Formal Total Synthesis of (-)-Balanol: Concise Approach to the Hexahydroazepine Segment Based on RCM

Article abstract of DOI:10.1021/jo991611g

A concise synthesis of the hexahydroazepine moiety 13 of (-)-balanol 1 is described that comprises only eight steps and is distinctly shorter than all previous reported approaches to this particular compound. Sharpless epoxidation of divinylcarbinol 4 and ring closing alkene metathesis (RCM) reaction for the formation of the heterocyclic scaffold 9 constitute the key transformations of this sequence. The latter reaction is best achieved with catalytic amounts of the ruthenium indenylidene complex 18 recently reported. Furthermore, it is demonstrated that RCM can be successfully carried out even in the presence of an azido function provided that Schrock's molybdenum alkylidene complex Mo(=NAr)(=CHCMe₂Ph)[OC(Me)(CF₃)₂]₂ (Ar = 2,6-diisopropylphenyl) is used as precatalyst.

Full text of DOI:10.1021/jo991611g

1738
J . Org. Chem. 2000, 65, 1738-1742
F or m a l Tota l Syn th esis of (-)-Ba la n ol: Con cise Ap p r oa ch to th e
Hexa h yd r oa zep in e Segm en t Ba sed on RCM
Alois Fu¨rstner* and Oliver R. Thiel
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/ Ruhr, Germany
Received October 15, 1999
A concise synthesis of the hexahydroazepine moiety 13 of (-)-balanol 1 is described that comprises
only eight steps and is distinctly shorter than all previous reported approaches to this particular
compound. Sharpless epoxidation of divinylcarbinol 4 and ring closing alkene metathesis (RCM)
reaction for the formation of the heterocyclic scaffold 9 constitute the key transformations of this
sequence. The latter reaction is best achieved with catalytic amounts of the ruthenium indenylidene
complex 18 recently reported. Furthermore, it is demonstrated that RCM can be successfully carried
out even in the presence of an azido function provided that Schrock’s molybdenum alkylidene
complex Mo(dNAr)(dCHCMe2Ph)[OC(Me)(CF3)2]2 (Ar ) 2,6-diisopropylphenyl) is used as precata-
lyst.
Sch em e 1
In tr od u ction
Balanol (1), a structurally unusual metabolite produced
by Verticillium balanoides1 and Fusarium merismoides,2
represents an important new lead structure in the quest
for selective inhibitors of protein kinase C (PKC). Since
activation of PKC is a critical step in the signal trans-
duction pathways controlling gene expression and cel-
lular proliferation,3 this family of enzymes constitutes a
formidable molecular target in the search for anticancer
agents and drugs controlling inflammation, cardiovas-
cular disorders, central nervous system dysfunction, and
even HIV infection. Although the selectivity of 1 itself
among the different PKC isozymes is poor, the IC50 values
in the low nanomolar range render it a particularly
promising lead structure, which has captured wide
attention as witnessed by extensive programs aiming at
the total synthesis of balanol4-9 and analogues with
superior selectivity profiles.10
independent routes, and procedures for linking them
together have also been elaborated.11,12 Although this
background may suggest that the synthetic challenges
posed by balanol have been fully met and further studies
are unnecessary to date, a closer inspection of the
available data is quite revealing. Except for one report,13
(6) (a) Lampe, J . W.; Hughes, P. F.; Biggers, C. K.; Smith, S. H.;
Hu, H. J . Org. Chem. 1994, 59, 5147. (b) Lampe, J . W.; Hughes, P. F.;
Biggers, C. K.; Smith, S. H.; Hu, H. J . Org. Chem. 1996, 61, 4572. (c)
Hu, H.; J agdmann, G. E.; Hughes, P. F.; Nichols, J . B. Tetrahedron
Lett. 1995, 36, 3659.
(7) (a) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.;
Naito, T. J . Org. Chem. 1998, 63, 4397. (b) Miyabe, H.; Torieda, M.;
Kiguchi, T.; Naito, T. Synlett 1997, 580. (c) Naito, T.; Torieda, M.;
Tajiri, K.; Ninomiya, I.; Kiguchi, T. Chem. Pharm. Bull. 1996, 44, 624.
(8) (a) Tanner, D.; Almario, A.; Ho¨gberg, T. Tetrahedron 1995, 51,
6061. (b) Tanner, D.; Tedenborg, L.; Almario, A.; Pettersson, I.;
Cso¨regh, I.; Kelly, N. M.; Andersson, P. G.; Ho¨gberg, T. Tetrahedron
1997, 53, 4857.
(9) Barbier, P.; Stadlwieser, J . Chimia 1996, 50, 530.
(10) For the preparation and biological evaluation of balanol ana-
logues see the following for leading references: (a) Koide, K.; Bunnage,
M. E.; Paloma, L. G.; Kanter, J . R.; Taylor, S. S.; Brunton, L. L.;
Nicolaou, K. C. Chem. Biol. 1995, 2, 601. (b) Defauw, J . M.; Murphy,
M. M.; J agdmann, G. E.; Hu, H.; Lampe, J . W.; Hollinshead, S. P.;
Mitchell, T. J .; Crane, H. M.; Heerding, J . M.; Mendoza, J . S.; Davis,
J . E.; Darges, J . W.; Hubbard, F. R.; Hall, S. E. J . Med. Chem. 1996,
39, 5215. (c) Lai, Y.-S.; Mendoza, J . S.; J agdmann, G. E.; Menaldino,
D. S.; Biggers, C. K.; Heerding, J . M.; Wilson, J . W.; Hall, S. E.; J iang,
J . B.; J anzen, W. P.; Ballas, L. M. J . Med. Chem. 1997, 40, 226. (d)
Mendoza, J . S.; J agdmann, G. E.; Gosnell, P. A. Bioorg. Med. Chem.
Lett. 1995, 5, 2211 and references therein.
From the retrosynthetic point of view, bisection of 1
at the ester linkage into a benzophenone carboxylic acid
2 and a hexahydroazepine domain 3 is obvious (Scheme
1). Both fragments have been prepared by various
(1) Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. M.;
J anzen, W. P.; Ballas, L. M.; Loomis, C. R.; J iang, J . B.; Katz, B.;
Steiner, J . R.; Clardy, J . J . Am. Chem. Soc. 1993, 115, 6452.
(2) Ohshima, S.; Yanagisawa, M.; Katoh, A.; Fujii, T.; Sano, T.;
Matsukuma, S.; Furumai, T.; Fujiu, M.; Watanabe, K.; Yokose, K.;
Arisawa, M.; Okuda, T. J . Antibiot. 1994, 47, 639.
(3) (a) Nishizuka, Y. Science 1992, 258, 607. (b) Nishizuka, Y. Nature
1988, 334, 661. (c) Bradshaw, D.; Hill, C. H.; Nixon, J . S.; Wilkinson,
S. E. Agents Actions 1993, 38, 135.
(4) (a) Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J . Am. Chem. Soc.
1994, 116, 8402. (b) Nicolaou, K. C.; Koide, K.; Bunnage, M. E. Chem.
Eur. J . 1995, 1, 454.
(5) Adams, C. P.; Fairway, S. M.; Hardy, C. J .; Hibbs, D. E.;
Hursthouse, M. B.; Morley, A. D.; Sharp, B. W.; Vicker, N.; Warner, I.
J . Chem. Soc., Perkin Trans. 1 1995, 2355.
(11) For a large scale adaptable synthesis of the benzophenone
fragment see: Hollinshead, S. P.; Nichols, J . B.; Wilson, J . W. J . Org.
Chem. 1994, 59, 6703.
(12) For further syntheses of the hexahydroazepine segment see:
(a) Cook, G. R.; Shanker, P. S.; Peterson, S. L. Org. Lett. 1999, 1, 615.
(b) Morie, T.; Kato, S. Heterocycles 1998, 48, 427. (c) Albertini, E.;
Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V.
Tetrahedron 1997, 53, 17177. (d) Mu¨ller, A.; Takyar, D. K.; Witt, S.;
Ko¨nig, W. A. Liebigs Ann. Chem. 1993, 651. (e) Tuch, A.; Sanie`re, M.;
Le Merrer, Y.; Depezay, J .-C. Tetrahedron: Asymm. 1996, 7, 2901. (f)
Wu, M. H.; J acobsen, E. N. Tetrahedron Lett. 1997, 38, 1693.
10.1021/jo991611g CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/23/2000

Formal Total Synthesis of (-)-Balanol
J . Org. Chem., Vol. 65, No. 6, 2000 1739
Sch em e 2a
all syntheses of the rather simple heterocyclic segment
3 in enantiomerically pure form require at least 12 steps.
This is noteworthy since distinctly different tactics have
been pursued en route to 3 which rely either (i) on the
exploitation of the chiral pool (D-serine, D-glucal, D-
isoascorbic acid, D-quinic acid), (ii) on the application of
ligand-controlled enantioselective transformations, or (iii)
often recourse to the resolution of racemates. In addition,
tedious separations of diastereomeric product mixtures
detract from the preparative appeal of some of these
approaches.
Bearing this analysis in mind, we were prompted to
develop a complementary synthesis of enantiomerically
pure 3 which is more satisfactory regarding the “economy
of steps” and which implements as many catalytic
transformations as possible. These strategic goals14,15
have been achieved by the eight-step sequence outlined
below, which includes a Sharpless epoxidation reaction16
for the control of the chiral centers and ring closing olefin
metathesis (RCM)13b,17 for the formation of the hetero-
cyclic scaffold as the key steps.
Resu lts a n d Discu ssion
Syn th esis of th e Hexa h yd r oa zep in e Rin g. Sharp-
less epoxidation16 of divinylcarbinol 4 performed as
described previously afforded product 5 in good chemical
yield and excellent optical purity (Scheme 2).18 O-Ben-
zylation19 followed by regioselective opening of the ox-
irane ring of compound 6 with allylamine (neat) affords
diene 7 in almost quantitative yield. Protection of the
secondary amine with a tert-butoxycarbonyl (Boc) group
readily provides compound 8 and sets the stage for the
envisaged ring closure of the diene via RCM.
This key transformation can be effected by different
ruthenium carbene complexes as discussed below in more
detail; optimum results are obtained by treatment of a
0.02 M solution of diene 8 in refluxing CH2Cl2 in the
presence of the ruthenium indenylidene complex 18 (5
mol %) as the precatalyst.20,21 Under these conditions, the
desired cycloalkene 9 is isolated in 87% yield. Subsequent
conversion of its secondary alcohol function into an azido
group is achieved with (PhO)2P(O)N3, diethyl azodicar-
boxylate, and PPh3 as the reagent combination.22
a
[a] (D)-(-)-DET, t-BuOOH, Ti(OiPr)4, -20 °C, cf. ref 18. [b]
NaH, BnBr, THF, 14 h, rt, 95%. [c] Allylamine (neat), 40 h, 70 °C,
94%. [d] Boc2O, Et3N, CH2Cl2, 16 h, rt, quant. [e] See Table 1. [f]
(PhO)2P(O)N3, PPh3, DEAD, THF, 2 h, rt, 59%. [g] Mo(dNAr)-
(dCHCMe2Ph)[OC(Me)(CF3)2]2 (Ar ) 2,6-diisopropylphenyl) (cat.),
CH2Cl2, 30 min, reflux, 94%. [h] (PhO)2P(O)N3, PPh3, DEAD, THF,
4 h, rt, 91%. [i] Pd/C (cat.), H2 (1 atm), F3CSO3H (1 equiv), 14 h,
rt. [j] p-BnOC6H4COCl, Et3N, CH2Cl2, 2 h, rt, 55% (over both
steps).
ibility of the standard metathesis catalysts toward azido
groups has not yet been investigated, we pursued this
possibility as well. Thus, reaction of alcohol 8 with
(PhO)2P(O)N3 under standard Mitsunobu conditions de-
livers azide 10 without incident.22 This diene, however,
fails to afford tetrahydroazepine 11 under standard
metathesis conditions; the only product that has been
Alternatively, the desired product 11 can be obtained
starting from diene 8 by reversing the order of azide
formation and RCM. Despite the fact that the compat-
(13) (a) The synthesis described by Naito et al. requires nine steps
and includes the resolution of racemic 3 as the final steps, cf. ref 7. (b)
Very recently, an RCM-based approach to 3 has been reported that is
distictly different from our one; it makes use of D-serine as the starting
material and comprises a 14-step linear sequence, cf. ref 12a.
(14) For a short account see: Fu¨rstner, A. Synlett 1999, 1523.
(15) For some total syntheses from our laboratory that we consider
to adhere to these objectives see: (a) Fu¨rstner, A.; Langemann, K. J .
Am. Chem. Soc. 1997, 119, 9130. (b) Fu¨rstner, A.; Mu¨ller, T. J . Am.
Chem. Soc. 1999, 121, 7814. (c) Fu¨rstner, A.; Weintritt, H. J . Am.
Chem. Soc. 1998, 120, 2817. (d) Fu¨rstner, A.; Szillat, H.; Gabor, B.;
Mynott, R. J . Am. Chem. Soc. 1998, 120, 8305. (e) Fu¨rstner, A.;
Langemann, K. J . Org. Chem. 1996, 61, 8746. (f) Fu¨rstner, A.; Seidel,
G.; Kindler, N. Tetrahedron 1999, 55, 8215. (g) Fu¨rstner, A.; Seidel,
G. J . Org. Chem. 1997, 62, 2332. (h) Fu¨rstner, A.; Grabowski, J .;
Lehmann, C. W. J . Org. Chem. 1999, 64, 8275.
(16) Review: J ohnson, R. A.; Sharpless, K. B. In Catalytic Asym-
metric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; p 103.
(17) Reviews: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413. (b) Fu¨rstner, A. Top. Catal. 1997, 4, 285. (c) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (d) Fu¨rstner,
A. Top. Organomet. Chem. 1998, 1, 37. (e) Ivin, K. J .; Mol, J . C. Olefin
Metathesis and Methathesis Polymerization, 2nd ed.; Academic Press:
New York, 1997.
(18) (a) Smith, D. B.; Wang, Z.; Schreiber, S. L. Tetrahedron 1990,
46, 4793. (b) J a¨ger, V.; Schro¨ter, D.; Koppenhoeffer, B. Tetrahedron
1991, 47, 2195.
(19) (a) Babine, R. E. Tetrahedron Lett. 1986, 27, 5791. (b) Hatakeya-
ma, S.; Sakurai, K.; Takano, S. J . Chem. Soc., Chem. Commun. 1985,
1759.
(20) Complex 18 is formed by reaction of (PPh3)3RuCl2 and
HCtCCPh2OH followed by substitution of the PPh3 ligands with PCy3
as shown in Scheme 4. Originally, it was believed that the complex
thus formed is a ruthenium allenylidene species: cf. Harlow, K. J .;
Hill, A. F.; Winton-Ely, J . D. E. T. J . Chem. Soc., Dalton Trans. 1999,
285. More detailed study, however, has shown that it is the rearranged
product, i.e., the indenylidene ruthenium complex 18: cf. Hill, A. F.;
Fu¨rstner, A.; Liebl, M.; Mynott, R.; Gabor, B.; J afarpour, L.; Nolan, S.
P., manuscript in preparation.
(21) Fu¨rstner, A.; Hill, A. F.; Liebl, M.; Winton-Ely, J . D. E. T. Chem.
Commun. 1999, 601.
(22) (a) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K.
Tetrahedron Lett. 1977, 23, 1977. (b) For a general review on Mit-
sunobu reactions see: Mitsunobu, O. Synthesis 1981, 1.

1740 J . Org. Chem., Vol. 65, No. 6, 2000
Fu¨rstner and Thiel
Sch em e 3a
Ta ble 1. F or m a tion of Tetr a h yd r oa zep in e 9 fr om Dien e
8 via RCM Ca ta lyzed by Differ en t Ru th en iu m
Com p lexesa
a
[a] Toluene, 20 h, 70 °C, 43%.
isolated from the reaction mixture is compound 14, the
structure of which has been unequivocally deduced from
NMR, IR, MS, and HRMS data (Scheme 3).
The conversion of 10 into product 14 is not a transition
metal mediated nitrene process but is just thermally
induced and takes place upon heating of azide 10 in
toluene at 70 °C in the absence of a catalyst. This result
suggests that the conversion of 10 into the desired
cycloalkene 11 via RCM might be successful if milder
conditions are used. In fact, the superior reactivity of
Schrock’s molybdenum alkylidene complex Mo(dNAr)-
(dCHCMe2Ph)[OCMe(CF3)2]223 (Ar ) 2,6-diisopropylphen-
yl) allows the reaction to occurr at 40 °C and delivers
product 11 in 94% yield.
With good access to compound 11 as the key interme-
diate of our synthesis secured, the final elaboration of
the targeted hexahydroazepine moiety of balanol is very
straightforward. Hydrogenation of 11 in MeOH contain-
ing F3CSO3H (1 equiv) saturates the heterocyclic ring,
liberates the amino group from its azido surrogate, and
simultaneously deprotects the benzyl ether function.
Acylation of the resulting amino alcohol 12 with p-
benzyloxybenzoic acid chloride delivers product 13, which
is directly amenable to the total synthesis of (-)-
balanol.4-12
a
All reactions are carried out in refluxing CH2Cl2 unless stated
b
otherwise. Catalyst 17 is replenished after the time indicated
in the table; see also Experimental Section. c In toluene at 80 °C.
Starting material (91%) recovered. e The catalyst is formed in
d
situ from [(p-cymene)RuCl2]2 (2.5 mol %) and PCy3 (5 mol %); the
reaction is carried out under irradiation of the mixture with neon
light, cf. ref 26. f In addition, 21% of product 15 have been isolated
(cf. Scheme 5).
To date, this approach constitutes the shortest (eight
steps) synthesis of the hexahydroazepine domain of (-)-1
in enantiomerically pure form and excellent overall yield.
It is worth mentioning that all key operations are
catalytic in nature (epoxidation, RCM, hydrogenolysis,
hydrogenation) and that this sequence may also lend
itself to scale-up. Finally, the route can be adapted to
the synthesis of the antipode of balanol simply by
switching from (D)-(-)-DET to (L)-(+)-DET in the initial
Sharpless epoxidation reaction, and it provides ample
opportunity for the preparation of analogues of 1 by
bifurcating from the blueprint described above at differ-
ent stages of the synthesis.
Sch em e 4
Com par ative In vestigation of Differ en t RCM Cata-
lysts. In an attempt to optimize the pivotal RCM step,
we have briefly investigated the performance of a set of
different ruthenium-based metathesis catalysts in the
conversion of diene 8 into tetrahydroazepine 9. Although
the species displayed in Table 1 were previously found
to be similarly effective in a number of cyclization
reactions, we noticed significant differences when applied
to this particular case.
satisfactory yields that served as the calibration point
for this comparative investigation (entries 1 and 2).
Replenishing the catalyst once during the reaction im-
proves the yields, thus indicating a limited lifetime of
the propagating species in solution (entries 3 and 4). We
were pleased to see that the recently disclosed inden-
ylidene carbene variant 18 performed slightly better and
gave optimum results in terms of catalyst turnover (cf.
entries 1/2 and 5).20,21 This complex is also particularly
attractive in view of its simple preparation from diphen-
ylpropargyl alcohol as the carbene source (Scheme 4).
Surprisingly, however, the cationic allenylidene species
1925, as well as the photochemically driven procedure26
in which the active species is formed in situ from
The classical Grubbs carbenes 16 and 17,24 when
applied under standard conditions (5 mol %, 2 mM
solution of the substrate in refluxing CH2Cl2, 24 h) give
(23) (a) Schrock, R. R.; Murdzek, J . S.; Bazan, G. C.; Robbins, J .;
DiMare, M.; O’Regan, M. J . Am. Chem. Soc. 1990, 112, 3875. (b)
Review: Schrock, R. R. Top. Organomet. Chem. 1998, 1, 1.
(24) (a) Nguyen, S. T.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem.
Soc. 1993, 115, 9858. (b) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J .
Am. Chem. Soc. 1996, 118, 100.

Formal Total Synthesis of (-)-Balanol
J . Org. Chem., Vol. 65, No. 6, 2000 1741
J ) 6.0, 2.3, 1.3 Hz), 2.73 (1 H, dd, J ) 12.2, 3.7 Hz), 2.65 (1
H, dd, J ) 12.2, 7.5 Hz), 2.24 (2 H, br s). 13C NMR (CDCl3,
75.5 MHz): δ 138.2, 136.7, 135.2, 128.4, 127.8, 127.6, 119.6,
Sch em e 5
115.9, 82.4, 71.6, 70.4, 52.2, 50.3. HRMS (CI) (C15H21NO2
+
H): calcd 248.1651, found 248.1655. Anal. Calcd for C15H21
-
NO2 (247.34): C 72.84, H 8.56, N 5.66. Found: C 72.87, H
8.49, N 5.75.
(2S,3R)-Allyl-(3-ben zyloxy-2-h yd r oxy-p en t-4-en yl)-ca r -
ba m ic Acid ter t-Bu tyl Ester (8). To a solution of amine 7
(494.7 mg, 2 mmol) in CH2Cl2 (20 mL) and Et3N (0.39 mL, 2.8
mmol) is added a solution of di-tert-butyl dicarbonate (Boc2O,
488.0 mg, 2.2 mmol) in CH2Cl2 (20 mL) at 0 °C, and the
resulting mixture is stirred at ambient temperature for 16 h.
Addition of water, extraction of the aqueous phase with EtOAc,
successive washing of the combined organic layers with
aqueous 2 N HCl and brine followed by drying over Na2SO4,
evaporation of the solvents, and flash chromatography of the
residue (pentane/ethyl acetate, 6/1) delivers compound 8 as a
commercially available [(p-cymene)RuCl2]2 and PCy3,
gave rather poor results. While the conversion of 8 was
low with the former catalyst, the latter system leads to
significant amounts of compound 15 (21%, mixture of
diastereomers) in addition to the desired cycloalkene 9
(49%). The formation of this byproduct is likely explained
by an initial isomerization of the double bond of allyl-
amine 8 followed by intramolecular attack of the second-
ary OH group onto the enamine thus formed (Scheme
5). The reason for this deviation from the regular me-
tathesis pathway is not yet clear since the [(p-cymene)-
RuCl2]2/PCy3/hν initiator system has shown no tendency
to isomerize double bonds in any previous application.26
pale yellow syrup (709 mg, quant.). [R]20 ) -28.4 (1.95,
D
CHCl3). 1H NMR (CDCl3, 300 MHz): δ 7.34-7.25 (5 H, m),
5.89-5.69 (2 H, m), 5.38-5.29 (2 H, m), 5.10-5.03 (2 H, m),
4.61 (1 H, d, J ) 11.8 Hz), 4.35 (1 H, d, J ) 11.8 Hz), 3.82-
3.77 (4 H, m), 3.39-3.35 (2 H, m), 3.15 (1 H, br s), 1.42 (9 H,
s). 13C NMR (CDCl3, 75.5 MHz): δ 157.5, 138.1, 135.0, 133.8,
128.3, 127.7, 127.6, 119.6, 116.2, 82.0, 80.2, 73.6, 70.3, 51.3,
50.0, 28.3. HRMS (CI) (C20H29NO4 + H) calcd 348.2175, found
348.2175. Anal. Calcd for C20H29NO4 (347.48): C 69.14, H 8.41,
N 4.03. Found: C 69.05, H 8.47, N 3.95.
Exp er im en ta l Section
Gen er a l. All reactions were carried out under Ar in
predried glassware using Schlenk techniques. The solvents
were dried by distillation over the drying agents indicated and
were stored and transferred under Ar: CH2Cl2 (P4O10), toluene
(Na/K), THF (Mg/anthracene), pyridine (KOH). Flash chro-
matography was conducted with Merck silica gel (230-400
mesh). For the instrumentation used and the spectra formats,
see the Supporting Information. Elemental analyses was
performed by Dornis & Kolbe, Mu¨lheim. NaH (suspension in
mineral oil) was thoroughly washed with pentane and dried
in vacuo prior to use; all other commercially available reagents
(Aldrich, Fluka) were used as received. Epoxyalcohol 5 (ee g
99%) was prepared from divinylcarbinol 4 (ca. 200 mmol)
according to literature procedures.18
(3S ,4R )-4-Be n zyloxy-3-h yd r oxy-2,3,4,7-t e t r a h yd r o-
a zep in e-1-ca r boxylic Acid ter t-Bu tyl Ester (9). Meth od
A (Table 1, entry 3). A solution of diene 8 (981 mg, 2.824 mmol)
and the ruthenium carbene 17 (116 mg, 0.141 mmol, 5 mol %)
in CH2Cl2 (300 mL) is refluxed for 20 h. After that time,
additional 17 (70 mg, 0.085 mmol, 3 mol %) is added, and
reflux is continued for another 22 h until TLC shows complete
conversion of the substrate. The solvent is evaporated, and
the residue is purified by flash chromatography (pentane/ethyl
acetate, 5/1 f 2/1) thus affording tetrahydroazepine 8 as a
pale yellow syrup (796 mg, 88%) that exhibits the following
analytical and spectroscopic properties: [R]20 ) -78.1 (1.54,
D
CH2Cl2). 1H NMR (CDCl3, 300 MHz): δ 7.36-7.24 (5 H, m),
5.76-5.63 (2 H, m), 4.68-4.61 (1 H, m), 4.57-4.45 (1 H, m),
4.35-4.08 (3 H, m), 3.94-3.90 (1 H, m), 3.74-3.62 (1 H, m),
3.20-3.10 (1 H, m), 2.36 (1 H, br s), 1.44 (9 H, s). 13C NMR
(CDCl3, 75.5 MHz): δ 154.9, 137.8, 130.2, 129.4, 129.0, 128.5,
127.6, 79.9, 76.8, 71.1, 70.6, 49.7, 47.8, 28.3. HRMS (CI)
(C18H25NO4 + H): calcd 320.1862, found 320.1857. Anal. Calcd
for C18H25NO4 (319.42): C 67.69, H 7.89, N 4.39. Found: C
67.53, H 7.83, N 4.39. Meth od B (Table 1, entry 5). A solution
of diene 8 (69.5 mg, 0.2 mmol) and the ruthenium indenylidene
complex 18 (9.2 mg, 0.01 mmol, 5 mol %)20,21 in CH2Cl2 (100
mL) is refluxed for 24 h. Evaporation of the solvent followed
by flash chromatography as described deliver tetrahydroazepine
9 (55.3 mg, 87%) the spectroscopic properties of which are
identical to those compiled above. Meth od C (Table 1, entry
7, and Scheme 5). Diene 8 (69.5 mg, 0.2 mmol) is added to a
solution of [(p-cymene)RuCl2]2 (3.1 mg, 0.005 mmol) and PCy3
(3.1 mg, 0.011 mmol) in CH2Cl2 (100 mL), and the resulting
mixture is refluxed for 120 h in a well illuminated hood
(OSRAM Lumilux neontubes).26 Workup as described above
delivers tetrahydroazepine 9 (31.3 mg, 49%) as well as product
15 (≈ 3:2 mixture of diastereoisomers) (14.8 mg, 21%). Proper-
(S)-2-((R)-1-Ben zyloxy-a llyl)-oxir a n e (6). NaH (1.20 g,
50 mmol) is added in small portions to a solution of epoxyal-
cohol 5 (4.43 g, 44.3 mmol)18 and (n-Bu)4NI (1.66 g, 4.5 mmol)
in THF (100 mL). After the evolution of gas has ceased, benzyl
bromide (10.7 mL, 90 mmol) is slowly introduced via syringe,
and the resulting suspension is stirred at ambient temperature
for 14 h. The reaction is carefully quenched by slow addition
of aqueous saturated NaHCO3, the aqueous layer is repeatedly
extracted with Et2O, the combined organic phases are dried
(Na2SO4), the solvent is evaporated, and the residue is purified
by flash chromatography (pentane/Et2O, 20/1) thus affording
product 6 as a colorless syrup (7.97 g, 95%). [R]20 ) -31.8
D
1
(1.36, CHCl3). H NMR (CDCl3, 300 MHz): δ 7.34-7.24 (5 H,
m), 5.88-5.76 (1 H, m), 5.37-5.31 (2 H, m), 4.63 (1 H, d, J )
11.9 Hz), 4.46 (1 H, d, J ) 11.9 Hz), 3.80 (1 H, dd, J ) 7.4, 4.2
Hz), 3.07 (1 H, m), 2.76 (1 H, dd, J ) 5.2, 4.0 Hz), 2.67 (1 H,
dd, J ) 5.2, 2.6 Hz). 13C NMR (CDCl3, 75.5 MHz): δ 138.1,
134.4, 128.3, 127.6, 127.5, 119.5, 79.3, 70.6, 53.2, 44.8. HRMS
(CI) (C12H14O2) calcd 190.1002, found 190.0994.
(2S,3R)-1-Allyla m in o-3-ben zyloxy-p en t-4-en -2-ol (7). A
solution of epoxide 6 (7.90 g, 41.5 mmol) in freshly distilled
allylamine (62.5 mL, 830 mmol) is refluxed for 40 h. Excess
allylamine is distilled off under reduced pressure. The re-
maining amine 7 is analytically pure and can be used in the
1
ties of compound 15 (Ma jor isom er ) H NMR (CD2Cl2, 200
MHz): δ 7.35-7.25 (5 H, m), 5.78-5.70 (1 H, m), 5.40-5.38
(1 H, m), 5.34-5.30 (1 H, m), 5.16 (1 H, dd, J ) 5.8, 5.8 Hz),
4.60 (1 H, d, J ) 11.8 Hz), 4.37 (1 H, d, J ) 11.8 Hz), 4.22-
4.14 (1 H, m), 3.96-3.75 (2 H, m), 3.36 (1 H, dd, J ) 10.5, 6.9
Hz), 1.79-1.57 (2 H, m), 1.42 (9 H, s), 0.88 (3 H, t, J ) 7.5
Hz). 13C NMR (CD2Cl2, 50.3 MHz): δ 157.4, 138.9, 135.5, 128.7,
128.2, 127.9, 119.6, 90.7, 81.5, 80.9, 78.9, 71.1, 47.3, 28.5, 27.8,
7.7. HRMS (CI) (C20H29NO4): calcd 347.2097, found 347.2095.
Anal. Calcd for C20H29NO4 (347.48): C 69.14, H 8.41, N 4.03.
Found: C 69.06, H 8.34, N 4.06. (Min or Isom er ) 1H NMR
(CD2Cl2, 200 MHz): δ 7.35-7.25 (5 H, m), 5.87-5.77 (1 H,
m), 5.40-5.38 (1 H, m), 5.34-5.30 (1 H, m), 5.06 (1 H, dd, J )
next step without further purification. Pale yellow syrup
1
(9.66 g, 94%). [R]20 ) -36.5 (2.04, CHCl3). H NMR (CDCl3,
D
300 MHz): δ 7.33-7.25 (5 H, m), 5.91-5.76 (2 H, m), 5.37-
5.33 (2 H, m), 5.16-5.03 (2 H, m), 4.62 (1 H, d, J ) 11.9 Hz),
4.36 (1 H, d, J ) 11.9 Hz), 3.77-3.73 (2 H, m), 3.21 (2 H, ddd,
(25) Fu¨rstner, A.; Picquet, M.; Bruneau, C.; Dixneuf, P. H. Chem.
Commun. 1998, 1315.
(26) Fu¨rstner, A.; Ackermann, L. Chem. Commun. 1999, 95.

1742 J . Org. Chem., Vol. 65, No. 6, 2000
Fu¨rstner and Thiel
5.4, 3.1 Hz), 4.63 (1 H, d, J ) 11.8 Hz), 4.43 (1 H, d, J ) 11.8
Hz), 4.04-3.98 (1 H, m), 3.96-3.75 (2 H, m), 3.10 (1 H, dd, J
) 10.2, 9.1 Hz), 1.79-1.57 (2 H, m), 1.44 (9 H, s), 0.86 (3 H, t,
J ) 7.5 Hz). 13C NMR (CD2Cl2, 50.3 MHz): δ 157.4, 138.9,
135.4, 128.7, 128.2, 127.9, 119.7, 90.4, 80.9, 80.0, 78.5, 71.1,
46.3, 28.5, 27.8, 8.3.
(2R,3R)-Allyl-(2-a zid o-3-b en zyloxy-p en t -4-en yl)-ca r -
ba m ic Acid ter t-Bu tyl Ester (10). To a solution of alcohol 8
(347.5 mg, 1.0 mmol) in THF (20 mL) are added PPh3 (1.05 g,
4.0 mol) and (PhO)2P(O)N3 (0.86 mL, 4.0 mmol). Diethyl
azodicarboxylate (DEAD, 0.63 mL, 4.0 mmol) is then added
dropwise via syringe, and the resulting mixture is stirred at
ambient temperature for 2 h. For workup, the solvent is
evaporated, the residue is suspended in EtOAc, insoluble
residues are removed by filtration through a short pad of silica,
and the filtrate is diluted with EtOAc and subsequently
washed with aqueous 2 N HCl and brine. The organic phase
is dried (Na2SO4), the solvent is evaporated, and the residue
is purified by flash chromatography (pentane/Et2O, 20/1) thus
w/w) is added to a solution of compound 11 (194 mg, 0.563
mmol) and trifluoromethanesulfonic acid (50 µL, 0.563 mmol)
in MeOH (15 mL), and the resulting suspension is stirred
under H2 (1 atm) for 14 h. The catalyst is filtered off through
a pad of Celite which is carefully rinsed with MeOH in several
portions. Evaporation of the solvent provides amine 12, which
is used in the subsequent step without further purification.
Et3N (0.79 mL, 5.63 mmol) and oxalyl chloride (73 µL, 0.845
mmol) are added to a solution of 4-benzyloxybenzoic acid (193
mg, 0.845 mmol) in CH2Cl2 (10 mL) at 0 °C, and the resulting
mixture is stirred for 30 min at ambient temperature. The acid
chloride thus formed is added to a solution of crude amine 12
prepared as described above. After stirring for 2 h at ambient
temperature, the reaction is quenched by the addition of MeOH
and pyridine, all volatiles are removed in vacuo, the residue
is dissolved in EtOAc, the organic phase is successively washed
with aqueous 2 N HCl, water, aqueous saturated NaHCO3,
and brine and is dried over Na2SO4 prior to evaporation of the
solvent. Purification of the crude product by flash chromato-
graphy (hexane/ethyl acetate, 1/1) provides the title compound
leading to analytically pure azide 10 as a colorless syrup (218
1
mg, 59%). [R]20 +38.1 (8.84, CH2Cl2). H NMR (CD2Cl2, 300
13 as colorless crystals (135 mg, 55% over both steps). [R]20
D
D
MHz): δ 7.37-7.28 (5 H, m), 5.85-5.70 (2 H, m), 5.43-5.34
(2 H, m), 5.14-5.05 (2 H, m), 4.63 (1 H, d, J ) 11.7 Hz), 4.37
(1 H, d, J ) 11.7 Hz), 4.03-3.61 (4 H, m), 3.48-3.42 (1 H, m),
3.10-2.99 (1 H, m), 1.45 (9 H, s). 13C NMR (CD2Cl2, 75.5
MHz): δ 155.3, 138.4, 135.1, 134.4, 128.6, 128.1 128.0, 120.5,
116.1, 81.7, 80.1, 70.7, 64.9, 50.9, 47.9, 28.4. HRMS (CI)
(C20H28N4O3 + H): calcd 373.2240, found 373.2240. Anal. Calcd
for C20H28N4O3 (372.47): C 64.49, H 7.58, N 15.04. Found: C
64.58, H 7.53, N 14.92.
) -2.4 (1.16, CH3OH). 1H NMR (CD2Cl2, 300 MHz): δ 8.92 (1
H, d, J ) 5.1 Hz), 7.86 (2 H, d, J ) 8.8 Hz), 7.47-7.34 (5 H,
m), 7.04 (2 H, d, J ) 8.8 Hz), 5.20 (1 H, br s), 5.13 (2 H, s),
4.07-4.00 (3 H, m), 3.78-3.72 (1 H, m), 3.29 (1 H, dd, J )
15.4, 5.1 Hz), 2.76 (1 H, td, J ) 12.2, 3.8 Hz), 1.89-1.59 (4 H,
m), 1.50 (9H, s). 13C NMR (CD2Cl2, 75.5 MHz): δ 168.4, 161.9,
157.7, 136.9, 129.3, 128.9, 128.4, 127.9, 126.5, 114.9, 80.9, 79.8,
70.4, 61.1, 50.6, 50.0, 33.1, 28.5, 27.4. HRMS (CI) (C25H32N2O5
+ H): calcd 441.2389, found 441.2371.
(3R,4R)-3-Azido-4-ben zyloxy-2,3,4,7-tetr ah ydr oazepin e-
1-ca r boxylic Acid ter t-Bu tyl Ester (11). Meth od A. A
solution of diene 10 (72 mg, 0.193 mmol) and the molybdenum
alkylidene complex Mo(dNAr)(dCHCMe2Ph)[OC(Me)(CF3)2]2
(Ar ) 2,6-diisopropylphenyl) (15 mg, 0.019 mmol)23 in carefully
degassed CH2Cl2 (20 mL) is refluxed for 30 min. Evaporation
of the solvent followed by flash chromatography of the crude
product (hexane/ethyl acetate, 20/1 f 10/1) gives compound
11 as a pale yellow syrup (63 mg, 94%). Meth od B. A solution
of diethyl azodicarboxylate (DEAD, 0.126 mL, 0.8 mmol) is
added dropwise via syringe to a solution of alcohol 9 (63.8 mg,
0.2 mmol), PPh3 (209 mg, 0.8 mmol), and (PhO)2P(O)N3 (0.172
mL, 0.8 mmol) in THF (5 mL), and the resulting mixture is
stirred for 4 h at ambient temperature. For workup, the solvent
is evaporated, the residue is suspended in EtOAc (10 mL),
insoluble residues are filtered off through a short pad of silica
and the filtrate is diluted with EtOAc. The organic phase is
washed with aqueous 2 N HCl and brine and dried over
Na2SO4, the solvent is evaporated, and the crude product is
purified by flash chromatography (pentane/tert-butylmethyl
ether, 20/1) to afford compound 11 as a pale yellow syrup (63
mg, 91%). [R]20D ) -26.3 (2.65, CH2Cl2). 1H NMR (CD2Cl2, 300
MHz): δ 7.40-7.29 (5 H, m), 5.76 (2 H, br s), 4.67 (1 H, d, J
) 11.5 Hz), 4.55 (1 H, d, J ) 11.5 Hz), 4.27-3.97 (2 H, m),
3.85-3.54 (4 H, m), 1.45 (9 H, s). 13C NMR (CD2Cl2, 75.5
MHz): δ 155.1, 138.3, 131.1, 129.8, 128.7, 128.3, 128.1, 80.5,
(R)-3-((R)-1-Ben zyloxy-a llyl)-5-m eth yl-6-oxo-3,6-d ih y-
d r o-2H-p yr a zin e-1-ca r boxylic Acid ter t-Bu tyl Ester (14).
A solution of azide 10 (72.0 mg, 0.193 mmol) in toluene (20
mL) is stirred at 70 °C for 20 h. Evaporation of the solvent
followed by flash chromatography (hexane/ethyl acetate, 4/1)
delivers product 14 as a colorless syrup (30.0 mg, 43%). 1H
NMR (CD2Cl2, 300 MHz): δ 7.33-7.27 (5 H, m), 5.96-5.83 (1
H, m), 5.36-5.29 (2 H, m), 4.63 (1 H, d, J ) 11.9 Hz), 4.39 (1
H, d, J ) 11.9 Hz), 4.08 (1 H, m), 3.93 (1 H, dd, J ) 13.1, 4.3
Hz), 3.81-3.73 (1 H, m), 3.55 (1 H, dd, J ) 13.1, 10.3 Hz),
2.18 (3 H, d, J ) 2.3 Hz), 1.49 (9H, s). 13C NMR (CD2Cl2, 75.5
MHz): δ 163.2, 156.2, 151.8, 138.6, 135.2, 128.7, 128.1, 128.0,
119.5, 83.9, 81.2, 71.0, 60.5, 44.4, 28.0, 21.4. HRMS (CI)
(C20H26N2O4 + H): calcd 359.1971, found 359.1973. Anal. Calcd
for C20H26N2O4 (358.44): C 67.02, H 7.31, N 7.82. Found: C
67.12, H 7.26, N 7.70.
Ack n ow led gm en t. We thank Dr. U. Widmer, F.
Hoffmann-LaRoche Ltd., Basel, for helpful discussions.
Generous financial support by the Max-Planck-Gesell-
schaft, the Deutsche Forschungsgemeinschaft (Leibniz
program), and the Fonds der Chemischen Industrie is
acknowledged with gratitude.
Su p p or tin g In for m a tion Ava ila ble: Compilation of the
IR and MS data of all products, and copies of the NMR spectra
of all new compounds. This material is available via the
Internet at http://www.acs.org.
79.1, 72.3, 64.0, 48.8, 47.5, 28.4. HRMS (CI) (C18H24N4O3
+
H): calcd 345.1927, found 345.1921. Anal. Calcd for C18H24N4O3
(344.41): C 62.77, H 7.02, N 16.27. Found: C 62.72, H 6.94,
N 16.19.
(3R ,4R )-3-(4-Be n zyloxy-b e n zoyla m in o)-4-h yd r oxy-
a zep a n e-1-ca r boxylic Acid ter t-Bu tyl Ester (13). Pd/C (5%
J O991611G