Vol. 120, No. 51, 1998 13289
129.2, 72.6, 72.4, 68.2, 26.0, 25.9, 18.0, -4.4, -4.8, -5.3, -5.4; up
67.0, 18.3; IR (cm-1) 3432, 2956, 2858, 1473, 1362, 1257, 1101; FAB
MS (m/z) 303 (43), 315 (100), 327 (39), 355 (93), 373 (26), 505 (36);
FAB HRMS calcd for C25H56O4Si3Na 527.3403, found 527.3384; [R]D
-38.4 (c 1.4, CHCl3).
For 18b: TLC Rf (1:4:6 toluene:CH2Cl2:petroleum ether) ) 0.41;
1H NMR δ 5.64-5.40 (m, 2H), 4.45 (m, 1H), 4.33 (m, 1H), 3.80 (m,
1H), 3.58 (m, 2H), 2.88 (d, J ) 2.3 Hz, 1H), 1.07 (d, J ) 6.3 Hz, 3H),
0.87 (m, 27H), 0.03 (m, 18H); 13C NMR δ down 133.7, 131.4, 72.8,
72.5, 67.7, 26.1, 25.9, 25.8, 25.7, 17.4, -4.4, -4.6, -4.7, -5.3, -5.4;
up 66.6, 18.5, 18.3, 18.0; IR (cm-1) 3407, 2930, 2862, 1466, 1256,
1091; FAB MS (m/z) 425 (5), 461 (100), 505 (21), 553 (M+ + Na,
59); FAB HRMS calcd for C25H56O4Si3Na 527.3385; found 527.3384;
[R]D -14.1 (c 1.2, CHCl3).
Alkene 18b to Alkene 18a. To a solution of Dess-Martin
periodinane (694 mg, 1.63 mmol) in 10 mL of CH2Cl2 was added alkene
18b (687 mg, 1.36 mmol) in 2 mL of CH2Cl2. The mixture was stirred
at room temperature for 3 h, and then 10 mL of 1:1 10% Na2S2O3:
saturated aqueous NaHCO3 was added. The mixture was stirred until
it turned clear. The layers were separated, and the mixture was
partitioned between CH2Cl2 and saturated aqueous NaHCO3. The
combined organic extract was dried (Na2SO4) and concentrated to give
the crude ketone (670 mg, 1.33 mmol) as a clear oil.
To the above crude ketone (670 mg, 1.33 mmol) in 7 mL of EtOH
was added NaBH4 (101 mg, 2.66 mmol) at room temperature. The
reaction mixture was stirred at room temperature for 3 h; water (8 mL)
was then added and stirring was continued for an additional 10 min.
The resulting mixture was partitioned between EtOAc and water. The
combined organic extracts were dried (Na2SO4) and concentrated. The
residue was chromatographed to give the desired alkene 18a (275 mg,
0.54 mmol, 40% yield from 18b) and its diastereomer 18b (254 mg,
0.50 mmol, 37% yield from 18b), each as a pale yellow oil.
Epoxide 19a and Epoxide 19b. To a flask containing alkene 18a
(1.09 g, 2.16 mmol) in 20 mL of CH2Cl2 was added mCPBA (50-
60%, 1.20 g, 3.49 mmol) in 2 mL of CH2Cl2. The mixture was stirred
at room temperature overnight and then was partitioned between
CH2Cl2 and saturated aqueous NaHCO3. The combined organic extracts
were dried (Na2SO4) and concentrated. The residue was chromato-
graphed to give the desired epoxide 19b (754 mg, 1.47 mmol, 67%
yield) and its diastereomer 19a (281 mg, 0.54 mmol, 25% yield), each
as a pale yellow oil.
For 19b: TLC Rf (8% MTBE/petroleum ether) ) 0.50; 1H NMR δ
3.84-3.67 (m, 5H), 3.11 (m, 2H), 2.50 (d, J ) 6.2 Hz, 1H), 1.17 (d,
J ) 6.4 Hz, 3H), 0.85 (m, 27 H), 0.07 (m, 18 H); 13C NMR δ down
74.0, 71.5, 68.1, 58.9, 57.5, 25.9, 25.8, 18.5, -4.3, -4.5, -4.6, -5.0,
-5.4; up 65.3, 18.3, 18.1; IR (cm-1) 3440, 2957, 2859, 1473, 1362,
1257, 1102; MS (m/z) 73 (100), 75 (35), 89 (19), 115 (19), 117 (19),
159 (39); HRMS calcd for C25H57O5Si3 521.3556, found 521.3514; [R]D
-0.9 (c 0.8, CHCl3). Anal. Calcd for C25H57O5Si3: C, 57.64; H, 10.83.
Found: C, 57.94; H, 11.95.
For 19a: TLC Rf (8% MTBE/petroleum ether) ) 0.48; 1H NMR δ
3.89 (m, 1H), 3.74 (m, 4H), 3.10 (m, 1H), 2.92 (m, 1H), 2.65 (d, J )
4.1 Hz, 1H), 1.20 (d, J ) 4.1 Hz, 3H), 0.85 (m, 27H), 0.03 (m, 18H);
13C NMR δ down 72.4, 70.3, 68.6, 56.7, 56.5, 25.8, 18.8, -4.3, -4.5,
-4.8, -5.0, -5.4; up 65.2, 18.3, 18.1, 18.0; IR (cm-1) 3440, 2958,
2858, 1474, 1361, 1259, 1116; FAB MS (m/z) 231 (46), 257 (38), 303
(100), 331 (33), 371 (22); FAB HRMS calcd for C25H56O5Si3Na
543.3333, found 543.3333; [R]D -23.7 (c 0.5, CHCl3).
Ketone 5b. Alcohol 19b (0.51 g, 0.97 mmol) in 1 mL of CH2Cl2
was added to a suspension of PCC mixture (1.26 g of 1:1:1 NaOAc:
4A molecular sieve:PCC, ground together, 1.94 mmol) in 6 mL of
CH2Cl2. The mixture was stirred at room temperature for 5 h; 10 mL
of Et2O was then added, and the mixture was filtered through a pad of
Celite. The solid was washed with 3 × 5 mL of Et2O. The filtrate was
concentrated, and the brown residue was chromatographed to give the
ketone 5b (0.39 g, 0.76 mmol, 78% yield) as a clear oil: TLC Rf (8%
MTBE/petroleum ether) ) 0.58; 1H NMR δ 4.36 (s, 2H), 3.83 (d, J )
4.5 Hz, 1H), 3.74-3.65 (m, 1H), 3.40-3.29 (m, 2H), 1.12 (d, J ) 6.4
Hz, 3H), 1.00-0.83 (m, 27 H), 0.14-0.02 (m, 18 H); 13C NMR δ
down 73.4, 70.8, 60.3, 55.6, 26.0, 25.8, 18.8, -4.3, -4.5, -4.6, -5.0,
-5.4, -5.5; up 203.6, 69.0, 18.3, 18.1; IR (cm-1) 2956, 2858, 1735,
1473, 1362, 1257, 1097; MS (m/z) 73 (100), 75 (38), 115 (39), 131
(45), 147 (30), 159 (70); HRMS calcd for C25H54O5Si3 518.3264, found
518.3279; [R]D -15.1 (c 1.2, CHCl3).
Cyclopentene 4b. Under nitrogen, n-BuLi (0.59 mL of 2.21 M in
hexane, 1.30 mmol) was added dropwise over 5 min at -60 °C to
(trimethylsilyl)diazomethane (0.72 mL, 2.0 M in hexane, 1.43 mmol)
in DME (4 mL). After 5 min at -60 °C, the dry ice bath was removed,
and the mixture was allowed to warm. Once it turned homogeneous
(about 5 min), the reaction mixture was then cooled to -40 °C
immediately, and ketone 5b (338 mg, 0.65 mmol) in 1 mL of DME
was added dropwise over 5 min. The solution was stirred at -30 to
-40 °C for another 45 min and then warmed to room temperature over
2 h. The resulting mixture was partitioned between saturated aqueous
NH4Cl and EtOAc. The combined organic extract was dried (Na2SO4)
and concentrated, and the residue was chromatographed to give the
cyclopentene 4b (253 mg, 0.49 mmol, 75% yield) as a clear oil: TLC
1
Rf (8% MTBE/petroleum ether) ) 0.66; H NMR δ 5.29 (t, J ) 2.0
Hz, 1H), 4.28 (ddd, J ) 1.8 Hz, J ) 4.8 Hz, J ) 7.2 Hz, 2H), 3.65 (m,
2H), 3.53 (t, J ) 2.7 Hz, 1H), 1.23 (d, J ) 6.1 Hz, 3H), 0.89 (m,
27H), 0.06 (m, 18H); 13C NMR δ down 133.3, 72.5, 56.9, 54.9, 25.9,
25.8, 17.7, -2.8, -3.0, -4.2, -4.8, -5.4; up 145.7, 85.8, 60.7, 18.4,
18.3, 18.0; IR (cm-1) 2929, 2856, 1471, 1255, 1124; MS (m/z) 73 (100),
147 (51), 159 (29), 356 (29), 382 (35), 457 (24), 499 (26), 515 (27);
HRMS calcd for C26H56O4Si3 516.3471, found 516.3486; [R]D -20.0
(c 1.2, CHCl3).
Alcohol 20. To a solution of cyclopentene 4b (97 mg, 0.19 mmol)
in 7 mL of THF in a Nalgene tube was added 7.1 mL of freshly
prepared, buffered pyridinium hydrofluoride (stock solution prepared
from 2.4 g of Aldrich pyridinium hydrofluoride, 5 mL of pyridine,
and 20 mL of THF). The reaction mixture was stirred at room
temperature for 2.5 h, and then 10 mL of saturated aqueous NaHCO3
was added slowly. After an additional 5 min, the layers were separated
and the aqueous layer was extracted with EtOAc (3 × 10 mL). The
combined organic extracts were dried (Na2SO4) and concentrated, and
the residue was chromatographed to give the alcohol 20 (58 mg, 0.14
mmol, 77% yield) as a white solid: TLC Rf (40% MTBE/petroleum
ether) ) 0.40; 1H NMR δ 5.36 (t, J ) 2.0 Hz, 1H), 4.29 (dd, J ) 2.1
Hz, J ) 2.9 Hz, 2H), 3.65 (m, 3H), 1.58 (d, J ) 5.9 Hz, 1H), 1.24 (d,
J ) 6.1 Hz, 3H), 0.85 (s, 9H), 0.84 (s, 9 H), 0.11 (s, 3H), 0.03 (s, 3H),
0.02 (s, 3H), -0.01 (s, 3H); 13C NMR δ down 134.6, 72.4, 57.0, 54.7,
25.9, 25.7, 17.7, -2.8, -2.9, -4.1, -4.8; up 145.3, 85.8, 60.6, 18.4,
18.0; IR (cm-1) 3380, 2929, 2857, 1252, 1121; MS (m/z) 73 (100), 75
(94), 119 (33), 159 (31), 242 (40); HRMS calcd for C20H40O4Si2
400.2483, found 400.2465; [R]D -18.9 (c 0.8, CHCl3).
Aldehyde 21. To a solution of Dess-Martin periodinane (115 mg,
0.27 mmol) in 3 mL of CH2Cl2 was added alcohol 20 (90 mg, 0.22
mmol) in 1 mL of CH2Cl2. The mixture was stirred at room temperature
for 10 min, and then 2 mL of 1:1 10% Na2S2O3:saturated aqueous
NaHCO3 was added. The mixture was stirred until it turned clear. The
layers were separated, and the mixture was partitioned between
CH2Cl2 and saturated aqueous NaHCO3. The combined organic extract
was dried (Na2SO4) and concentrated. The residue was chromatographed
to provide the aldehyde 21 (78 mg, 0.20 mmol, 87% yield) as a white
1
solid: TLC Rf (5% MTBE/petroleum ether) ) 0.42; H NMR δ 9.73
(s, 1H), 6.39 (t, J ) 2.2 Hz, 1H), 4.03 (t, J ) 2.6 Hz, 1H), 3.76 (m,
2H), 1.29 (d, J ) 6.3 Hz, 3H), 0.85 (s, 9H), 0.81 (s, 9H), 0.13 (s, 3H),
0.03 (s, 3H), 0.00 (s, 3H), -0.04 (s, 3H); 13C NMR δ down 188.0,
156.1, 72.1, 53.8, 53.6, 25.8, 25.7, 17.8, -0.01, -3.1, -4.1, -4.8; up
146.3, 86.4, 18.4, 17.9; IR (cm-1) 2931, 2858, 1691, 1473, 1372, 1254,
1202, 1125; MS (m/z) 73 (100), 75 (22), 103 (16), 115 (21), 147 (32),
159 (50); HRMS calcd for C20H38O4Si2 398.2329, found 398.2309. [R]D
-70.6 (c 0.5, CHCl3).
Formamide 22. To a solution of the above aldehyde 21 (72 mg,
0.18 mmol), 2-methyl-2-butene (0.41 mL of 2.0 M in THF, 0.81 mmol)
and NaH2PO4‚H2O (25 mg, 0.18 mmol) dissolved in a mixture of 3
mL of t-BuOH and 0.9 mL of water was added NaClO2 (80%, 69 mg,
0.61 mmol) portionwise over 2 min. The yellow mixture was stirred at
room temperature for 1 h, and then the reaction was quenched with 3
mL of freshly prepared saturated aqueous NaHSO3. The layers were
separated, and the aqueous layer was extracted with EtOAc (3 × 5
mL) at pH ) 7.0. The combined organic extract was dried (Na2SO4)

13290 J. Am. Chem. Soc., Vol. 120, No. 51, 1998
Taber et al.
and concentrated to give the crude acid (73 mg) as a white solid: TLC
Rf (15% MeOH/CH2Cl2) ) 0.33.
stirred at -78 °C for 40 min, and the reaction was then quenched by
the addition of saturated aqueous NaHCO3 (4 mL) at -78 °C. The
mixture was allowed to warm to room temperature, the layers were
separated, and the mixture was partitioned between CH2Cl2and saturated
aqueous NaHCO3. The combined organic extracts were dried (Na2SO4)
and concentrated. The residue was chromatographied to provide the
isonitrile 23 (19 mg, 0.048 mmol, 52% yield) as a white solid: TLC
To a stirred solution of the above crude acid (73 mg) in 3 mL of
dry THF at room temperature was added NaH (7.2 mg of 60% in
mineral oil, 0.18 mmol). The reaction mixture was stirred for 10 min
at room temperature and then cooled to 0 °C, and a solution of
(PhO)2P(O)N3 (52 mg, 0.19 mmol) in 2 mL of THF was added in one
portion. The mixture was stirred at 0 °C for 1 h and at room temperature
for 6 h. The mixture was partitioned between Et2O and water. The
combined organic extracts were dried (Na2SO4) and concentrated. The
residue was eluted through 3 g of silica gel to afford the unstable acyl
azide (55 mg, 0.13 mmol) as a clear oil: TLC Rf (5% MTBE/petroleum
ether) ) 0.62; IR (cm-1) 2930, 2858, 2136, 1697, 1560, 1384, 1258.
The above acyl azide (55 mg, 0.13 mmol) in 1.5 mL of dry benzene
was maintained at reflux until the TLC showed no starting material
(about 1.75 h). The solution was then concentrated to give the unstable
isocyanate as a thick clear oil: IR (cm-1) 2948, 2860, 2262, 1488,
1366, 1113.
1
Rf (5% MTBE/petroleum ether) ) 0.53; H NMR δ 5.64 (t, J ) 2.3
Hz, 1H), 3.71 (m, 3H), 1.25 (d, J ) 6.2 Hz, 3H), 0.85 (s, 9H), 0.84 (s,
9H), 0.12 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.00 (s, 3H); 13C NMR δ
170.2, 137.8, 128.9, 84.2, 71.9, 57.3, 53.5, 25.5, 25.4, 18.2, 17.7, 17.2,
-3.3, -3.5, -4.6, -5.3; IR (cm-1) 2956, 2859, 2115, 1473, 1259,
1120; MS (m/z) 57 (29), 73 (100), 75 (22), 115 (25), 147 (51), 159
(64); HRMS calcd for C20H37NO3Si2 395.2400 found 338.3315 + C4H8;
[R]D -18.1 (c 0.5, CHCl3).
Isonitrin B (2). To a stirred solution of isonitrile 23 (19 mg, 0.048
mmol) in dry THF (5 mL) at 0 °C was added tetrabutylammonium
fluoride (0.11 mL of 1.0 M in THF, 0.11 mmol) and solid NH4Cl (13
mg, 0.24 mmol). The reaction mixture was stirred at 0 °C for 30 min,
5 mL of Et2O was then added, and the mixture was filtered through
0.5 g of silica gel. The filtrate was concentrated in vacuo, and the residue
was chromatographed to give isonitrin B (2) (5.5 mg, 0.033 mmol,
To a flask containing 1.5 mL of t-BuOH was added NaBH4 (9.5
mg, 0.25 mmol), followed immediately by 0.3 mL of distilled water.
After 15 s of stirring at room temperature, this mixture was added all
at once to the flask containing the neat isocyanate. The resulting mixture
was stirred at room temperature for 2 min; MeOH (2 mL) was then
added, and stirring was continued for 5 an additional min. The mixture
was concentrated in vacuo, and saturated aqueous Na2HPO4 (2 mL)
was added. The layers were separated, and the aqueous layer was
extracted with EtOAc (3 × 2 mL). The combined organic extracts were
dried (Na2SO4) and concentrated, and the residue was chromatographed
to give the formamide 22 (38 mg, 0.092 mmol, 52% yield from
aldehyde 21) as a clear oil, a 3:1 mixture of geometrical isomers by
integration of selected peaks in the 1H NMR spectrum of the mixture:
1
68% yield) as a white solid: TLC Rf (10% THF/CH2Cl2) ) 0.34; H
NMR δ 5.90 (t, J ) 2.2 Hz, 1H), 3.88-3.82 (m, 2H), 3.78 (t, J ) 2.4
Hz, 1H), 2.47 (s, 1H), 2.36 (d, J ) 5.9 Hz, 1H), 1.19 (d, J ) 6.5 Hz,
3H); 13C NMR δ down 171.5, 135.3, 130.5, 82.4, 69.6, 57.4, 55.5,
16.9; IR (cm-1) 3410, 2111, 1627, 1380, 1103; MS (m/z) 58 (23), 67
(20), 68 (51), 81 (21), 86 (100), 96 (39), 122 (23); HRMS calcd for
C8H9NO3 167.0579, found 167.0582; [R]D -92.2 (c 0.2, MeOH).
Acknowledgment. We thank the donors of the Petroleum
Research Fund, administered by the American Chemical Society,
for support of this work. We thank Dr. Robert M. Adlington
1
TLC Rf (20% EtOAc/petroleum ether) ) 0.36; H NMR δ 8.53 (d, J
) 11.4 Hz, 0.3H), 8.27 (d, J ) 1.2 Hz, 0.7H), 7.20 (bs, 0.3H), 7.01
(bs, 0.7H), 5.59 (t, J ) 2.3 Hz, 0.7H), 4.83 (t, J ) 2.3 Hz, 0.3H), 3.66
(m, 3H), 1.26 (d, J ) 6.2 Hz, 2.1H), 1.25 (d, J ) 6.3 Hz, 0.9H), 0.84
(m, 18H), 0.10 (m, 12H); 13C NMR δ down 158.4, 157.5, 120.1, 115.5,
72.7, 57.2, 53.6, 25.9, 25.8, 25.7, 18.4, -2.9, -3.0, -4.2, -4.8; up
138.5, 136.6, 114.6, 85.1, 18.4, 17.9; IR (cm-1) 3320, 2956, 2858, 1684,
1560, 1473, 1256, 1116; MS (m/z) 57 (24), 73 (100), 75 (42), 147
(18), 159 (22), 254 (23); HRMS calcd for C20H39NO4Si2 413.2400,
found 413.2418; [R]D -16.4 (c 1.0, CHCl3).
1
for providing an H NMR spectrum of isonitrin B.
Supporting Information Available: Additional experimen-
1
tal procedures, H and 13C spectra for compounds 2, 4b, 5b,
15, and 17-23, full crystallographic details including crystal
data and structure refinement, atomic coordinates, bond lengths
and angles, and anisotropic displacement coefficients (39 pages,
print/PDF). See any current masthead page for ordering
information and Web access instructions.
Isonitrile 23. To a stirred solution of dry formamide (38 mg, 0.092
mmol) in CH2Cl2 (6 mL) under nitrogen at -78 °C was added dry
diisopropylethylamine (0.096 mL, 0.55 mmol) followed by triflic
anhydride (39 mg, 0.14 mmol) in 1 mL of CH2Cl2. The solution was
JA981700V