Total synthesis of (±)- and (+)-valienamine via a strategy derived from new palladium-catalyzed reactions

Article abstract of DOI:10.1021/ja973081g

A new strategy toward glycosidase inhibitors, represented by valienamine, which is such an inhibitor itself as well as a critical unit of pseudooligosaccharides that function this way, evolved from two newly developed palladium-catalyzed reactions. The applicability of a palladium(0)-catalyzed net regioselective cis-hydroxyamination derives from the reaction of vinyl epoxides with isocyanates. The utilization of a cocatalyst in this reaction is required in this case and may prove generally useful. A bidentate phosphate proved to be the most effective ligand. The requisite substrate was available via a Diels-Alder protocol and allowed the obtention of (±)-valienamine in only seven steps. The inability to perform the Diels-Alder reaction asymmetrically led to a different asymmetric synthesis of the pivotal epoxide intermediate in enantiomerically pure form, which derived from asymmetric palladium-catalyzed reactions. Using the desymmetrization of meso enedicarboxylates, the net equivalence of an asymmetric cis-hydroxycarboxylation led to the enantiomerically pure desired epoxide. (+)-Valienamine was available in 14 steps by this route.

Full text of DOI:10.1021/ja973081g

1732
J. Am. Chem. Soc. 1998, 120, 1732-1740
Total Synthesis of (()- and (+)-Valienamine via a Strategy Derived
from New Palladium-Catalyzed Reactions
Barry M. Trost,* Louis S. Chupak, and Thomas Lu1bbers
Contribution from the Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
ReceiVed September 2, 1997
Abstract: A new strategy toward glycosidase inhibitors, represented by valienamine, which is such an inhibitor
itself as well as a critical unit of pseudooligosaccharides that function this way, evolved from two newly
developed palladium-catalyzed reactions. The applicability of a palladium(0)-catalyzed net regioselective cis-
hydroxyamination derives from the reaction of vinyl epoxides with isocyanates. The utilization of a cocatalyst
in this reaction is required in this case and may prove generally useful. A bidentate phosphite proved to be
the most effective ligand. The requisite substrate was available via a Diels-Alder protocol and allowed the
obtention of (()-valienamine in only seven steps. The inability to perform the Diels-Alder reaction
asymmetrically led to a different asymmetric synthesis of the pivotal epoxide intermediate in enantiomerically
pure form, which derived from asymmetric palladium-catalyzed reactions. Using the desymmetrization of
meso enedicarboxylates, the net equivalence of an asymmetric cis-hydroxycarboxylation led to the enantio-
merically pure desired epoxide. (+)-Valienamine was available in 14 steps by this route.
The development of a new methodology offers the op-
valienamine including validamine, valiolamine, and hydroxy-
portunity to open new strategies for the total synthesis of
complex natural products. We had developed a reaction that,
combined with epoxidation, allows the net equivalent of a
chemo-, regio-, and diastereoselective cis-hydroxyamination.1
Similarly, our efforts in developing asymmetric allylic alkyla-
tions have led to a sequence effecting the net equivalent of an
asymmetric cis vicinal hydroxycarboxylation.2 These methods
appear to be particularly suitable for the synthesis of glycosidase
inhibitors.
The importance of polysaccharides in a myriad of cellular
functions including energy transfer and storage, intercellular
communication and recognition, and intramolecular protein and
lipid function makes their processing an interesting target for
the design and development of therapeutic agents. Pseudooli-
gosaccharides represented by acarbose,3 adiposin,4 trestatin,5 and
amylostatin,6 are potent glycosidase inhibitors and have thera-
peutic value. For example, acarbose inhibits degradation of
sucrose and starch, the former leading to its use as an oral
antidiabetic.7 Additionally, the validamycin A complex is an
antifungal used in the treatment of rice sheath blight.8
Common to all of these pseudooligosaccharides is the
aminocyclitol unit valienamine (1).9 Derivatives related to
validamine are also found as components of pseudooligosac-
charides.4,10 It has also been shown that these aminocyclitols
are potent glycosidase inhibitors in their own right. The
N-alkylated valiolamine AO-128 is also undergoing clinical
(1) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987, 109, 3792.
(2) Trost, B. M.; Li, L.; Guile, S. D. J. Am. Chem. Soc. 1992, 114, 8745.
(3) Schmidt, D.; Frommer, W.; Junge, B.; Mu¨ller, K.; Wingender, W.;
Trutsheit, E. Naturwissenschaften 1977, 64, 536.
(4) Kameda, Y.; Asano, N.; Yoshikawa, M.; Mabui, K.; Horii, S.;
Fukawase, H. J. Antibiot. 1983, 36, 1157.
(5) Itoh, J.; Omoyo, S.; Shomura, T.; Ogino, H.; Iwamatsu, K.; Inouye,
S. J. Antibiot. 1981, 34, 1424, 1429.
(6) Sakairi, N.; Kuzuhara, H. Tetrahedron Lett. 1982, 23, 5327.
(7) Hillebrand, J.; Berchtold, P. In Enzyme Inhibitors; Brodbeck, U., Ed.;
Verlag Chemie: Basel, 1980; p 153.
(8) Kameda, Y.; Asano, N.; Yoshikawa, M.; Matsui, K. J. Antibiot. 1980,
33, 1575. Kameda, Y.; Asano, N.; Yoshikawa, M.; Matsui, K.; Horii, S.;
Fukase, H. J. Antibiot. 1982, 35, 1624.
trials for use as an oral antidiabetic. Their potent activity and
the success of analogues stimulated much synthetic activity.
Valienamine has been synthesized in both racemic and enan-
tiomerically pure form. In all but three cases, the stereochem-
istry of the oxygens at carbons 4, 5, and 6 is derived from
D-glucose.11 In the other instances, the stereochemistry derived
from the cyclitol quebrachitol12 or from resolution of a Diels-
(9) Kameda, Y.; Horii, S. J. Chem. Soc., Chem. Commun. 1972, 746,
747. Kameda, Y.; Asano, N.; Teranoshi, M.; Amatsui, K. J. Antibiot. 1980,
33, 1573.
(10) Horri, S.; Fukase, H.; Matsuo, T.; Asano, N.; Matsui, K. J. Med.
Chem. 1986, 29, 1038.
S0002-7863(97)03081-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/12/1998

Total Synthesis of (()- and (+)-Valienamine
Scheme 1. Retrosynthesis of (+)-Valienamine
J. Am. Chem. Soc., Vol. 120, No. 8, 1998 1733
Chart 1
Alder adduct.13 A significant drawback of many of these routes
arises from lengthy protecting group manipulation. We wish
to record a new strategy for the synthesis of (()- and
(+)-valienamine that provides an efficient approach to racemic
valienamine and the ability to convert this strategy into an
asymmetric synthesis. In the course of these studies, a new
protocol invoking the importance of cocatalysis for the pal-
ladium-based cis-hydroxyamination sequence and a new ap-
plication of the asymmetric palladium-catalyzed hydroxycar-
boxylation15 sequence evolved.
Figure 1. Molecular modeling of 6a.
reaction followed by epoxidation as in eq 1 (Chart 1).16 To
minimize aromatization in the Diels-Alder reaction, the reaction
was performed without solvent and at 80 °C. Methylene blue
was added to minimize polymerization of the reactants. In some
runs, small amounts of ethyl benzoate and the silyl ether of
ethyl salicylate could be detected by GC and 1H NMR. Because
of the sensitivity of 6, it was generally used directly in the next
step without purification. Chemoselective epoxidation with
m-CPBA in methylene chloride gave a 78% yield of a 9:1 ratio
of 5a:7a. Almost identical results were obtained in benzene,
but the workup proved more facile using methylene chloride.
The major isomer was assigned as depicted based upon
consideration of molecular modeling and precedent.16 As
depicted in Figure 1, the nearly planar nature of the cyclohexa-
diene ring places the siloxy group virtually orthogonal to that
plane and suggests a bias for the epoxidizing agent to approach
trans to the siloxy group. The 9:1 mixture was not resolvable
and thus was employed in the next step.
Retrosynthesis
Scheme 1 presents a retrosynthetic analysis. A key aspect
of this strategy is the installation of the amino alcohol unit via
an opening of an allylic epoxide with net retention of config-
uration (transformation 3 f 2).14 The relative stereochemistry
of the oxygen substituents of 3 derives from steric control by
the allylic silyl ethers during epoxidation of 4 and 6. This
sequence translates into an asymmetric synthesis if 6 can be
made enantiomerically pure.
Synthesis of (()-Valienamine
The synthesis of 5 followed the literature precedent for the
synthesis of the triethylsilyl derivative via a Diels-Alder
(11) (a) Park, T. K.; Danishefsky, S. J. Tetrahedron Lett. 1994, 35, 2667.
(b) Nicotra, F.; Panza, L.; Ronchetti, F.; Russo, G. Gazz. Chim. Ital. 1989,
119, 577. (c) Sakairi, N.; Kuzuhara, H. Tetrahedron Lett. 1982, 23, 5327.
(d) Schmidt, R. R.; Ko¨hn, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 482.
(e) Fukase, H.; Horii, S. J. Org. Chem. 1992, 57, 3642, 3651. (f) Yoshikawa,
M.; Cha, B. C.; Okaichi, Y.; Takinami, Y.; Yokokawa, Y.; Kitagawa, I.
Chem. Pharm. Bull. 1988, 36, 3714, 4236. (g) For a synthesis of the
racemate, see: Ogawa, S.; Chida, N.; Suami, T. J. Org. Chem. 1983, 48,
1023.
Base-promoted E2 elimination in the presence of a silyl
chloride simultaneously ring opened the epoxide and silylated
the alcohol to give the cyclohexadiene 8a (eq 2, Chart 2). DBU
assisted by a catalytic amount of DMAP at room temperature
gave a 76% yield in methylene chloride and a 74% yield in
benzene. Aromatization was avoided by the use of ambient
temperature and only a small excess of base. After flash
(12) Paulsen, H.; Heiker, F. R. Annalen 1981, 2180.
(13) (a) Knapp, S.; Naughton, A. B. J.; Dhar, T. G. M. Tetrahedron
Lett. 1992, 33, 1025. (b) Ogawa, S.; Shibata, Y.; Nose, T.; Suami, T. Bull.
Chem. Soc. Jpn. 1985, 58, 3387. (c) Ogawa, S.; Iwasawa, T.; Nose, T.;
Suami, S.; Ito, M.; Saito, Y. J. Chem. Soc., Perkin Trans. 1 1985, 903.
(14) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987, 109, 3792.
Trost, B. M.; Hurnaus, R. Tetrahedron Lett. 1989, 28, 375.
(15) Trost, B. M.; Li, L.; Guile, S. D. J. Am. Chem. Soc. 1992, 114,
8745.
(16) (a) Schlessinger, R. H.; Lopes, A. J. Org. Chem. 1981, 46, 2. (b)
After our work, the Diels-Alder utilized herein was reported; see:
Kozlowski, M. C.; Tom, N. J.; Seto, C. T.; Sefler, A. M.; Bartlett, P. A. J.
Am. Chem. Soc. 1995, 117, 2128. Kozlowski, M. C.; Bartlett, P. A. J. Am.
Chem. Soc. 1991, 113, 5897.

1734 J. Am. Chem. Soc., Vol. 120, No. 8, 1998
Trost et al.
Chart 2
capture with ring closure at O rather than N to give 11a in
modest yield. Assuming that N-protonated 15 was the species
cyclizing, a Lewis acid that might preferentially coordinate at
O rather than at N was employed. Indium acetylacetonate17
proved ineffective. On the other hand, use of trimethyltin
acetate18 was successful but still produced both 10 and 12 with
triisopropyl phosphite as the ligand. The optimum conditions
employed 5 mol % of palladium acetate, 15 mol % of bidentate
ligand 14 (to minimize hydrogen shift), and 10 mol % of
trimethyltin acetate to produce a 54% yield of 10a in addition
to a 19% yield of 11a. It should be noted that the O-alkylated
product 11a can isomerize to the thermodynamically more stable
N-alkylated product 10a.
Figure 2. Molecular modeling of 8a.
Adjustment of the ester oxidation level simultaneously cleaves
the oxazolidinone. LAH proved too indiscriminate. DIBAL-H
served well. The oxazolidinone was more reactive than the
ester. Thus, with 2 equiv of DIBAL-H, a 1.6:1 ratio of 17a
and 16a was obtained in addition to recovered starting material.
Figure 3. Molecular modeling of 9a.
chromatography, only the trans diastereomer 8a was isolated.
The loss of the minor diastereomer 7a may derive from a faster
base-catalyzed aromatization since small amounts of an aromatic
product could be detected in the crude reaction product.
Figure 2 depicts the most stable conformation of 8a based
upon a molecular mechanics calculation. This model indicates
that the orthogonality of both siloxy groups with respect to the
plane of the cyclohexadiene hinders both faces for chemose-
lective epoxidation. The greater proximity of the 5-siloxy group
to the double bond suggests its effect should be larger.
Gratifyingly, epoxidation with m-CPBA proceeded at room
temperature in 86% yield to give a single diastereomer assigned
as 9a. The trans-diaxial nature of the siloxy groups is confirmed
by the 2.1-Hz coupling of the vicinal hydrogens at C-5 and C-6.
More significantly, a W-type long-range 2.1-Hz coupling
between C-4 and C-6 supports the stereochemistry of the
epoxidation as depicted (see Figure 3). The epoxide 9a is quite
stable as suggested by the fact it can be distilled at 200 °C at
0.05 Torr without decomposition.
The key step is the ring opening of the epoxide 9 with a
nitrogen nucleophile at the allylic position with retention of
configuration. We turned to the palladium-catalyzed addition
of isocyanates with vinyl epoxides as illustrated in eq 3 (Chart
3). Treatment of epoxide 9a under the previously employed
conditions of (dba)3Pd2‚CHCl3 and triisopropyl phosphite gave
no reaction. A number of variations summarized in a table in
the supporting information, involving changes of ligands and
palladium, led to either no reaction, the product of hydrogen
shift 12, or uncharacterized products.
No products wherein the ester but not the oxazolidinone was
reduced were detected. On the other hand, the “ate” complex
between DIBAL-H and n-butyllithium produced a 1.4:1 ratio
of 16b:16a; i.e., no reduction of the ester was observed.
Employing 5.5 equiv of DIBAL-H produced 17b predominantly
with some amount of the formate 17a. For the best yields,
quenching of the reaction proved important. Addition of a
mixture of 30% aqueous potassium tartrate and triethanolamine
was efficaceous. It was best to treat the crude mixture of 17a
and 17b with methanolic sodium methoxide. In this way, a
76% yield of 17b was obtained from 10a.
The final stage involves removal of the protecting groups.
In the first iteration, the tosyl group of 17b was first removed
using sodium in liquid ammonia, but only a 40% yield (brsm)
of the amine 18 was obtained (eq 4, Chart 4). Desilylation of
18 using TBAF gave (()-valienamine (1), which was character-
ized as its pentaacetate 20 in 50% yield. A more satisfactory
sequence inverted the two steps. Desilylation of 17b with TBAF
gave a 55% yield of N-tosylvalienamine (19), which improved
to 82% upon use of aqueous HF in acetonitrile. Dissolving
(17) Cf.: Trost, B. M.; Sharma, S.; Schmidt, T. J. Am. Chem. Soc. 1992,
114, 7904. Trost, B. M.; Sharma, S.; Schmidt, T. Tetrahedron Lett. 1993,
34, 7183.
(18) Cf.: Trost, B. M.; King, S. A.; Schmidt, T. J. Am. Chem. Soc. 1989,
111, 5902.
Addition of camphorsulfonic acid to promote ionization and
stabilize the intermediate 13 by protonation led to the desired

Total Synthesis of (()- and (+)-Valienamine
J. Am. Chem. Soc., Vol. 120, No. 8, 1998 1735
Chart 3
Chart 4
Chart 5
metal reduction of 19 provided (()-valienamine, which was
characterized as its pentaacetate in 56% yield. A more
convenient operation started with oxazolidinone 10 through the
four steps without purification of any intermediates to deliver
the pentaacetate 20 in 33% overall yield (average 76% per step),
which is identical with what is obtained wherein each step begins
with purified material. Thus, this sequence requires seven steps
to (()-valienamine and proceeds in 10-15% overall yield from
ethyl propiolate and 1-(tert-butyldimethylsiloxy)-1,3-butadiene,
the latter being available in one step from crotonaldehyde.19
methylmandeloxy)-1,3-butadiene,19,21 unsuccessfully. Use of an
acrylate synthon of a propiolate such as the sulfones 21 and 22
in order to examine a chiral auxiliary as well as a chiral Lewis
acid-catalyzed reaction did not give encouraging results.
A completely different strategy emerges from the consider-
ation of the introduction of a double bond R to the ester of 23
(eq 5, Chart 5). An asymmetric synthesis of 23 via an
Asymmetric Synthesis
An asymmetric synthesis of cyclohexadiene 6 converts the
above sequence into an asymmetric synthesis of valienamine.
The most direct method would be an asymmetric Diels-Alder
reaction. In contrast to the case of acrylate-type dienophiles,
the propiolate type have not been examined very extensively
and the reported studies have not been encouraging.20 We
examined the use of a diene containing a chiral auxiliary, 1-(O-
(19) Trost, B. M.; Chupak, L. S.; Lu¨bbers, T. J. Org. Chem. 1997, 62,
736.
(20) Ishihara, K.; Kondo, S.; Kurihara, H.; Yamamoto, H.; Ohashi, S.;
Inagaki, S. J. Org. Chem. 1997, 62, 3026.
(21) Trost, B. M.; O’Krongly, D.; Belletire, J. L. J. Am. Chem. Soc.
1980, 102, 7595. Tripathy, R.; Carroll, P. J.; Thornton, E. R. J. Am. Chem.
Soc. 1991, 113, 7630 and earlier references therein.

1736 J. Am. Chem. Soc., Vol. 120, No. 8, 1998
Trost et al.
Chart 6
Chart 7
asymmetric Diels-Alder reaction is a potentially more tradi-
tional approach. However, this asymmetric Diels-Alder reac-
tion has not been recorded.22 An alternative strategy from
dibenzoate 24, however, also looked very attractive, especially
since 24 is available in one step from cyclohexa-1,3-diene.23
Larger scale asymmetric alkylations of the dibenzoate with
(phenylsulfonyl)nitromethane at 0.8 M (with respect to 24) were
best performed in 3:1 THF-water rather than pure THF to
maintain homogeneity (eq 6, Chart 6). Under these conditions,
alkylation to form 25 was complete within 15 min with less
than 0.25 mol % of the palladium catalyst. The second stage
of the alkylation leading to the cyclized product 26 requires a
“mismatched” ionization and was therefore considerably slower.
Thus, it proved effective to add an achiral catalyst at this stage,
tetrakis(triphenylphosphine)palladium, to complete the cycliza-
tion in a shorter time frame. In this way, isoxazoline-N-oxide
26 was reproducibly obtained in 87% yield and with >99% ee.
The product was deoxygenated with stannous chloride, solvo-
lyzed to the methoxy derivative, and reduced with molybdenum
hexacarbonyl as previously described15 to give 23 enantiomeri-
cally pure. In the isoxazole reduction, it was essential to adsorb
the crude reaction onto silica gel and expose it to air overnight
for good yields, presumably to aid decomplexation of the metal
from the product.24 Sulfenylation of the dianion25 generated
from 23 with 2,2-dipyridyl disulfide26 gave a 4:1 separable
mixture of diastereomers (eq 7, Chart 7). The major one was
assigned as depicted in 27a based upon delivery of the
sulfenylating agent trans to the alkoxy group. The fact that
this new stereocenter is subsequently lost led us not to rigorously
establish this stereochemistry. After protection of the free
hydroxyl group to form 28a, oxidation gave a 1:1 mixture of
diastereomers of the sulfoxide 28c. Thermolysis in toluene
effected elimination of one diastereomer to 6b. Attempts to
force the less reactive sulfoxide to eliminate by increasing the
reaction time or temperature gave mostly aromatized product.
Attempts to influence the ratio of sulfoxide diastereomers by
changing the oxidizing agent were not extensively made because
the use of selenium results in a resolution of the problem.
Because selenoxides are more labile than sulfoxides and also
epimerize at selenium rather rapidly, whereas sulfoxides do
not,27 we anticipated the above difficulty would be circum-
vented. Selenylation proceeded equivalently to sulfenylation
to give a 5:1 ratio of diastereomers that readily separated, the
major one being depicted as 27b. Silylation to 28b and
oxidation with m-CPBA at -78 °C forms the selenoxide 28d.
Warming to 0 °C at this point only effected aromatization. On
the other hand, addition of 2-methoxypropene as a selenenic
acid trap prior to warming did produce the desired diene 6b.
Both selenide diastereomers participate equally well in the
elimination. Thus, the mixture of selenide diastereomers was
normally employed for the elimination. As before, the sensitiv-
ity of this cyclohexadiene, which requires only the elimination
of a silanol to aromatize, led us to effect direct epoxidation to
give the stable epoxides 5b and 7b in a 9:1 ratio as before.
The sequence from the epoxide 5b generally follows that used
for racemic substrates in the ethyl ester series with the yields
being somewhat higher in most cases. The yield of the silylative
oxide ring opening to 8b improved to 90% by adding the
epoxide to a mixture of the silyl chloride, DMAP, and DBU.
Its epoxidation to 9b proceeded in 88% yield. The critical
conversion of the epoxide 9b to the oxazolidinone 10b occurred
in 70% yield with only a small amount of the O-alkylated
compound 11b being observed by changing the order of addition
(see Experimental Section). Transformation of oxazolidinone
to (+)-valienamine, isolated as its pentaacetate, was performed
without isolation of the intermediates in 31% overall yield for
four steps (average 75% yield per step). Comparison of the
(22) For an asymmetric reaction of 1-acetoxy-1,3-butadiene using a chiral
auxiliary, see: Mayer, S. C.; Pfizenmayer, A. J.; Jouillie´, M. M. J. Org.
Chem. 1996, 61, 1655.
(23) Ba¨ckvall, J. E.; Granberg, K. L.; Hopkins, R. B. Acta Chim. Scand.
1990, 44, 492.
(24) Guarna, A.; Guidi, A.; Gote, A.; Drandi, A.; Desarlo, F. Synthesis
1989, 175.
(25) Hermann, J. L.; Schlessinger, R. H. Tetrahedron Lett. 1973, 26,
2429.
(26) Trost, B. M.; Parquette, J. F. J. Org. Chem. 1993, 58, 1579.
(27) Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1.

Total Synthesis of (()- and (+)-Valienamine
J. Am. Chem. Soc., Vol. 120, No. 8, 1998 1737
spectral properties to those recorded confirms its identity. Our
[R]D +23.8 (c ) 0.5, CHCl3) compares favorably to the
literature, [R]D +23.4 (c ) 0.77, CHCl3)13a and +24 (c ) 1,
CHCl3).11b The asymmetric synthesis requires 14 steps from
dibenzoate 24 to give valienamine in 1-2% overall yield.
crotepoxide, pipepoxide,16a and an isochorismate synthase
inhibitor16b as well as cyclitols and aminocyclitols in general.
Experimental Section
Reactions were generally conducted under a positive pressure of dry
nitrogen within flame-dried glassware. Reactions were sealed with red
rubber septa and magnetically stirred. THF and diethyl ether were
distilled from sodium/benzophenone ketyl prior to use. Methylene
chloride and acetonitrile were distilled from calcium hydride prior to
use. Methanol was distilled from magnesium methoxide prior to use.
Common reagents and materials were purchased from commercial
sources and purified by recrystallization or distillation. Anhydrous
solvents and reaction mixtures were transferred by oven-dried syringe
or cannula. Flash chromatography employed ICN silica gel (Kiesselgel
60, 230-400 mesh). Analytical TLC was performed with 0.2-mm
coated commercial silica plates (E. Merck, DC-Platten Kieselgel 60
Conclusions
The palladium-catalyzed ring opening of epoxides in the
presence of isocyanates constitutes a useful entry to cis-amino
alcohols, a common feature in many biologically important
systems. The palladium-initiated ionization of the epoxide
requires stabilization of the developing alkoxide anion. Ap-
parently, the isocyanate was insufficient in playing this role in
this case. In some cases, protonic solvents such as alcohols or
water can play this role28 but are incompatible with the
isocyanate. The sensitivity of the palladium catalyst toward
decomposition and the direct decomposition of the epoxide with
typical Lewis acids preclude the use of common Lewis acids
to promote this process. Trimethyltin acetate nicely balances
reactivity so that only the desired catalytic reaction occurred.
This cocatalyst had previously been successfully used in
catalyzing the additions of TMM-PdL2 to carbonyl groups18
and may prove to be a generally useful cocatalyst for catalysts
derived from sensitive low-valent homogeneous complexes.
F254). NMR spectra were obtained from Gemini GEM-200 (200-MHz)
or Gemini GEM-300 (300-MHz) instruments at the frequencies
indicated. 1H NMR chemical shifts are reported in ppm from residual
CDCl3 (7.24 ppm) or acetone-d6 (29.8 ppm). 13C NMR chemical shifts
are reported in ppm from residual CDCl3 (77.0 ppm). IR spectra were
obtained using a Perkin-Elmer paragon 500 FT-IR spectrometer.
Melting points were determined on a Thomas-Hoover oil bath
apparatus and were not corrected. Analytical gas chromatography was
performed on a Varian star 3600 gas chromatograph with a 10-m ×
0.25-mm poly(dimethylsiloxane) column. Mass spectral analyses were
performed by the NIH Mass Spectral Facility at the School of Pharmacy,
University of CaliforniasSan Francisco on a Kratos MS-90 instrument
with an ionizing current of 98 mA and an ionizing voltage of 70 eV.
Microanalyses were performed by M-H-W Laboratories, Phoenix,
AZ. Optical rotation data were acquired with a Jasco DIP-360 digital
polarimeter at the sodium D line (589 nm) in the solvent and
concentration indicated. Chiral HPLC was performed on Chiralpak
AD and Chiralcel OD columns.
(-)-(1S,2S)-Bis[(diphenylphosphino)benzamido]cyclohexane. The
title compound was prepared as previously reported from scalemic
(1S,2S)-diaminocyclohexane of 94% ee. Scalemic bis amide (7.0 g)
was heated in 95:5 ethanol:water (145 mL) until dissolved. After aging
at 4 °C overnight, the crystalline ligand was isolated by filtration and
dried under house vacuum overnight to give 6.65 g (95% recovery) of
ligand of >99% ee as determined by chiral HPLC using a Chiracel
OD column eluting with 90:10 heptane:2-propanol containing 0.1%
diethylamine.
The superior performance of the bidentate phosphite ligand
14 should also be noted.29 Phosphite ligands have proven their
effectiveness in a number of palladium-catalyzed allylic alkyl-
ations, presumably because they are both σ-donors and π-ac-
ceptors. Thus, they can be particularly effective at facilitating
both the ionization event as well as the nucleophilic addition.
Use of a bidentate phosphite like 14 can have a number of
effects including minimization of undesirable hydrogen shift
processes.
The asymmetric synthesis of the cyclohexadiene 6 is also
noteworthy. The sensitivity of this compound makes a strategy
invoking an asymmetric Diels-Alder reaction that relies on
Lewis acid catalysis rather doubtful. Indeed, the conditions for
the thermal reaction of ethyl propiolate and 1-siloxy-1,3-
butadiene must be very carefully controlled to prevent aroma-
tization. Any attempt to catalyze the reaction by Lewis acid
catalysis led to aromatization. This belief was further borne
out by some efforts to use enantiocontrolled Diels-Alder
reactions either by asymmetric catalysis or by use of a chiral
auxiliary. The racemic synthesis is the shortest to date.
Resolution of one of the intermediates could obviously convert
it into an asymmetric synthesis as well. The only asymmetric
syntheses not starting from carbohydrates, one of which started
with the racemic O-acetate ester corresponding to 23, employed
resolutions and required more than 16 steps13a compared to 7
here. The need to manipulate the multifunctionality of carbo-
hydrates makes asymmetric syntheses from these enantiomeric
precursors sufficiently long that the asymmetric synthesis
reported herein compares favorably in length even though it
begins with an achiral building block. This report represents
the first asymmetric synthesis from achiral starting materials
not employing a resolution. Modification of this route should
also be able to provide access to interesting analogues and other
members of this family of glycosidase inhibitors. The inter-
mediates reported herein also constitute the equivalent of
asymmetric syntheses of numerous targets including senepoxide,
(3aR,7aS)-3-(Benzenesulfonyl)-cis-3a,5,6,7a-tetrahydro-4H-cyclo-
hex[d]isoxazole-2-oxide (26). cis-(1,4-Dibenzoyloxy)-2-cyclohexene
(24) (6.44 g, 20 mmol), (phenylsulfonyl)nitromethane (4.25 g, 21.1
mmol), π-allylpalladium chloride dimer (0.0207 g, 0.055 mmol),
(1S,2S)-bis[(diphenylphosphino)benzamido]cyclohexane (0.139 g, 0.2
mmol), and sodium bicarbonate (3.6 g, 42.8 mmol) were placed in a
flask under argon. A solution of THF:water (3:1, 25 mL; degassed by
three freeze-thaw cycles under Ar) was added. The reaction progressed
from colorless to yellow in 1 h, indicative of the completion of the
first alkylation. At this time, (dibenzylideneacetone)palladium (0.0998
g, 0.092 mmol) and triphenylphosphine (0.191 g, 0.73 mmol) dissolved
in 5 mL of THF for 20 min were added. After heating at 60 °C for 4
h, the reaction was cooled and ethyl acetate (100 mL) and water (50
mL) were added. The organic layer was extracted with NaOH (5%
aqueous, 3 × 60 mL) and brine (60 mL). The combined aqueous phases
were extracted with methylene chloride (3 × 50 mL). The combined
organic layers were dried (MgSO4), and the solvent was removed in
vacuo. The crude solids were chromatographed on silica gel with a
20-30% ethyl acetate in hexane gradient to give the product (4.85 g,
27
17.4 mmol, 87%), [R]D -126.4° (c ) 1.16, CH2Cl2), mp ) 96-98
°C (ether). Alternatively, the product was isolated by crystallization
of the crude solid from hot hexanes. IR (neat): 1607, 1587, 1447,
1339 cm-1 1H NMR (300 MHz, CDCl3): δ 8.06 (d, J ) 7.7 Hz, 2
.
H), 7.72 (dd, J ) 7.7, 7.3 Hz, 1 H), 7.60 (dd, J ) 8.1, 7.3 Hz, 2 H),
6.27 (m, 1 H), 5.76 (dd, J ) 10.2, 1.8 Hz, 1 H), 5.04 (dd, J ) 7.7, 1.7
Hz, 1 H), 3.75 (m, 1 H), 2.25 (m, 2 H), 1.81 (m, 2 H). 13C NMR (75
MHz, CDCl3): δ 138.9, 136.5, 135.2, 129.7, 129.4, 121.8, 120.3, 73.6,
(28) Trost, B. M.; Scanlan, T. S. J. Am. Chem. Soc. 1989, 111, 4988.
(29) Trost, B. M.; Vos, B.; Brzezowski, C.; Martina, D. P. Tetrahedron
Lett. 1992, 33, 717.

1738 J. Am. Chem. Soc., Vol. 120, No. 8, 1998
Trost et al.
42.7, 22.7, 22.6. Anal. Calcd for C13H13NO4S: C, 55.90; H, 4.69; N,
5.01; S, 11.48. Found: C, 55.60; H, 4.47; N, 4.91; S, 11.35.
cm-1
.
1H NMR (300 MHz, CDCl3): δ 7.57 (d, J ) 8.1 Hz, 2 H), 7.39
(t, J ) 7.4 Hz, 1 H), 7.30 (dd, J ) 7.4, 8.1 Hz, 2 H), 5.86 (m, 2 H),
4.40 (m, 1 H), 3.57 (s, 3 H), 3.24 (d, J ) 7.4 Hz, 1 H), 2.27 (m, 1 H),
2.2-1.9 (m, 3 H). 13C NMR (75 MHz, CDCl3): δ 173.5, 138.2, 130.3,
129.5, 128.8, 127.1, 125.8, 68.7, 54.3, 51.8, 25.2, 23.6. HRMS Calcd
for C14H16O3Se (80Se): 312.0264. Found: 312.02547. HRMS Calcd
for C14H16O3Se (78Se): 310.0272. Found: 310.0273.
(3aR,7aS)-3-(Phenylsulfonyl)-cis-3a,5,6,7a-tetrahydro-4H-cyclo-
hex[d]isoxazole (6). To a solution of the nitronate 26 (5.65 g, 20.3
mmol) in acetonitrile (30 mL) was added SnCl2‚H2O (9.5 g, 42.1 mmol).
After the pink solution was stirred for 24 h at room temperature, the
acetonitrile was removed in vacuo and ether (250 mL) and KF (14 g,
241 mmoL) were added. After the solution was stirred for 120 min,
the supernatant was diluted with ether (350 mL) and extracted with
water (50 mL) and brine (50 mL). The organic phase was dried
(MgSO4) and the solvent removed in vacuo to give a yellow solid (4.51
g) which was used without further purification. On smaller scales,
chromatography on silica gel with 5:1 ethyl acetate:hexanes provided
the title compound in 88% yield. [R]D27 -167.7° (c ) 1.01, CH2Cl2).
Minor diastereomer [R]D28 +28.70° (c ) 0.54, CH2Cl2). IR (neat):
3470, 1728, 137, 1260 cm-1 1H NMR (300 MHz, CDCl3): δ 7.60
.
(d, J ) 8.1 Hz, 2 H), 7.40 (t, J ) 7.4 Hz, 1 H), 7.30 (dd, J ) 7.4, 8.1
Hz, 2 H), 5.82 (dt, J ) 10.5, 2.8 Hz, 1 H), 5.74 (dm, J ) 10.5 Hz, 1
H), 4.52 (br s, 1 H), 3.52 (s, 3 H), 3.30 (d, J ) 3.2 Hz, 1 H), 2.30 (m,
1 H), 2.2-1.9 (m, 3 H). 13C NMR (75 MHz, CDCl3): δ 173.4, 138.1,
129.5, 128.9, 127.3, 126.0, 67.6, 57.4, 51.9, 25.7, 23.6.
IR (neat): 1584, 1560, 1448, 1329, 1311 cm-1 1H NMR (300 MHz,
.
(1S,2S)-Methyl 2-[(tert-Butyldimethylsilanyl)oxy)-1-(phenylsele-
nenyl)cyclohex-3-enecarboxylate (28b). tert-Butyldimethylsilyl chlo-
ride (0.88 g, 5.8 mmol), imidazole (0.5 g, 7.3 mmol), and N,N-dimethyl-
4-aminopyridine (0.03 g, 0.25 mmol) were dissolved in CH2Cl2 (5 mL)
and the resulting solids removed by filtration. The solution (0.8 mL,
0.94 mmol) was added to alcohol 15 (0.145 g, 0.47 mmol) and stirred
at room temperature for 44 h. The solution was filtered through silica
gel to remove solids and the solvent removed in vacuo. The residue
was chromatographed with 0-3% ethyl acetate:petroleum ether gradient
CDCl3): δ 8.03 (d, J ) 7.1 Hz, 2 H), 7.74 (t, J ) 7.6 Hz, 1 H), 7.62
(dd, J ) 7.6, 7.1 Hz, 2 H), 6.22 (m, 1 H), 5.86 (m, 1 H), 5.03 (dd, J
) 8.8, 2.6 Hz, 1 H), 3.69 (ddd, J ) 8.8, 4.9, 4.3 Hz, 1 H), 2.15 (m, 3
H), 1.85 (m, 1 H). 13C NMR (50 MHz, CDCl3): δ 164.1, 138.6, 135.3,
134.9, 129.9, 129.4, 121.7, 80.5, 44.3, 22.2, 21.9. HRMS Calcd for
C7H6NO3S (M+ - C6H7O): 184.0068. Found: 184.0047. HRMS
Calcd for C6H8 (M+ - C7H5NO4): 80.0626. Found: 80.0626.
(3aR,7aS)-3-Methoxy-cis-3a,5,6,7a-tetrahydro-4H-cyclohex[d]is-
oxazole. The crude yellow solid from nitronic ester reduction and
potassium carbonate (14 g, 101 mmol) in 100 mL of methanol were
heated at reflux for 1 h. After the mixture was cooled to room
temperature, methylene chloride (150 mL) and water (150 mL) were
added. The organic layer was extracted with brine (10 mL) and the
solvent removed in vacuo. The resultant oil was chromatographed on
silica gel with 1:6 ethyl acetate:petroleum ether to give the title
compound (1.76 g, 11.5 mmol, 57% for two steps), [R]D27 +127.7° (c
) 0.68, CH2Cl2). On smaller scales, the product was obtained in 86%
yield for a 76% overall yield for the two steps. IR (neat): 1622, 1452,
20
to give a clear oil (0.173 g, 0.41 mmol, 86.5%), [R]D +155.1° (c )
2.15, CH2Cl2): IR (neat): 1732, 1474, 1438, 1253, 1048 cm-1 1H
.
NMR (300 MHz, CDCl3): δ 7.55 (d, J ) 8.3 Hz, 2 H), 7.35 (dd, J )
7.2 Hz, 1 H), 7.28 (dd, J ) 7.2, 8.3 Hz, 2 H), 5.88 (dt, J ) 9.6, 2.8
Hz, 1 H), 5.78 (m, 1 H), 4.42 (d, J ) 5.1 Hz, 1 H), 3.47 (s, 3 H), 2.45
(m, 1 H), 2.25-2.1 (m, 2 H), 1.94 (dd, J ) 5.7, 12.3 Hz, 1 H), 0.79 (s,
9 H), 0.03 (s, 3 H), -0.01 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ
173.9, 139.2, 132.5, 130.7, 130.3, 128.0, 127.6, 68.9, 57.8, 52.9, 27.1,
25.3, 23.7, 19.3, -2.3, -3.7. Anal. Calcd for C20H30O3SeSi: C, 56.45;
H, 7.11. Found: C, 56.68; H, 6.91.
1395, 1379, 1343 cm-1 1H NMR (200 MHz, CDCl3): δ 6.05 (ddd, J
.
The 1R,2S diastereomer was prepared from the minor selenenylation
product in the same manner as above. [R]D27 +103.2° (c ) 0.48, CH2-
Cl2); mp 72-73 °C (petroleum ether). IR (neat): 1726, 1472, 1738,
) 10.1, 4.0, 4.0 Hz, 1 H), 5.72 (dddd, J ) 10.1, 3.8, 1.8, 1.7 Hz, 1 H),
4.85 (ddd, J ) 8.6, 2.4, 1.1 Hz, 1 H), 3.83 (s, 3 H), 3.18 (ddd, J )
12.5, 7.1, 5.3 Hz, 1 H), 1.96 (m, 3 H), 1.75 (m, 1 H). 13C NMR (50
MHz, CDCl3): δ 170.7, 133.3, 124.2, 77.2, 57.5, 42.3, 22.0, 20.6.
HRMS Calcd for C8H11NO2: 153.07898. Found: 153.0790.
1261, 1064 cm-1 1H NMR (300 MHz, CDCl3): δ 7.60 (d, J ) 8.3
.
Hz, 2 H), 7.35 (dd, J ) 7.2 Hz, 1 H), 7.28 (dd, J ) 7.2, 8.3 Hz, 2 H),
5.75 (m, 2 H), 4.75 (d, J ) 2.4 Hz, 1 H), 3.27 (s, 3 H), 2.45 (m, 1 H),
2.3 (m, 1 H), 2.08 (m, 2 H), 0.96 (s, 9 H), 0.22 (s, 3 H), 0.13 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ 171.0, 138.2, 130.4, 129.0, 128.6, 128.1,
127.7, 67.7, 58.3, 51.3, 27.0, 25.8, 24.9, 18.2, -3.7, -4.8. Anal. Calcd
for C20H30O3SeSi: C, 56.45; H, 7.11. Found: C, 56.36; H, 7.05.
Preparation of rac-3-(tert-Butyldimethylsiloxy)-2-carboethoxy-
cyclohexa-1,4-diene (6a). A neat mixture of 1-(tert-butyldimethylsi-
loxy)buta-1,3-diene (1.84 g, 10.0 mol), ethyl propiolate (1.12 g, 11.4
mmol), and one crystal of methylene blue was subjected to three
freeze-thaw cycles. After the tube was sealed, the mixture was heated
at 80 °C for 5 days. Any volatile compound was removed in vacuo
for 2 h and the resultant product (2.56 g, 9.06 mmol, 91%) used directly
(1S,2R)-Methyl cis-2-Hydroxy-3-cyclohexene-1-carboxylate (23).
After purging a solution of the above isoxazole (2.0 g, 13.05 mmol),
molybdenum hexacarbonyl (3.5 g, 13.25 mmol), and boric acid (2.45
g, 39.6 mmol) in acetonitrile (90 mL) and methanol (45 mL) and water
(1.5 mL) with a stream of Ar for 15 min, it was heated at reflux for 3
h. The black reaction was cooled and poured into a recrystallization
dish. Silica gel was added until a thick slurry formed. The slurry was
dried open to air for 24 h. The silica gel was washed with ether to
extract the product as a dark oil. Kugelrohr distillation (110 °C at 5
mmHg) gave the product as a water clear oil (1.25 g, 8.0 mmol, 61%),
26
[R]D +203.18° (c ) 1.27, CH2Cl2). On a smaller scale, the product
in the next step. IR (film): 1715, 1473, 1463, 1396 cm-1 1H NMR
.
was obtained in 77% yield by flash chromatography on silica gel eluting
with a gradient of 3:1 to 1:1 hexanes:ethyl acetate. IR (neat): 3455,
(200 MHz, CDCl3): δ 7.00 (m, 1 H), 5.88 (br s, 2 H), 5.10 (m, 1 H),
4.30 (dq, J ) 10.8, 7.1 Hz, 1 H), 4.17 (dq, J ) 10.8, 7.1 Hz, 1 H),
2.94 (m, 1 H), 2.70 (m, 1 H), 1.31 (t, J ) 7.1 Hz, 3 H), 0.86 (s, 9 H),
0.13 (s, 3 H), 0.10 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 167.1,
137.3, 132.2, 128.4, 125.0, 61.5, 60.3, 27.1, 25.6, 17.9, 14.1, -4.5,
-4.7. HRMS Calcd for C15H26O3Si (M+): 282.1651. Found: 282.1664.
Preparation of rac-5a and (+)-5b. rac-5a. m-CPBA (1.21 g, 7.0
mmol) was added portionwise to a mixture of diene 6a (0.988 g, 3.50
mmol) and sodium bicarbonate (0.890 g, 10.5 mmol) in 15 mL of
benzene. After 9 h at room temperature, the reaction was filtered and
the supernatant diluted with benzene. The organic layer was washed
with saturated aqueous sodium bisulfate, saturated aqueous sodium
bicarbonate, and brine. After drying (MgSO4), filtration, and evapora-
tion, flash chromatography (5:1 hexane:ether) gave a colorless oil (840
mg, 2.81 mmol, 80% yield). IR (film): 1713, 1472, 1463, 1415, 1371
1730, 1655, 1436, 1304 cm-1 1H NMR (300 MHz, CDCl3): δ 5.91
.
(m, 2 H), 4.45 (d, J ) 4.6 Hz, 1 H), 3.76 (s, 3 H), 2.75 (d, J ) 6.1 Hz,
1 H), 2.63 (m, 1 H), 2.25-1.94 (m, 4 H). 13C NMR (75 MHz,
CDCl3): δ 175.6, 131.9, 128.2, 64.3, 52.1, 45.4, 25.2, 19.6. HRMS
Calcd for C8H12O3 (M+): 156.0786. Found: 156.0808.
(1S,2S)-Methyl 2-Hydroxy-1-(phenylselenenyl)cyclohex-3-enecar-
boxylate (27) and (1R,2S)-Methyl 2-Hydroxy-1-(phenylselenenyl)-
cyclohex-3-enecarboxylate. Alcohol 23 (0.156 g, 1.0 mmol) in THF
(1 mL) was added to LDA (2.4 mmol in 1.5 mL of hexane and 2.5 mL
of THF) at -78 °C. The yellow solution was stirred at -78 °C for 40
min and then at 0 °C for 10 min. Solid diphenyldiselenide (0.319 g,1.02
mmol) was added. After 3 h at 0 °C, the reaction was diluted with
ether and washed with NaHSO4 (10% aqueous, 1 × 10 mL), NaOH
(5% aqueous, 1 × 10 mL), and brine (1 × 5 mL). The organic phase
was dried (MgSO4), the solvent removed in vacuo, and the residue
chromatographed on silica gel with a 15-30% ethyl acetate:petroleum
ether gradient to give a major diastereomer (0.141 g, 0.45 mmol, 45%)
and a minor diastereomer (0.027 g, 0.09 mmol, 9%). Major diastere-
omer [R]D28 +46.5° (c ) 0.66, CH2Cl2). IR (neat): 3469, 1728, 1437
cm-1 1H NMR (200 MHz, CDCl3): δ 6.74 (ddd, J ) 7.5, 5.0, 2.5
.
Hz, 1 H), 5.05 (qd, J ) 4.5, 1.5 Hz, 1 H), 4.25 (dq, J ) 11.5, 5.0, 2.5
Hz, 1 H), 5.05 (qd, J ) 4.5, 1.5 Hz, 1 H), 4.25 (dq, J ) 11.5, 7.1 Hz,
1 H), 4.14 (dq, J ) 11.5, 7.1 Hz, 1 H), 3.30 (m, 2 H), 2.73 (m, 2 H),
1.29 (t, J ) 7.1 Hz, 3 H), 0.87 (s, 9 H), 0.18 (s, 3 H), 0.10 (s, 3 H). 13
C

Total Synthesis of (()- and (+)-Valienamine
J. Am. Chem. Soc., Vol. 120, No. 8, 1998 1739
NMR (75 MHz, CDCl3): δ 166.4, 135.2, 129.7, 62.7, 60.5, 54.2, 49.2,
25.7, 25.6, 17.9, 14.0, -4.9, -5.0. HRMS Calcd for C14H26O4Si: C,
60.37; H, 8.78. Found: C, 60.19; H, 8.53.
1-3% ethyl acetate:petroleum ether, (-)-9b (0.061 g, 0.15 mmol, 88%),
[R]D20 -140.26° (c ) 3.05, CH2Cl2). IR (neat): 1721, 1473 cm-1. 1H
NMR (300 MHz, CDCl3): δ 7.28 (d, J ) 4.2 Hz, 1 H), 4.56 (dd, J )
2.1 Hz, 1 H), 4.25 (dd, J ) 2.1 Hz, 1 H), 3.76 (s, 3 H), 3.53 (m, 1 H),
3.42 (dd, J ) 4.0 Hz, 1 H), 0.86 (br s, 18 H), 0.16 (s, 3 H), 0.15 (s, 3
H), 0.12 (s, 3 H), 0.11 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 166.6,
137.6, 134.0, 69.3, 68.1, 58.0, 51.8, 45.1, 25.6, 17.9, 17.8, -4.5, -4.8,
-4.9, -5.1. HRMS Calcd for C20H38O5Si2 (M+): 414.2258. Found:
414.2248.
(+)-5b. To a mixture of phenylselenide 28b (0.173 g, 0.406 mmol)
and CaCO3 (0.17 g, 1.7 mmol) in dichloromethane (12.5 mL) at -78
°C was added m-CPBA (0.081 g, 0.469 mmol) in dichloromethane (2.5
mL). After 15 min, 2-methoxypropene (0.377 g, 5.22 mmol) was
added. After an additional 15 min at -78 °C, the reaction was removed
from the cooling bath and stirred 45 min. The solvent was removed
in vacuo. The residue was chromatographed immediately with 5:95
ethyl acetate:petroleum ether to give semipure diene 6b (0.10 g). This
compound was immediately epoxidized as above using sodium
bicarbonate (0.206 g, 2.24 mmol) and m-CPBA (0.14 g, 0.81 mmol)
in 1.5 mL of dichloromethane. After 20 h at room temperature, water,
sodium bisulfite, and ethyl acetate were added. After the organic layer
(MgSO4) was dried, the solvent was removed in vacuo and the residue
was chromatographed with 5:95 ethyl acetate:petroleum ether to give
Preparation of 10a and 10b. rac-10a. A solution of the active
catalyst was generated by sequential addition to 1 mL of THF of
palladium acetate (11.2 mg, 0.05 mmol), phosphite 14 (50.8 mg, 0.30
mmol), and n-butyllithium (66.7 µL, 0.10 mmol, 1.5 M in hexanes).
After 30 min at room temperature, epoxide 9a (0.428 g, 1.0 mmol) in
1 mL of THF, p-toluenesulfonylisocyanate (0.59 g, 3.0 mmol), and
trimethyltin acetate (22.3 mg, 0.10 mmol) were added. Heating at reflux
for 42 h, concentration in vacuo, and direct flash chromatography (10:1
hexane:ethyl acetate) gave 10a (337.2 mg, 0.54 mmol, 54% yield) and
11a (56.1 mg, 0.09 mmol, 9% yield). 10a: IR (film): 1791, 1722,
25
scalemic epoxide 5b (0.053 g, 0.2 mmol, 48.3% for two steps), [R]D
+1.60° (c ) 2.57, CH2Cl2).
1598, 1472, 1464, 1367 cm-1 1H NMR (300 MHz, CDCl3): δ 7.78
.
Preparation of rac-8a and (-)-8b. rac-8a. DBU (0.760 g, 5.50
mmol) in 1 mL of dichloromethane was added to a solution of epoxide
5a (1.18 g, 3.95 mmol), TBDMS-Cl (0.72 g, 4.78 mmol), and DMAP
(0.048, 0.41 mmol) in 7 mL of dichloromethane. After stirring 24 h
at room temperature, the reaction was diluted with ether, washed with
saturated aqueous sodium bicarbonate and brine, dried (MgSO4), and
evaporated in vacuo. The residue was flash chromatographed (19:1
hexane:ethyl acetate) to give rac-8a (1.24 g, 3.00 mmol, 76% yield).
(br d, J ) 8.5 Hz, 2 H), 7.28 (br d, J ) 8.5 Hz, 2 H), 5.14 (dd, J )
8.6, 4.5 Hz, 1 H), 4.52 (br s, 1 H), 4.58-4.55 (m, 1 H), 4.35 (dq, J )
10.9, 7.2 Hz, 1 H), 4.23 (dq, J ) 10.9, 7.2 Hz, 1 H), 4.12 (dd, J ) 3.2,
2.4 Hz, 1 H), 2.40 (s, 3 H), 1.36 (t, J ) 7.2 Hz, 3 H), 0.81 (s, 9 H),
0.63 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H), 0.03 (s, 3 H), -0.13 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ 165.7, 150.4, 145.5, 135.5, 135.1, 132.5,
129.7 (2 C), 128.8 (2 C), 73.6, 68.8, 64.9, 61.3, 52.0, 25.3, 25.1, 21.4,
17.6, 17.4, 14.0, -5.2, -5.3, -5.5. HRMS Calcd for C28H44NO8SSi2
(M+ - CH3): 610.2326. Found: 610.2315. 11a: IR (film): 1718,
IR (film): 1712, 1587, 1472, 1463, 1405 cm-1 1H NMR (300 MHz,
.
CDCl3): δ 7.10 (dd, J ) 5.1, 1.5 Hz, 1 H), 6.20 (dd, J ) 9.4, 4.9 Hz,
1 H), 6.15 (ddd, J ) 9.4, 5.2, 1.0 Hz, 1 H), 4.57 (br s, J ) 1.3 Hz, 1
H), 4.28 (dq, J ) 10.9, 7.1 Hz, 1 H), 4.18 (dq, J ) 10.9, 7.1 Hz, 1 H),
4.10 (dd, J ) 4.8, 1.6 Hz, 1 H), 1.31 (t, J ) 7.1 Hz, 3 H), 0.86 (s, 9
H), 0.82 (s, 9 H), 0.16 (s, 3 H), 0.10 (s, 3 H), 0.07 (s, 3 H), 0.04 (s, 3
H). 13C NMR (75 MHz, CDCl3): δ 167.2, 133.0, 132.7, 129.8, 123.8,
69.8, 67.8, 60.3, 25.6, 25.5, 17.9, 17.8, 14.1, -4.5, -4.7, -4.8, -5.2.
HRMS Calcd for C15H24O3Si (M+ - TBDSOH): 280.1495. Found:
280.1485.
1638, 1472, 1464, 1363 cm-1 1H NMR (300 MHz, CDCl3): δ 7.81
.
(d, J ) 6.5 Hz, 2 H), 7.24 (d, J ) 7.9 Hz, 2 H), 6.88 (d, J ) 4.7 Hz,
1 H), 5.50 (dd, J ) 8.1, 4.8 Hz, 1 H), 4.77 (ddd, J ) 8.1, 2.5, 1.5 Hz,
1 H), 4.64 (dd, J ) 3.1, 1.5 Hz, 1 H), 4.32 (dq, J ) 10.8, 7.1 Hz, 1 H),
4.27 (t, J ) 2.9 Hz, 1 H), 4.22 (dq, J ) 10.7, 7.1 Hz, 1 H), 2.30 (s, 3
H), 1.33 (t, J ) 7.1 Hz, 3 H), 0.81 (s, 9 H), 0.80 (s, 9 H), 0.13 (s, 3 H),
0.10 (s, 3 H), 0.09 (s, 3 H), 0.02 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ 165.2, 158.6, 143.3, 138.9, 137.5, 129.3 (2 C), 128.4 (2 C),
127.2, 77.2, 77.1, 68.7, 65.0, 61.5, 25.4, 25.3, 21.3, 17.7, 17.6, 13.9,
-5.0, -5.3 (2 C). HRMS Calcd for C25H38NO8SSi2 (M+ - t-C4H9):
568.1857. Found: 568.1873.
(-)-8b Epoxide. Epoxide (+)-5b (0.056 g, 0.19 mmol) was added
to a 0 °C solution of TBDMS-Cl (0.037 g, 0.25 mmol), DBU (0.038
g, 0.25 mmol), and DMAP (0.0025 g, 0.020 mmol) in 0.5 mL of
dichloromethane. The cooling bath was removed, the reaction per-
formed, and the product purified (99.6:0.4 petroleum ether:ethyl acetate)
10b. The catalyst was prepared as above from recrystallized
palladium acetate (11 mg, 0.05 mmol), phosphite 14 (51 mg, 0.14
mmol), and n-butyllithium (0.075 mL, 1.35 M in hexane, 0.101 mmol)
in 2 mL of THF. Tosyl isocyanate (0.29 g, 1.48 mmol) and an aliquot
of the palladium solution (0.5 mL, 0.0125 mmol) were added
sequentially to epoxide 9b (0.061 g, 0.15 mmol) and trimethyltin acetate
(0.018 g, 0.08 mmol) under Ar. After heating and workup as above,
28
as above to give (-)-8b (0.066 g, 0.17 mmol, 90%), [R]D -305.1°
(c ) 3.29, CH2Cl2). IR (neat): 1715, 1651, 1589, 1463, 1437 cm-1
.
1H NMR (300 MHz, CDCl3): δ 7.07 (dd, J ) 1.3, 9.4 Hz, 1 H), 6.15
(m, 2 H), 4.54 (s, 1 H), 4.08 (d, J ) 4.4 Hz, 1 H), 3.75 (s, 3 H), 0.84
(s, 9 H), 0.80 (s, 9 H), 0.14 (s, 3 H), 0.09 (s, 3 H), 0.06 (s, 3 H), 0.02
(s, 3 H). 13C NMR (75 MHz, CDCl3): δ 167.4, 133.1, 132.9, 129.4,
123.6, 69.9, 68.0.0, 51.5, 25.7, 25.6, 18.0, 17.9, -4.3, -4.7, -5.0.
HRMS Calcd for C20H38O4Si2 (M+): 398.2309. Found: 398.2306.
Preparation of rac-9a and (-)-9b. rac-9a. m-CPBA was added
portionwise to a mixture of diene 8a (2.82 g, 6.83 mmol) and sodium
bicarbonate (1.72 g, 20.5 mmol) in 17 mL of methylene chloride. After
stirring 3 h at room temperature, the reaction was filtered and diluted
with ether. The resultant organic layer was washed with saturated
aqueous sodium bisulfite, sodium bicarbonate, and brine. After drying
(MgSO4) and evaporation in vacuo, the residue was flash chromato-
graphed (12:1 hexane:ethyl acetate) or distilled (bp 175-200 °C at
0.025 Torr, bath temperature) to give rac-9a (1.71 g, 3.99 mmol, 86%
20
10b [0.064 g, 0.11 mmol, 70% yield, [R]D -32.6° (c ) 1.0, CH2-
Cl2)] was obtained. IR (CDCl3): 1788, 1721, 1472, 1438, 1363 cm-1
.
1H NMR (300 MHz, CDCl3): δ 7.92 (d, J ) 8.4 Hz, 2 H), 7.27 (m, 3
H), 5.12 (dd, J ) 4.7, 8.5 Hz, 1 H), 4.55 (m, 2 H), 4.11 (m, 1 H), 3.83
(s, 3 H), 2.41 (s, 3 H), 0.81 (s, 9 H), 0.65 (s, 9 H), 0.08 (s, 3 H), 0.07
(s, 3 H), 0.03 (s, 3 H), -0.12 (s, 3 H). 13C NMR (75 MHz, CDCl3):
δ 165.9, 150.1, 145.4, 134.9, 132.4, 129.6, 128.7, 73.6, 68.8, 65.1, 52.2,
25.5, 25.3, 17.8, 17.6, -4.9, -5.0, -5.1, -5.2. HRMS Calcd for
C24H36NO8SSi2 (M+ - t-C4H9): 554.1700. Found: 554.1714.
Preparation of (3S,4S,5R,6R)-5,6-Bis(tert-Butyldimethylsiloxyl)-
1-(hydroxymethyl)-3-[N-(p-toluenesulfonyl)amino]cyclohex-1-en-4-
ol (17b). DIBAL-H (2.75 mL, 1.0 M in hexane, 2.75 mmol) was added
over 30 min to a -78 °C solution of oxazolidinone 10a (0.313 g, 0.50
mmol) in 1.5 mL of dichloromethane. After 2 h at -78 °C, methanol
was added and the reaction allowed to warm to room temperature, at
which point 30% aqueous sodium potassium tartrate and triethanolamine
were added until a clear solution resulted. After extraction with ethyl
acetate, the resulting organic layer was washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. The residue was
dissolved in 5 mL of methanol containing a catalytic amount of sodium
methoxide and the resultant solution stirred overnight at room tem-
perature. After concentration in vacuo and flash chromatography (3:1
hexane:ethyl acetate), rac-17b (212 mg, 0.38 mmol, 76% yield) was
obtained. In the same way, oxazolidinone 10b (0.064 g, 0.10 mmol)
yield). IR (film): 1720, 1475, 1473, 1395 cm-1 1H NMR (300 MHz,
.
CDCl3): δ 7.27 (d, J ) 4.2 Hz, 1 H), 4.57 (dd, J ) 2.1 Hz, 1 H), 4.27
(dq, J ) 10.9, 7.1 Hz, 1 H), 4.25 (m, 1 H), 4.15 (dq, J ) 10.9, 7.1 Hz,
1 H), 3.51 (dt, J ) 3.8, 2.4 Hz, 1 H), 3.40 (t, J ) 4.0 Hz, 1 H), 1.28
(t, J ) 7.1 Hz, 3 H), 0.84 (s, 18 H), 0.14 (s, 3 H), 0.11 (s, 3 H), 0.10
(s, 3 H), -0.01 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 166.3, 137.4,
134.4, 69.3, 67.9, 60.7, 57.9, 45.1, 25.5, 25.4, 17.8, 17.7, 14.0, -4.6,
-4.9, -5.0, -5.3. HRMS Calcd for C20H37O5Si2: C, 58.83; H, 9.40.
Found: C, 58.71; H, 9.20
(-)-9b. Diene 8b (0.067 g, 0.17 mmol), sodium bicarbonate (0.84
g, 1 mmol), and m-CPBA (0.061 g, 0.36 mmol) in 0.5 mL of
dichloromethane as above gave, after flash chromatography eluting with

1740 J. Am. Chem. Soc., Vol. 120, No. 8, 1998
Trost et al.
was converted to the crude enantiomerically pure aminodiol 17b, which
color disappeared. Evaporation of the ammonia gave racemic valie-
namine 1, which was characterized as its pentaacetate. Valienamine
was dissolved in a mixture of 2 mL of pyridine and 10 mL of acetic
anhydride at room temperature. After stirring overnight, the reaction
was diluted with dichloromethane, and the resulting solution was
washed with saturated aqueous sodium bicarbonate (caution: foaming)
followed by brine. After drying (MgSO4), filtration, and concentration,
the residue was flash chromatographed (gradient from 1:1 hexane:ethyl
acetate to pure ethyl acetate) to give 20 (32.4 mg, 0.084 mmol, 56%
yield), mp 178-180 °C (ether-ethanol) [lit.11g mp 180-181 °C]. The
above was repeated using crude enantiomerically pure tetraol 19 to
give (+)-valienamine pentaacetate (20) (0.012 g, 0.031 mmol, 31%)
in four steps from 10b, [R]D28 +23.8° (c ) 0.5, CHCl3), mp 90.5-93
°C (ether-ethanol) [lit.8 mp 95 °C]. IR (CDCl3): 1745, 1709, 1502,
was taken directly onto the next step. IR (film): 3481, 1472, 1464,
1331 cm-1 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J ) 7.9 Hz, 2
.
H), 7.28 (d, J ) 7.9 Hz, 2 H), 5.61 (q, J ) 1.7 Hz, 1 H), 5.39 (br d,
J ) 9.6 Hz, 1 H, exchangeable), 4.50 (m, 2 H), 3.99 (m, 1 H), 3.96 (br
s, 1 H), 3.92 (dd, J ) 4.2, 2.5 Hz, 1 H), 3.75 (d, J ) 10.1 Hz, 1 H,
exchangeable), 3.26 (dtt, J ) 10.1, 4.2, 1.4 Hz, 1 H), 2.41 (s, 3 H),
0.86 (s, 9 H), 0.78 (s, 9 H), 0.13 (s, 3 H), 0.12 (s, 3 H), -0.01 (s, 3 H),
-0.11 (s, 3 H). 13C NMR (300 MHz, CDCl3): δ 143.5, 138.3, 137.2,
129.9 (2 C), 127.3 (2 C), 125.6, 70.1, 69.3, 67.8, 63.9, 50.6, 25.4, 25.3,
21.3, 17.5, -4.9, -5.2, -5.4, -5.5. Anal. Calcd for C24H38NO6SSi2
(M+ - CH4CH3H2): 524.1958. Found: 524.1922.
N-(p-Toluenesulfonyl)valienamine (19). Aqueous hydrofluoric acid
(0.13 mL, 10 M in water, 2.6 mmol) was added to a solution of diol
17b (147 mg, 0.26 mmol) in 2.6 mL of acetonitrile. After 16 h at
room temperature, the precipitate, which formed, was removed by
filtration. The filtrate was concentrated in vacuo and the resulting
residue purified by flash chromatography (4:1 methanol:chloroform)
to give 20.9 mg of 19. The initial precipitate was neutralized by
dissolving in methanol and adding calcium carbonate. After the solution
was filtered and concentrated, the residue was purified by flash
chromatography to give an additional 50 mg of 19 for a total of 70.9
mg (0.21 mmol, 82% yield). More conveniently, after stirring the initial
reaction mixture for 16 h, the reaction was added to methanol containing
potassium carbonate. Workup consisted of adding brine and extraction
with ethyl acetate followed by purification as above. For the enan-
tiomerically pure substrate, the crude product was used directly in the
1477, 1371 cm-1 1H NMR (200 MHz, CDCl3): δ 5.89 (q, J ) 1.4
.
Hz, 1 H), -5.69 (br d, J ) 8.7 Hz, 1 H), 5.46 (dd, J ) 9.4, 6.4 Hz, 1
H), 5.36 (db, J ) 6.7 Hz, 1 H), 5.11 (d, J ) 4.6 Hz, 1 H), 5.09-4.98
(m, 1 H), 4.65 (dq, J ) 13.2, 1.1 Hz, 1 H), 4.39 (d, J ) 13.3 Hz, 1 H),
2.07 (s, 9 H), 2.06 (s, 3 H), 2.02 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ 171.1, 170.5, 170.3, 170.2, 170.1, 134.2, 126.2, 70.7, 68.9,
68.2, 62.7, 44.6, 22.9, 20.6, 20.4 (3 C). Anal. Calcd for C17H23NO9:
C, 52.98; H, 6.02; N, 3.63. Found: C, 53.00; H, 5.96; N, 3.55.
Acknowledgment. We thank the National Institutes of
Health, General Medical Sciences, for their generous support
of our programs. T. L. was supported by the Deutsche
Forschunggesellschaft. Mass spectra were kindly provided by
the Mass Spectrometry Center of UCSF supported by the
Division of Research Resources of the National Institutes of
Health.
next step. IR (KBr): 3500, 3380, 1451 cm-1 1H NMR (300 MHz,
.
CD3COCD3): δ 7.79 (d, J ) 8.1 Hz, 2 H), 7.37 (d, J ) 8.1 Hz, 2 H),
6.26 (br d, J ) 8.1 Hz, 1 H), 5.35 (br s, 1 H), 4.30-3.50 (m, 10 H),
2.41 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 143.0, 141.6, 139.9,
130.1 (2 C), 127.2 (2 C), 120.0, 72.0, 70.0, 69.8, 61.8, 51.8, 21.2. Anal.
Calcd for C14H19NO6S: C, 51.05; H, 5.81; N, 4.25; S, 9.73. Found:
C, 50.79; H, 6.02; N, 4.10; S, 9.46.
Preparation of Valienamine (1) and Its Pentaacetate (20). Small
pieces of sodium were added to a solution of tetraol 19 (0.049 g, 0.15
mmol) in 10 mL of liquid ammonia at -78 °C until the blue color
persisted, at which point ammonium chloride was added until the blue
Supporting Information Available: Table and accompany-
ing text for the variation of catalyst conditions for epoxide and
isocyanate addition (2 pages). See any current masthead page
for ordering and Internet access instructions.
JA973081G