Organometallic enantiomeric scaffolding: Organometallic chirons. Total synthesis of (-)-Bao Gong Teng A by a molybdenum-mediated [5+2] cycloaddition

Article abstract of DOI:10.1021/ja055623x

Bao Gong Teng A, an optically active tropane alkaloid with hypotensive and miotic activity isolated from the Chinese herb Erycibe obtusifolia Benth, was synthesized by an "organometallic chiron" strategy in which single enantiomers of TpMo(CO)₂

Full text of DOI:10.1021/ja055623x

Published on Web 12/16/2005
Organometallic Enantiomeric Scaffolding: Organometallic
Chirons. Total Synthesis of (-)-Bao Gong Teng A by a
Molybdenum-Mediated [5+2] Cycloaddition
Yongqiang Zhang and Lanny S. Liebeskind*
Contribution from the Sanford S. Atwood Chemistry Center, Emory UniVersity,
1515 Dickey DriVe, Atlanta, Georgia 30322
Received August 27, 2005; E-mail: chemLL1@emory.edu
Abstract: Bao Gong Teng A, an optically active tropane alkaloid with hypotensive and miotic activity isolated
from the Chinese herb Erycibe obtusifolia Benth, was synthesized by an “organometallic chiron” strategy
in which single enantiomers of TpMo(CO)2(η3-pyridinyl) complexes are produced in quantity and then
elaborated easily and efficiently to generate, after demetalation, highly enantiopure advanced synthetic
intermediates possessing the tropane core.
Scheme 1. (-)-Bao Gong Teng A from “Organometallic Chiron” 2
Introduction
In recent years both TpMo(CO)2(η3-pyranyl) and TpMo(CO)2-
(η3-pyridinyl) complexes have begun to be developed as
versatile organometallic enantiomeric scaffolds for the asym-
metric construction of a wide variety of heterocyclic systems
[Tp ) hydridotris(pyrazolyl)borate].1 Readily available and
easily synthesized single enantiomers of these conceptually
simple organometallic π-complexes function as organometallic
chirons2 from which widely differing families of complex
organic structures can be elaborated in an enantiospecific
fashion.3,1b,d-g,i,j Herein is described an example of the synthetic
versatility of the organometallic chiron approach, the total
synthesis of the Chinese herbal medicine (-)-Bao Gong Teng
A 1 from the multipurpose enantiomeric scaffold 2 (Scheme
1).
Bao Gong Teng A is an optically active tropane alkaloid that
was isolated from the Chinese herb Erycibe obtusifolia Benth.4
It has hypotensive and miotic activities and has been used for
the treatment of glaucoma.5 Bao Gong Teng A’s biological
activity along with its structural features and a limited avail-
ability from natural resources has stimulated interest in its
synthesis.6 Two earlier syntheses of 16a,b utilized an attractive
strategy whereby the basic carbon skeleton was constructed via
a 1,3-dipolar cycloaddition of dipolarophiles to the betaine of
a 3-hydroxypyridinium salt, a reaction developed by Katritzky.7
(1) (a) Shu, C.; Liebeskind, L. S. J. Am. Chem. Soc. 2003, 125, 2878. (b)
Arraya´s, R. G.; Liebeskind, L. S. J. Am. Chem. Soc. 2003, 125, 9026. (c)
Alcudia, A.; Arraya´s, R. G.; Liebeskind, L. S. J. Org. Chem. 2002, 67,
5773. (d) Shu, C.; Alcudia, A.; Yin, J.; Liebeskind, L. S. J. Am. Chem.
Soc. 2001, 123, 12477. (e) Arraya´s, R. G.; Liebeskind, L. S. J. Am. Chem.
Soc. 2001, 123, 6185. (f) Yin, J.; Llorente, I.; Villanueva, L. A.; Liebeskind,
L. S. J. Am. Chem. Soc. 2000, 122, 10458. (g) Moretto, A. F.; Liebeskind,
L. S. J. Org. Chem. 2000, 65, 7445. (h) Malinakova, H. C.; Liebeskind, L.
S. Org. Lett. 2000, 2, 4083. (i) Malinakova, H. C.; Liebeskind, L. S. Org.
Lett. 2000, 2, 3909. (j) Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc. 1999,
121, 5811. (k) Ward, Y. D.; Villanueva, L. A.; Allred, G. D.; Liebeskind,
L. S. J. Am. Chem. Soc. 1996, 118, 897.
(2) Three fundamentally different approaches have been widely used to address
the requirement for control of absolute stereochemistry in organic synthe-
sis: (i) syntheses that use materials originating from the “chiral pool” either
as “chirons” (Hanessian, S. Pure Appl. Chem. 1993, 65, 1189; Hanessian,
S. Total Synthesis of Natural Products: The “Chiron” Approach; Pergamon
Press: Oxford, U.K., 1983) or as auxiliaries (Blaser, H. U. Chem. ReV.
1992, 92, 935); (ii) enzymatic (Humphrey, A. J.; Turner, N. J. In Enzyme
Chemistry; 3rd ed.; Suckling, C. J., Gibson, C. L., Pitt, A. R., Eds.; Blackie
Academic & Professional: London, 1998; pp 105-136) or classical
resolutions; and (iii) metallo- (Ojima, I., Ed. Catalytic Asymmetric Synthesis,
2nd ed.; Wiley: New York, 2000) or organocatalytic (Dalko, P. I.; Moisan,
L. Angew. Chem. 2004, 43, 5138; Seayad, J.; List, B. Org. Biomol. Chem.
2005, 3, 719) asymmetric transformations. Organometallic chirons represent
a fourth conceptual approach to enantiocontrolled bond construction. This
strategy entails the production, in quantity, of a single enantiomer of a
metal π-complex of an unsaturated organic ligand and the subsequent
synthetic elaboration of the scaffold over a number of steps to generate,
after demetalation, an advanced compound possessing multiple stereo-
centers. In this strategy the stoichiometric nature of the chemistry is
mitigated by the use of a single metal moiety either to activate the organic
ligand for multiple enantiocontrolled functionalizations or to open pathways
for unique bond constructions not easily achieved by traditional synthetic
manipulations. Particularly versatile organometallic chirons are conceptually
simple yet allow the construction of widely differing families of structures.
(3) Transition metal π-complexes are powerful scaffolds for the enantio-
controlled construction of complex carbo- and heterocycles: (a) Pearson,
A. J. In AdVances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.;
JAI: Stamford, CT, 1989; Vol. 1, p 1. (b) Harman, W. D. Chem. ReV.
1997, 97, 1953. (c) Li, C.-L.; Liu, R. S. Chem. ReV. 2000, 100, 3127. (d)
Pape, A. R.; Kaliappan, K. P.; Kundig, E. P. Chem ReV. 2000, 100, 2917.
(e) Paley, R. S. Chem. ReV. 2002, 102, 1493. (f) Harman, W. D. Top.
Organomet. Chem. 2004, 7, 95. Also see footnotes 1 and 8.
(4) (a) Yao, T.-R.; Chen, Z.-N. Yaoxue Xuebao 1979, 14, 731; Chem. Abstr.
1980, 93, 101406n. (b) Yao, T.; Chen, Z.; Yi, D.; Xu, G. Yaoxue Xuebao
1981, 16, 582; Chem. Abstr. 1982, 96, 48972c.
(5) (a) Shanger Department of Pharmacology. Yaoxue Tongbao 1981, 16, 51;
Chem. Abstr. 1981, 95, 126046z. (b) Shanghai Second Medical College.
Yaoxue Tongbao 1981, 16, 55; Chem. Abstr. 1981, 95, 138453t.
(6) (a) Racemic synthesis: Jung, M. E.; Zeng, L.; Peng, T.; Zeng, H.; Le, Y.;
Su, J. J. Org. Chem. 1992, 57, 3528. (b) Asymmetric synthesis: Pham, V.
C.; Charlton, J. L. J. Org. Chem. 1995, 60, 8051. (c) Synthesis of 6-endo
diastereomer: Pei, X. F.; Shen, J. X. Heterocycles 1993, 36, 2549.
(7) Dennis, N.; Katritzky, A. R.; Takeuchi, T. Angew. Chem., Int. Ed. Engl.
1976, 15, 1.
9
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J. AM. CHEM. SOC. 2006, 128, 465-472
465

A R T I C L E S
Zhang and Liebeskind
Scheme 2. Synthesis of the Racemic Tropane Core 5 via a
“1,5-Michael” Reaction
matography. The undesired isomer (-)-endo-5 was then con-
verted to the exo isomer via a base-catalyzed epimerization
rendering the [5+2] route to the azabicyclo[3.2.1] core highly
efficient overall. In the previous syntheses of Bao Gong Teng
A the 1,3-dipolar cycloaddition used to construct the bicyclic
skeleton proceeded with lower selectivities (exo/endo ) 3:2;6a
diastereoselectivity + enantioselectivity ) 13:76b).
The envisioned total synthesis of Bao Gong Teng A was first
probed in the racemic series. As with the previously reported
syntheses,6a,b two major synthetic challenges must be overcome
in elaborating the Bao Gong Teng A substituent pattern: (1)
the 2-hydroxyl group must be formed with high exo (axial)
stereoselectivity by reduction of the carbonyl group, and 2) the
6-exo acetoxy group must be generated with high efficiency
by a Baeyer-Villiger oxidation of the corresponding acetyl
group. Beginning with (()-exo-5, which was generated with
high efficiency from molybdenum scaffold 2 (see Scheme 2),
ceric ammonium nitrate- (CAN-) mediated oxidative demeta-
lation afforded the requisite bicyclic diketone (()-6 in 87% yield
(Scheme 4). Chemoselective protection of the saturated carbonyl
group was best accomplished by Lewis acid-promoted ketal
exchange12 between 2-ethyl-2-methyl-1,3-dioxolane and (()-6
to produce the enone (()-7 in 85% yield. Luche reduction13 of
(()-7 gave a single endo (equatorial) diastereomer (()-8 of an
allylic alcohol in quantitative yield.14 Catalytic hydrogenation
with 5% Pd-C led to reduction of the olefinic double bond as
well as cleavage of the N-Cbz protecting group to give a
secondary amine that was reprotected in situ with CbzCl to
provide (()-9b in 95% yield. Subsequent ketone deprotection
Scheme 3. Synthesis of (-)-5 via a [5+2] Cycloaddition
Results and Discussion
Organometallic chiron 2 provides the opportunity for two
novel molybdenum-mediated approaches to the azabicyclo-
[3.2.1]octane framework of Bao Gong Teng A. First, an
intramolecular “1,5-Michael” reaction of an enolate to an
internal oxo-η3-allylmolybdenum moiety, as depicted in the
conversion 2 f 3 f 4 f 5 in Scheme 2, was explored with
racemic 5, which was easily constructed by (i) gentle acidic
hydrolysis of the racemic scaffold 21g,i to give the oxo-η3-
pyridinyl complex 3 in 95-100% yield followed by (ii) a
Mukaiyama-Michael reaction with methyl vinyl ketone (90%
yield). Then, by use of the recently described 1,5-Michael
procedure,8 racemic 4 was transformed into (()-5 in 97% yield
and with 40:1 exo-endo diastereoselectivity.
In comparison, the same tropane core 5 could be prepared in
one step directly from the TpMo(CO)2(η3-pyridinyl) scaffold 2
by a regio- and stereocontrolled [5+2] cycloaddition of methyl
vinyl ketone,1h,i albeit with lower exo-endo diastereoselectivity
than the “1,5-Michael” sequence (Scheme 3). Nevertheless, the
undesired endo isomer was easily epimerized to the desired exo
isomer, making the [5+2] protocol the shorter and preferred
method for rapidly constructing quantities of the tropane core.
Thus, treatment of 3.9 g of >99% ee 5-methoxy η3-pyridinyl-
molybdenum complex (-)-2 (easily prepared on a 10 g scale
according to a previously established protocol1i) with 2 equiv
of methyl vinyl ketone in the presence of 0.5 equiv of EtAlCl2
furnished a mixture of the two diastereomeric [5+2] cyclo-
adducts (exo/endo ) 5:1-7:1) in very high yield within 1 min
at 0 °C without degradation of the enantiomeric excess.9-11
These epimers were readily separated by flash column chro-
15
promoted by catalytic Pd(CH3CN)2Cl2 gave (()-10b, which
was followed by Baeyer-Villiger oxidation to afford racemic
N-Cbz-2-epi-Bao Gong Teng A (()-11b in 77% overall yield
from (()-9b.16 Unfortunately, all attempts to invert the C-2
hydroxyl stereochemistry of 9 by Mitsunobu chemistry led only
to the recovery of the endo isomer (()-9b,17 suggesting a
possible double inversion sequence caused by participation of
Cbz group.18 Completion of a synthesis of (()-2-epi-1 proceeded
by removal of the Cbz protecting group via hydrogenolysis
(91%).
The inability to invert the stereochemistry of 2-epi-1 neces-
sitated a slightly modified strategy to produce the desired axial
C-2 hydroxyl directly from a ketonic precursor. Given our
experience with the racemic series chemistry, the successful
strategy was carried out with the highly enantiopure exo isomer
(-)-5a that was produced by the [5+2] cycloaddition of >99%
ee 5-methoxy η3-pyridinylmolybdenum complex (-)-2 with
(12) McMurry, J. E.; Isser, S. J. J. Am. Chem. Soc. 1972, 94, 7132.
(13) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
(14) Reduction of (()-7 with NaBH4 in refluxing ethanol afforded a 1:1 mixture
of (()-8 and its R,â-saturated analogue (()-9b with complete endo
selectivity in 85% yield.
(15) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H. Tetrahedron Lett.
1985, 26, 705. Alternate methods of deprotection were not as efficient.
(16) Baeyer-Villiger oxidation for this type of bicyclic compound with mCPBA
is a slow and low-yielding reaction (54% after 7 days in CHCl3;6a 52%
after 10 days in 1:2 benzene/CHCl36b). Fortunately, however, Baeyer-
Villiger oxidation of (()-10b with recrystallized mCPBA in benzene for 5
days produced the desired ester (()-11b in 77% yield along with the
recovery of about 10% of the starting material (()-10b.
(17) Although the intermediate p-nitrobenzoate was not isolated, TLC and HPLC
analysis of the Mitsunobu reaction mixture showed the disappearance of
the starting material and the formation of the new product (assumed to be
the p-nitrobenzoate). Subsequent basic hydrolysis resulted in the isolation
of the endo alcohol rather than its exo isomer.
(18) See references for neighboring-group participation of the Cbz group: (a)
Coward, J. K.; Lok, R. J. Org. Chem. 1973, 38, 2546. (b) Ginsburg, S.;
Wilson, I. B. J. Am. Chem. Soc. 1964, 86, 4716.
(8) Zhang, Y.; Liebeskind, L. S. J. Am. Chem. Soc. 2005, 127, 11258.
(9) All molybdenum complexes used in this study are air-stable, yellow to
orange solids, and are easily accessible on a multigram scale by simple
benchtop techniques.
(10) Previously described conditions for the molybdenum-mediated [5+2]
cycloadditions involved the potential risk of partial racemization of the
molybdenum complex;1j therefore improved conditions described within
the Experimental Section were developed to minimize the racemization of
(-)-2.
(11) The yields are significantly dependent on the quality of the Lewis acid
EtAlCl2 and can vary in the range of 40-95%.
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466 J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006

Synthesis by an Organometallic Chiron Approach
A R T I C L E S
Scheme 4. Total Synthesis of (()-2-epi-Bao Gong Teng A
a CAN, Et3N, THF/H2O, 0 °C to room temperature, 87%. b 2-Ethyl-2-methyl-1,3-dioxolane, BF3‚Et2O, CHCl3, 35 min, 85%. c NaBH4, CeCl3‚7H2O,
CHCl3/EtOH, -78 °C, 10 min, 98%. d (i) Pd/C, H2, MeOH; (ii) CbzCl, NaHCO3, H2O/CH3OH/THF, 95%. e Pd(CH3CN)2Cl2 (8 mol %), acetone, 99%.
f mCPBA, benzene, 78%. g Pd(OH)2/C, H2, EtOH/EtOAc, 91%.
Scheme 5. Total Synthesis of (-)-Bao Gong Teng A, (-)-1
a CAN, Et3N, THF/H2O, 0 °C to room temperature, 88%. b 2-Ethyl-2-methyl-1,3-dioxolane, BF3‚Et2O, CHCl3, 35 min, 82%. c ClRh(PPh3)3, t-BuOH/
THF, 24 h, 85%. d L-Selectride, THF, -78 °C, 1 h, >21:1 dr, 94%. e Pd(CH3CN)2Cl2 (8%), acetone, 99%. f mCPBA, benzene, 75%. g Pd(OH)2/C, H2,
EtOH/ EtOAc, 92%.
methyl vinyl ketone (followed by base-induced equilibration
of the endo to the exo cycloadduct) as shown in Scheme 3.
The reaction sequence from (-)-exo-5 through (+)-6 to
selectively protected (+)-7 mimicked that used for the racemic
series, described above. Rather than attempt reduction on the
unsaturated ketone (+)-7, the requisite axial C-2 alcohol (-)-
9a was established after hydrogenation of the double bond of
(+)-7 with Wilkinson’s catalyst. Dramatically, reduction of the
saturated ketone (+)-12 with L-Selectride furnished the desired
carbinol (-)-9a as a colorless oil in high yield (94%) and with
excellent stereoselectivity (9a:9b >21:1). Various other hydride
reducing agents such as NaBH4, LiAl(Ot-Bu)3H, LiAlH4, and
DIBAL in various solvents afforded the undesired endo isomer
9b as the major component (9a:9b ) 1:20). It is of interest to
note that, in the previously published syntheses, hydride
reduction of N-benzyl protected analogues of the saturated
ketone 12 did afford the desired 2-exo alcohol in varying yields
and selectivities (for NaBH4, exo/endo ) 18:1, yield 59%;6a
for LiAl(Ot-Bu)3H, exo/endo ) 3:1, yield 83%6b). It is not clear
why, in comparison to other reducing agents, L-Selectride is
so highly selective for generating the desired axial alcohol when
the nitrogen atom of the saturated ketone (+)-12 is protected
with a Cbz group.
by recrystallization from a mixture of methylene chloride and
hexanes. Finally, the total synthesis was completed by hydro-
genolytic removal of the Cbz protecting group to afford (-)-
Bao Gong Teng A (-)-1 (240 mg), whose spectroscopic data
1
(HRMS, H, 13C NMR) were in good agreement with those
reported in the literature.4,6a,6b,19 This synthesis, together with
the X-ray structure of (-)-11a, confirmed the proposed absolute
configuration of (-)-Bao Gong Teng A.20 We note that (-)-
Bao Gong Teng A produced from this work is a colorless
crystalline material with a melting point of 76-8 °C, while the
previously reported Bao Gong Teng A, either synthesized6a,b
or isolated from nature,4a was claimed as an oily product. The
benzoic acid salt of (-)-Bao Gong Teng A was also prepared
and crystallized as colorless needles from benzene (mp 141-3
°C, lit.4a 138-9 °C).
Conclusion
The ability of a high enantiopurity TpMo(CO)2(η3-pyridinyl)
complex to function as an “organometallic chiron” has been
demonstrated by an efficient, concise, and enantiocontrolled
construction of (-)-Bao Gong Teng A (Scheme 5). Under the
(19) Bao Gong Teng A from this work: mp 76-78 °C; [R]25 -29.6° (c )
D
0.97, EtOH); [R]25 -21.3° (c ) 1.83, H2O). Bao Gong Teng A benzoic
D
acid salt from this work: mp 141-143 °C [lit.4a 138-139 °C]; [R]25
-13.8° (c ) 1.32, EtOH); [R]25D -10.8° (c ) 0.8, H2O) [lit.4b [R]28D -7.21D°
(c ) 0.97, H2O)]. Pham and Charlton6b reported that the optical rotation
Having established the requisite axial alcohol, mild depro-
tection of the carbonyl group of (-)-9a followed by Baeyer-
Villiger oxidation furnished N-Cbz (-)-Bao Gong Teng A, (-)-
11a, in 74% overall yield and 99.3% ee with complete retention
of configuration at C-6. The ee was further increased to >99.9%
of Bao Gong Teng A in their asymmetric synthesis is [R]23 -7.6° (c )
D
0.34, H2O).
(20) Wang, P.; Yao, T.; Chen, Z. Huaxue Xuebao 1989, 47, 1002; Chem. Abstr.
1990, 113, 78746.
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A R T I C L E S
Zhang and Liebeskind
(()-3 (3.0 g, 5.04 mmol) were successively added Et3N (775 µL, 5.55
mmol) and TBSOTf (1.27 mL, 5.55 mmol). The reaction mixture was
stirred at room temperature for about 10 min and was then cooled to
-78 °C. To this cold solution was rapidly added a premixed 25 mL
CH2Cl2 solution of methyl vinyl ketone (MVK; 585 µL, 7.21 mmol)
and titanium tetrachloride (1.0 M in CH2Cl2, 6.55 mL, 6.55 mmol) via
syringe. [The MVK was first dissolved in 10 mL of CH2Cl2 and then
cooled to -78 °C. To this cold solution was then added titanium
chloride (1.0 M solution in CH2Cl2) via syringe.] The reaction mixture
was stirred at -78 °C for 10 min, quenched with 1 mL of saturated
sodium bicarbonate aqueous solution at -78 °C, and then partitioned
between brine and dichloromethane. The organic layer was separated
and the aqueous layer was extracted with dichloromethane. The organic
layers were combined and dried with Na2SO4, and solvent was removed
under vacuum to afford a crude product. The crude product was purified
by flash column chromatography (hexanes-EtOAc 1:1) to afford (()-4
as an orange solid (3.03 g, 90%). (()-4: TLC (Rf ) 0.58, hexanes-
influence of EtAlCl2 >99% ee (-)-(2R)-dicarbonyl[hydridotris-
(1-pyrazolyl)borato][(η3-2,3,4)-1-benzoxycarbonyl -5-methoxy-
1,2-dihydropyridin-2-yl]molybdenum reacts with methyl vinyl
ketone within 1 min at 0 °C to generate a tropane core [5+2]
adduct in 89% yield without loss of ee. This cycloadduct was
easily and very efficiently transformed into (-)-Bao Gong Teng
A, with a key step being the highly selective generation of the
2-exo alcohol of the natural product.
In the “organometallic chiron” strategy, single enantiomers
of a metal π-complex are produced, in quantity, and then
elaborated easily and efficiently to generate, after demetalation,
highly enantiopure advanced synthetic intermediates. The stoi-
chiometric nature of the depicted chemistry is mitigated by the
low cost of molybdenum and the use of a single metal moiety
to activate the organic ligand for unique bond constructions not
easily achieved by traditional synthetic manipulations. Related
as well as divergent “organometallic chiron” strategies for the
synthesis of other heterocyclic natural products of biological
interest are under development.
1
EtOAc 1:1). IR (cm-1): 1969 (s), 1864 (s), 1706 (m), 1664 (m). H
NMR (a mixture of two rotamers): δ 8.56 (d, J ) 1.9 Hz, 0.5 H), 8.42
(d, J ) 1.9 Hz, 0.5 H), 8.37 (d, J ) 1.9 Hz, 0.5 H), 7.70 (d, J ) 1.9
Hz, 0.5 H), 7.67 (s, 1H), 7.64 (d, J ) 2.2 Hz, 0.5 H), 7.62 (d, J ) 2.2
Hz, 0.5 H), 7.58 (d, J ) 2.4 Hz, 0.5 H), 7.53 (d, J ) 2.2 Hz, 0.5 H),
7.48-7.52 (m, 2 H), 7.40-7.43 (m, 1 H), 7.35-7.38 (m, 2 H), 7.33
(dd, J ) 6.4 and 1.5 Hz, 0.5 H), 7.08 (dd, J ) 6.4 and 1.6 Hz, 0.5 H),
6.27-6.30 (m, 1.5 H), 6.23 (t, J ) 2.2 Hz, 0.5 H), 6.21 (t, J ) 2.2 Hz,
0.5 H), 5.81 (t, J ) 2.2 Hz, 0.5 H), 5.24 (s, 0.5 H), 5.23 (AB quartet,
J ) 11.4 Hz, 0.5 H), 4.74 (dd, J ) 6.0 and 1.9 Hz, 0.5 H), 4.71 (dd,
J ) 6.0 and 1.9 Hz, 0.5 H), 4.03 (t, J ) 6.2 Hz, 0.5 H), 3.91 (t, J )
6.2 Hz, 0.5 H), 3.69 (t, J ) 6.7 Hz, 0.5 H), 3.61 (dd, J ) 7.0 and 5.1
Hz, 0.5 H), 2.44-2.71 (m, 2 H), 2.17 (s, 1.5 H), 2.10 (s, 1.5 H), 2.05-
2.15 (m, 2 H). 13C NMR: δ 225.9, 225.2, 222.9, 221.7, 207.8, 207.4,
197.5, 196.9, 154.9, 153.9, 147.6, 147.5, 147.1, 144.6, 140.8, 140.5,
136.7, 136.6, 136.46, 136.39, 135.7, 135.4, 135.09, 135.04, 129.00,
128.96, 128.8, 128.6, 128.4, 106.5, 106.4, 106.05, 106.01, 98.4, 95.3,
69.4, 68.7, 65.2, 64.5, 59.6, 58.8, 57.5, 57.4, 39.6, 39.1, 30.1, 27.3,
26.7. HRMS (FAB) calcd for C28H28BMoN7O6 (M+): 667.1248.
Found: 667.1245.
Experimental Section
Since almost all of the Tp molybdenum complexes decompose at
about 180-200 °C, melting points are not significant and are not shown
in the Experimental Section. Unless otherwise specified, all reactions
were carried out under a nitrogen or argon atmosphere, and all reaction
flasks were flamed or oven-dried prior to use. The nomenclature for
determining the chirality of the molybdenum complexes is straight-
forward.21
Preparation of the Molybdenum Complexes. The racemate (()-2
was prepared according to a literature procedure.1g,i The experimental
procedures and characterization data for (-)-2 and its precursors are
given in the Supporting Information.
(A) (()-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(2R,6R)-
(η3-2,3,4)-1-benzyloxycarbonyl-5-oxo-5,6-dihydro-2H-pyridin-2-yl]-
molybdenum [(()-3]. To a round-bottomed flask charged with
molybdenum complex (()-2 (4.51 g, 7.41 mmol) in CH2Cl2 (10 mL)
was added a solution of HCl in methanol (50 mL, 37% HCl:MeOH:
H2O ) 1:12:1 v/v/v) at 0 °C. The solution was stirred for 5 h at room
temperature to give an orange suspension. The suspension was extracted
with CH2Cl2 (50 mL × 3). The organic phases were combined and
washed with brine (20 mL × 3). The solvent was removed under
reduced pressure to give (()-3 as an orange solid (4.4 g, 100%). TLC
(Rf ) 0.62, hexanes-EtOAc 1:1). IR (CH2Cl2, cm-1) 1961 (s), 1864
1
(s), 1702 (s), 1664 (s). H NMR (a mixture of two rotamers): δ 8.45
(()-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(1R,2R,5S,6S)-
(η3-2,3,4)-6-acetyl-8-benzyloxycarbonyl-2-methoxy-8-azabicyclo-
[3.2.1]oct-3-en-2-yl]molybdenum [(()-exo-5], (()-Dicarbonyl[hy-
dridotris(1-pyrazolyl)borato][(1R,2R,5S,6R)-(η3-2,3,4)-6-acetyl-8-
benzyloxycarbonyl-2-methoxy-8-azabicyclo[3.2.1]oct-3-en-2-
yl]molybdenum [(()-endo-5], (-)-Dicarbonyl[hydridotris(1-pyraz-
olyl)borato][(1R,2R,5S,6S)-(η3-2,3,4)-6-acetyl-8-benzyloxycarbonyl-
2-methoxy-8-azabicyclo[3.2.1]oct-3-en-2-yl]molybdenum [(-)-exo-
5], and (-)-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(1R,2R,
5S,6R)-(η3-2,3,4)-6-acetyl-8-benzyloxycarbonyl-2-methoxy-8-
azabicyclo[3.2.1]oct-3-en-2-yl]molybdenum [(-)-endo-5]: (A) 1,5-
Michael-Type Addition Reactions to Generate (()-5. To a solution
of the molybdenum complex (()-4 (100 mg, 0.15 mmol) in CH2Cl2
(7.5 mL) was added solid potassium trimethylsilanolate (57.9 mg, 0.45
mmol). The reaction mixture was stirred at room temperature for 1 h.
Me3OBF4 (55.5 mg, 0.723 mmol) was added as a solid and the mixture
was then stirred at room temperature for 40 min. The reaction mixture
was directly poured on a short pad of silica gel. Elution with 50%
ethyl acetate in hexanes, concentration, and then flash chromatographic
purification afforded the molybdenum complexes (()-exo-5 (97 mg,
95%) and (()-endo-5 (2 mg, 2%). Note: the diastereoselectivity is
(d, J ) 1.9 Hz, 0.4 H), 8.42 (d, J ) 1.9 Hz, 0.6 H), 8.31 (d, J ) 1.9
Hz, 0.6 H), 7.76 (d, J ) 1.9 Hz, 0.4 H), 7.74 (d, J ) 1.9 Hz, 0.6 H),
7.70 (d, J ) 1.9 Hz, 0.4 H), 7.65 (d, J ) 1.9 Hz, 0.6 H), 7.62 (d, J )
1.9 Hz, 0.6 H), 7.60 (d, J ) 1.9 Hz, 0.4 H), 7.58 (d, J ) 1.9 Hz, 0.4
H), 7.47-7.52 (m, 1.6 H), 7.40-7.44 (m, 2.0 H), 7.27-7.38 (m, 3.0
H), 7.22 (dd, J ) 6.4 and 1.9 Hz, 0.4 H), 6.28-6.30 (m, 1.6 H), 6.22-
6.24 (m, 1.0 H), 5.97 (t, J ) 2.2 Hz, 0.4 H), 5.27 (AB quartet, J )
11.4 Hz, 0.4 H), 5.24 (s, 0.6 H), 4.74-4.77 (m, 1.0 H), 4.09 (t, J )
6.4 Hz, 0.6 H), 3.98 (t, J ) 6.4 Hz, 0.4 H), 3.41 (AB quartet, J ) 20.0
Hz, 0.4 H), 3.39 (AB quartet, J ) 19.7 Hz, 0.6 H). 13C NMR: δ 225.2,
224.7, 222.8, 222.1, 193.7, 193.0, 154.8, 154.0, 147.5, 147.4, 144.7,
143.6, 141.6, 141.5, 136.7, 136.62, 136.48, 136.44, 135.7, 135.5, 135.0,
129.1, 128.9, 128.8, 128.7, 128.4, 128.0, 106.36, 106.34, 106.1, 106.0,
94.0, 92.4, 69.1, 68.3, 64.7, 64.4, 64.1, 63.6, 48.1, 48.0. HRMS (ESI)
calcd for C24H23BMoN7O5 ([M + H]+): 598.0908. Found: 598.0905.
(B) (()-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(2R,6R)-(η3-
2,3,4)-1-benzyloxycarbonyl-5-oxo-6-(3′-oxobutyl)-5,6-dihydro-2H-
pyridin-2-yl]molybdenum [(()-4]. To a 30 mL CH2Cl2 solution of
(21) Sloan, T. E. Top. Stereochem. 1981, 12, 1.
9
468 J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006

Synthesis by an Organometallic Chiron Approach
A R T I C L E S
strongly correlated to the trapping time with the Meerwein salt. HPLC
analysis of the reaction mixture indicated a ratio of exo/endo ) 17:1
in 4 h after addition of Meerwein salt. Prolongation of the reaction
time to 15 h resulted in a ratio of exo/endo ) 5:1. (()-exo-5: TLC (Rf
) 0.49, hexanes-EtOAc 1:1). IR (cm-1): 1930 (s), 1841 (s), 1710
(s). 1H NMR (a mixture of two rotamers): δ 8.42 (d, J ) 1.6 Hz, 0.4
H), 8.39 (d, J ) 1.6 Hz, 0.6 H), 7.97 (d, J ) 1.9 Hz, 0.6 H), 7.95 (d,
J ) 1.6 Hz, 0.4 H), 7.63 (d, J ) 1.6 Hz, 0.4 H), 7.60 (m, 2.6 H), 7.47
(d, J ) 2.2 Hz, 1 H), 7.27-7.34 (m, 5 H), 6.23 (t, J ) 2.2 Hz, 1.2 H),
6.18-6.21 (m, 0.8 H), 6.14-6.15 (m, 1 H), 5.08 (AB quartet, J )
12.4 Hz, 0.8 H), 5.03 (AB quartet, J ) 12.1 Hz, 1.2 H), 4.77(d, J )
6.0 Hz, 0.6 H), 4.69 (d, J ) 3.8 Hz, 0.4 H), 4.65 (d, J ) 5.8 Hz, 0.4
H), 4.57 (d, J ) 4.1 Hz, 0.6 H), 4.11 (dd, J ) 7.6 and 4.1 Hz, 0.4 H),
4.03 (dd, J ) 7.6 and 4.1 Hz, 0.6 H), 3.39-3.41 (m, 1 H), 3.33-3.36
(m, 1 H), 3.30 (s, 1.8 H), 3.22 (s, 1.2 H), 2.55-2.61 (m, 1 H), 2.31 (s,
1.2 H), 2.12 (s, 1.8 H), 2.05 (dd, J ) 12.4 and 7.9 Hz, 0.6 H), 1.98
(dd, J ) 12.9 and 8.1 Hz, 0.4 H). 13C NMR: δ 228.6, 228.3, 227.6,
227.5, 206.0, 205.9, 153.65, 153.56, 146.4, 144.8, 140.68, 140.60, 136.8,
136.6, 136.5, 136.1, 135.70, 135.66, 134.5, 128.5, 128.4, 128.3, 128.1,
127.9, 105.8, 105.6, 67.4, 62.8, 62.4, 59.5, 59.3, 59.14, 59.13, 58.5,
56.8, 56.6, 52.7, 52.4, 33.9, 33.7, 29.2, 29.1. HRMS (FAB) calcd for
C29H30BMoN7O6 (M+): 681.1405. Found: 681.1415. (()-endo-5: TLC
(Rf ) 0.69, hexanes-EtOAc 1:1). IR (cm-1): 1930 (s), 1845 (s), 1702
(s). 1H NMR (a mixture of two rotamers): δ 8.42, 8.40 (two singlets,
1 H total), 7.97 (s, 1 H), 7.61, 7.60 (s, 2 H), 7.49 (d, J ) 1.9 Hz, 1 H),
7.46 (d, J ) 1.9 Hz, 1 H), 7.32-7.44 (m, 6 H), 6.22 (s, 1 H), 6.19 (s,
1 H), 6.15 (t, J ) 1.9 Hz, 1 H), 5.18 (AB quartet, J ) 12.4 Hz, 0.8 H),
5.15 (AB quartet, J ) 12.4 Hz, 1.2 H), 4.94 (s, 0.6 H), 4.87 (s, 0.4 H),
4.67 (d, J ) 5.2 Hz, 0.4 H), 4.58 (d, J ) 5.2 Hz, 0.6 H), 3.71 (dd, J
) 7.6 and 4.3 Hz, 1 H), 3.44 (m, 0.6 H), 3.37 (m, 1 H), 3.31 (m, 0.4
H), 3.27 (s, 1.2 H), 3.23 (s, 1.8 H), 2.60 (m, 1 H), 2.38 (s, 1.8 H), 2.36
(s, 1.2 H), 2.10 (m, 0.4 H), 1.94 (m, 0.6 H). 13C NMR: δ 229.4, 229.0,
227.7, 227.4, 205.32, 205.31, 153.9, 153.4, 146.2, 144.8, 140.3, 140.2,
136.6, 136.5, 136.1, 135.6, 135.4, 134.5, 128.5, 128.1, 105.7, 105.6,
67.6, 59.3, 58.5, 58.2, 57.8, 57.1, 57.0, 56.9, 56.8, 56.0, 53.6, 53.4,
33.0, 32.6, 30.74, 30.67, 29.8. HRMS (FAB) calcd for C29H30BMoN7O6
(M+): 681.1405. Found: 681.1418.
mg, 9%). Other bases gave poor results (Et3N, no isomerization; 25 wt
% sodium methoxide in methanol overnight, exo:endo ) 9.5:1;
potassium trimethylsilanolate overnight, exo:endo ) 5.2:1; potassium
tert-butoxide overnight, exo:endo ) 1:3.3.).
Synthesis of (()-2-epi-Bao Gong Teng A: (A) (()-(1R,5R,6S)-
6-Acetyl-8-benzyloxycarbonyl-8-azabicyclo[3.2.1]oct-3-en-2-one [(()-
6] and (+)-(1R,5R,6S)-6-Acetyl-8-benzyloxycarbonyl-8-azabicyclo-
[3.2.1]oct-3-en-2-one [(+)-6]. To an orange solution of the molybdenum
complex (()-exo-5 (2.23 g, 3.27 mmol) and triethylamine (684 µL,
4.92 mmol) in a 3:1 mixture of THF/H2O (160 mL) at 0 °C (ice bath)
open to air was added a solution of ceric ammonium nitrate (14.33 g,
26.2 mmol) in H2O (80 mL) dropwise over 5 min. After completion of
the addition, the color faded and a light yellow solution formed. The
ice bath was removed and the reaction mixture was stirred for an
additional 10 min at room temperature and then partitioned between
dichloromethane (100 mL) and water (100 mL). The organic layers
were washed with brine and dried with Na2SO4, and solvents were
removed under vacuum to provide the crude product. The crude product
was purified by flash chromatography to afford (()-6 (850 mg, 87%)
as a colorless oil.
(()-6. TLC (Rf ) 0.27, hexanes-EtOAc 1:1). IR (cm-1): 1702 (s).
1H NMR: (a mixture of two rotamers) δ 7.28-7.38 (m, 6 H), 6.03
(dd, J ) 9.8 and 1.6 Hz, 1 H), 5.11 (AB quartet, J ) 12.4 Hz, 2 H),
5.06 (br s, 1 H), 4.80 (br s, 0.4 H), 4.73 (br s, 0.6 H), 3.04 (dd, J ) 9.2
and 3.8 Hz, 1 H), 2.82 (br s, 0.6 H), 2.66 (br s, 0.4 H), 2.29 and 2.24
(br s, 3.4 H), 1.91 (br s, 1.6 H). 13C NMR: δ 204.7, 204.5, 195.5,
195.1, 154.3, 154.1, 151.9, 150.9, 135.9, 128.7, 128.4, 128.15, 128.06,
67.9, 64.3, 56.5, 56.0, 54.8, 53.9, 29.9, 28.5, 27.5, 27.3. HRMS (FAB)
calcd for C17H18NO4 ([M + H]+): 300.1236. Found: 300.1230.
Similar treatment of (-)-exo-5 (2.66 g, 3.91 mmol) with triethyl-
amine (816 µL, 5.86 mmol) and CAN (17.14 g, 31.3 mmol) in a 1:1
mixture of THF/H2O (240 mL) afforded (+)-6 (1.03 g, 88%) as a
colorless oil, [R]25 +106.5° (c ) 0.84, CH2Cl2).
D
(B) (()-(1R,5R,6S)-8-Benzyloxycarbonyl-6-(1-methyl-1,1-dioxa-
cyclopentyl)-8-azabicyclo[3.2.1]oct-3-en-2-one [(()-7] and (+)-
(1R,5R,6S)-8-Benzyloxycarbonyl-6-(1-methyl-1,1-dioxacyclopentyl)-
8-azabicyclo[3.2.1]oct-3-en-2-one [(+)-7]. To a solution of (()-6 (1.14
g, 3.76 mmol), 2-ethyl-2-methyl-1,3-dioxolane (2.63 g, 22.6 mmol),
and ethylene glycol (67.8 mg, 0.75 mmol) in 150 mL of chloroform
was added boron trifluoride diethyl etherate (520 µL, 4.14 mmol) via
syringe. The reaction mixture was stirred at ambient temperature for
35 min. Gas chromatographic-mass spectrometric (GC-MS) analysis
of the reaction mixture indicated a mixture of three different compounds,
(()-7 (96%), (()-6 (1%), and the doubly protected product (3%). The
reaction was quenched with 1 mL of saturated sodium bicarbonate and
then partitioned between dichloromethane (50 mL) and brine (100 mL).
The organic layer was separated and the aqueous layer was extracted
with dichloromethane (30 mL × 2). The organic layers were combined
and dried with sodium sulfate, and solvents were removed under
vacuum to afford an oily residue. The residue was further purified by
flash chromatography to afford (()-7 (1.12 g, 85%). Note: the doubly
protected product and the starting material (()-6 could not be separated
efficiently by flash column chromatography. However, treatment of
the mixture (∼10%) with boron trifluoride etherate in acetone for 7 h
gave the starting material (()-6 that could be used in the next protection
reaction in good yield. This treatment avoided the loss of the starting
material (()-6.
(B) [5+2] Cycloadditions to (()-5 and (-)-5. The previously
reported procedure1i for [5+2] cycloadditions was modified to shorten
the reaction time by increasing the mole percentage of Lewis acid,
increasing the mole percentage of MVK, and conducting the reaction
at low temperature (0 °C), which increased the yield and reduced the
potential risk of racemization of products. To a solution of the
molybdenum complex (()-2 (3.20 g, 5.38 mmol) and methyl vinyl
ketone (874 µL, 10.78 mmol) in dichloromethane (80 mL) at 0 °C was
added a 1.0 M solution of EtAlCl2 in hexanes (8.06 mL, 8.06 mmol)
via syringe. The reaction was stirred 0 °C for only 1 min. The reaction
mixture was poured directly onto a short pad of silica gel. Elution with
50% ethyl acetate in hexanes, concentration, and then flash chromato-
graphic purification afforded the molybdenum complexes (()-exo-5
(3.66 g, 76.1%) and (()-endo-5 (0.73 g, 15.2%).
To a solution of the molybdenum complex (-)-2 (3.64 g, 5.98 mmol)
and methyl vinyl ketone (970 µL, 11.96 mmol) in dichloromethane
(100 mL) was added a 1.0 M solution of EtAlCl2 in hexanes (2.99
mL, 2.99 mmol) via syringe. The reaction was stirred 0 °C for 1 min.
A similar workup afforded the molybdenum complexes (-)-exo-5 (3.27
g, 78%) and (-)-endo-5 (0.46 g, 11%). (-)-exo-5, [R]25D -260° (c )
0.83, CH2Cl2). (-)-endo-5, [R]25 -235° (c ) 0.89, CH2Cl2).
(()-7. TLC (Rf ) 0.42, hexanes-EtOAc 1:1). IR (cm-1): 1702 (s).
1H NMR (a 60:40 mixture of two rotamers): δ 7.43 (dd, J ) 9.5 and
5.4 Hz, 0.6 H), 7.28-7.37 (m, 5.4 H), 5.97 (d, J ) 9.5 Hz, 0.6 H),
5.96 (d, J ) 9.5 Hz, 0.4 H), 5.12 (AB quartet, J ) 12.4 Hz, 0.8 H),
5.11 (AB quartet, J ) 12.4 Hz, 1.2 H), 4.87 (d, J ) 5.4 Hz, 0.6 H),
4.76 (m, 1.4 H), 3.88-4.05 (m, 3.6 H), 3.75-3.78 (m, 0.4 H), 2.28-
D
(C) Base-Catalyzed Isomerization from Endo to Exo Isomers.
To a solution of the pure endo isomer (-)-endo-5 (400 mg, 0.587 mmol)
in 10 mL of CH2Cl2 were added potassium trimethylsilanolate (7.6 mg,
0.059 mmol) and 25 wt % sodium methoxide in methanol (27 µL, 0.119
mmol). The reaction mixture was stirred at ambient temperature for
10 min. HPLC analysis of the mixture indicated a ratio of exo:endo )
10:1. Flash column chromatographic purification afforded the exo
isomer (-)-exo-5 (321 mg, 80%) and the endo isomer (-)-endo-5 (35
2.39 (m, 2 H), 1.80-1.89 (m, 1 H), 1.28 (s, 1.8 H), 1.25 (s, 1.2 H). 13
C
NMR: δ 196.4, 196.0, 154.3, 153.9, 152.9, 136.4, 128.72, 128.67,
128.4, 128.3, 128.2, 127.9, 127.5, 127.3, 110.35, 110.28, 67.5, 67.4,
9
J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006 469

A R T I C L E S
Zhang and Liebeskind
65.4, 65.2, 65.0, 64.83, 64.78, 64.68, 55.8, 55.6, 51.4, 50.5, 28.1, 27.2,
22.3, 21.7. HRMS (FAB) calcd for C19H22NO5 ([M + H]+): 344.1498.
Found: 344.1486.
residue was purified by flash column chromatography to afford (()-
9b (369 mg, 95%) as a colorless oil.
(()-9b. TLC (Rf ) 0.18, hexanes-EtOAc 1:1). IR (cm-1): 3424
(br, s), 1698 (s). 1H NMR (a 55:45 mixture of two rotamers): δ 7.30-
7.36 (m, 5 H), 5.133 (AB quartet, J ) 12.4 Hz, 1.1 H), 5.132 (s, 0.9
H), 4.31 (br s, 0.45 H), 4.29 (dd, J ) 6.7 and 3.3 Hz, 0.55 H), 4.25
(dd, J ) 6.7 and 3.3 Hz, 0.45 H), 3.86-4.03 (m, 4.0 H), 3.76-3.79
(m, 1.0 H), 2.09-2.18 (m, 3.0 H), 1.66-1.92 (m, 3.0 H), 1.40-1.56
(m, 2.0 H), 1.25 (s, 1.25 H), 1.21 (s, 1.65 H). 13C NMR: δ 153.7,
153.4, 137.2, 137.0, 128.6, 128.2, 128.1, 127.9, 111.5, 111.4, 68.8,
68.0, 66.9, 66.8, 65.2, 65.0, 64.8, 59.1, 55.0, 54.9, 54.5, 49.9, 49.4,
30.2, 29.6, 26.7, 26.4, 26.2, 25.6, 21.4, 20.9. HRMS (FAB) calcd for
C19H26NO5 ([M + H]+): 348.1811. Found: 348.1815.
(E) (()-(1R,2R,5R,6S)-6-Acetyl-8-benzyloxycarbonyl-8-azabicyclo-
[3.2.1]octan-2-ol [(()-10b]. To a solution of (()-9b (41 mg, 0.139
mmol) in acetone (5 mL) was added Pd(CH3CN)2Cl2 (1.58 mg, 0.011
mmol). The mixture was stirred at ambient temperature overnight. Water
(1 mL) was added to quench the reaction, and the solvent was removed
under vacuum. The residue was partitioned between brine and di-
chloromethane. The organic layer was separated and the aqueous layer
was extracted with dichloromethane (5 mL × 3). The organic layers
were combined and dried with sodium sulfate, and solvents were
removed under vacuum to afford an oily crude product. The crude
product was further purified by flash column chromatography to afford
(()-10b (36 mg, 99%) as a colorless oil.
(()-10b. TLC (Rf ) 0.14, hexanes-EtOAc 1:1). IR (cm-1): 3420
(br, m), 1698 (s). 1H NMR (a 50:50 mixture of two rotamers): δ 7.32-
7.38 (m, 5.0 H), 5.09-5.15 (m, 2.0 H), 4.47 (br s, 1.0 H), 4.33 (br s,
0.5 H), 4.26 (br s, 0.5 H), 3.90 (br s, 0.5 H), 3.81 (br s, 0.5 H), 2.84
(m, 1.0 H), 2.16 (s, 1.5 H), 2.22 (s, 1.5 H), 2.07-2.30 (m, 2.0 H),
1.88-2.01 (m, 2.0 H), 1.61-1.78 (m, 2.0 H), 1.42-1.49 (m, 1.0 H).
13C NMR: δ 207.3, 153.8, 153.7, 136.7, 128.7, 128.2, 128.1, 128.0,
68.2, 67.6, 67.2, 59.1, 55.7, 55.2, 54.5, 53.9, 29.7, 29.2, 28.2, 28.1,
26.3, 25.9, 25.4, 25.2. HRMS (FAB) calcd for C17H22NO4 ([M + H]+):
304.1549. Found: 304.1537. Calcd for C17H21LiNO4 ([M + Li]+):
310.1631. Found: 310.1635.
Similar treatment of a mixture of (+)-6 (1.02 g, 3.41 mmol), 2-ethyl-
2-methyl-1,3-dioxolane (2.37 g, 20.5 mmol), and ethylene glycol (61.4
mg, 0.68 mmol) in 120 mL of chloroform with boron trifluoride diethyl
etherate (471 µL, 3.75 mmol) afforded (+)-7 (0.96 g, 82%) as a
colorless oil, [R]25 +95.5° (c ) 0.94, CH2Cl2).
D
(C) (()-(1R,2R,5R,6S)-8-Benzyloxycarbonyl-(1-methyl-1,1-di-
oxacyclopentyl)-8-azabicyclo[3.2.1]oct-3-en-2-ol [(()-8]. A solution
of (()-7 (1.00 g, 2.91 mmol) and cerium(III) chloride heptahydrate
(1.19 g, 3.19 mmol) in a mixture of ethanol (35 mL) and chloroform
(20 mL) was stirred at ambient temperature for 20 min until the cerium
salts completely dissolved. The reaction mixture was cooled to -78
°C (dry ice/acetone bath) and then a solution of sodium borohydride
(127 mg, 3.35 mmol) in 5 mL of ethanol was added via syringe. The
mixture was stirred for 10 min. TLC monitoring of the reaction indicated
a very clean conversion. The reaction was quenched with 1 mL of water
and then partitioned between dichloromethane (50 mL) and brine (100
mL). The organic layer was separated and the aqueous layer was
extracted with dichloromethane (30 mL × 2). The organic layers were
combined and dried with sodium sulfate, and solvents were removed
under vacuum to afford an oily residue. The residue was further purified
by flash column chromatography to afford (()-8 (984 mg, 98%) as a
colorless oil. (()-8: TLC (Rf ) 0.24, hexanes-EtOAc 1:1). IR (cm-1):
1
3428 (br, s), 1698 (s), 1436 (s). H NMR: (a 50:50 mixture of two
rotamers) δ 7.30-7.36 (m, 5 H), 6.13 (ddd, J ) 9.5, 5.2, and 1.4 Hz,
0.5 H), 6.07 (ddd, J ) 9.5, 4.8, and 1.4 Hz, 0.5 H), 5.50 (td, J ) 9.8
and 1.9 Hz, 0.5 H), 5.47 (td, J ) 9.5 and 1.9 Hz, 0.5 H), 5.14 (AB
quartet, J ) 12.4 Hz, 1.0 H), 5.13 (AB quartet, J ) 12.4 Hz, 1.0 H),
4.81 (d, J ) 4.8 Hz, 0.5 H), 4.69 (d, J ) 4.8 Hz, 0.5 H), 4.52 (t, J )
6.0 Hz, 0.5 H), 4.50 (d, J ) 5.2 Hz, 0.5 H), 4.48 (t, J ) 5.7 Hz, 0.5
H), 4.41 (d, J ) 5.2 Hz, 0.5 H), 3.83-4.02 (m, 3.5 H), 3.72-3.76 (m,
0.5 H), 2.44 (t, J ) 8.8 Hz, 0.5 H), 2.42 (t, J ) 8.8 Hz, 0.5 H), 2.35-
2.38 (m, 1 H), 2.03 (d, J ) 5.2 Hz, 0.5 H), 1.94 (ddd, J ) 10.5, 7.6,
and 2.9 Hz, 0.5 H), 1.90 (ddd, J ) 11.0, 8.1, and 2.9 Hz, 0.5 H), 1.75
(d, J ) 6.2 Hz, 0.5 H), 1.22 (s, 1.5 H), 1.18 (s, 1.5 H). 13C NMR: δ
153.7, 153.5, 137.1, 136.9, 134.5, 133.7, 128.7, 128.6, 128.2, 128.1,
128.0, 127.9, 110.71, 110.66, 68.8, 68.3, 67.1, 66.9, 66.3, 65.0, 64.9,
64.6, 57.9, 57.8, 54.5, 54.1, 53.4, 52.7, 25.2, 24.3, 21.8, 21.3. HRMS
(FAB) calcd for C19H24NO5 ([M + H]+): 346.1631. Found: 346.1653.
Calcd for C19H23LiNO5 ([M + Li]+): 352.1736. Found: 352.1719.
(D) (1) (()-(1R,2R,5R,6S)-8-Benzyloxycarbonyl-6-(1-methyl-1,1-
dioxacyclopentyl)-8-azabicyclo[3.2.1]octan-2-ol [(()-9b]. To a solu-
tion of (()-8 (100 mg, 0.332 mmol) in methanol (10 mL) was added
5% Pd-C (30 mg). The mixture was stirred overnight under a hydrogen
atmosphere and then filtered through a layer of Celite to remove the
Pd-C catalyst. The solvent was removed under vacuum to afford the
secondary amine (quantitative yield) as a white solid. The solid was
dissolved in 12 mL of acetone. To the solution were added potassium
carbonate (68.7 mg, 0.448 mmol) and benzyl chloroformate (52.1 µL,
0.365 mmol). The mixture was refluxed for 8 h and the solvent was
removed under vacuum. The residue was partitioned between dichloro-
methane (10 mL) and brine (10 mL). The organic layer was separated
and the aqueous layer was extracted with dichloromethane (5 mL ×
3). The organic layers were combined and dried with sodium sulfate,
and solvents were removed under vacuum to afford an oily crude
product. The crude product was further purified by flash column
chromatography to afford (()-9b (75 mg, 75%) as a colorless oil.
(2) Alternative Approach to (()-9b. The free amine (250 mg, 1.18
mmol) was dissolved with a mixture of solvents (12 mL, H2O:MeOH:
THF ) 2:1:1). To this solution were added sodium bicarbonate (199
mg, 2.37 mmol) and benzyl chloroformate (236 µL, 1.65 mmol). After
the mixture was stirred at ambient temperature for 2 h, brine was added
and the mixture was extracted with dichloromethane. The organic layer
was dried with sodium sulfate and concentrated under vacuum. The
(F) (()-(1R,2R,5R,6S)-6-Acetyloxy-8-benzyloxycarbonyl-8-aza-
bicyclo[3.2.1]octan-2-ol [(()-11b]. To a solution of (()-10b (85 mg,
0.28 mmol) in 6 mL of benzene was added m-chloroperbenzoic acid
(purified by recrystallization of the commercially available material
1
from CH2Cl2 until the H NMR spectrum showed it was pure) (146
mg, 0.84 mmol). The reaction mixture was stirred at ambient temper-
ature for 2 days, and an additional amount of mCPBA (97 mg, 0.56
mmol) was added. The mixture was stirred for an additional 3 days.
Brine and saturated aqueous NaHCO3 solution were added, the organic
layer was separated, and the aqueous layer was extracted with
dichloromethane (5 mL × 3). The organic layers were combined,
washed with a 1:1 mixture of brine and saturated aqueous NaHCO3
solution and then with saturated aqueous Na2S2O3 solution, and dried
with sodium sulfate. The solvents were removed under vacuum to afford
an oily crude product. The crude product was further purified by flash
column chromatography to afford (()-11b (69.8 mg, 78%) as a
colorless solid.
(()-11b. TLC (Rf ) 0.41, hexanes-EtOAc 1:3). M.p. 89-90 °C.
1
IR (cm-1): 3428 (br, m), 1729 (sh, s), 1702 (s). H NMR (a 55:45
mixture of two rotamers): δ 7.32-7.38 (m, 5.0 H), 5.16 (s, 0.9 H),
5.15 (AB quartet, J ) 12.4 Hz, 1.1 H), 4.992 (dd, J ) 7.6 and 2.9 Hz,
0.45 H), 4.986 (dd, J ) 7.7 and 2.4 Hz, 0.55 H), 4.39 (dd, J ) 7.2 and
2.9 Hz, 0.55 H), 4.31 (dd, J ) 7.2 and 2.9 Hz, 0.45 H), 4.20 (br s,
0.45 H), 4.15 (br s, 0.55 H), 3.88 (dt, J ) 9.9 and 4.9 Hz, 0.55 H),
3.79 (dd, J ) 9.3 and 5.0 Hz, 0.45 H), 2.49 (dd, J ) 13.6 and 4.5 Hz,
0.45 H), 2.48 (dd, J ) 13.6 and 4.5 Hz, 0.55 H), 2.05 (s, 1.35 H), 2.00
(s, 1.65 H), 1.84-1.95 (m, 2.0 H), 1.60-1.79 (m, 3.0 H), 1.26-1.36
(m, 1.0 H). 13C NMR: δ 171.14, 171.10, 154.3, 154.0, 136.7, 128.7,
128.3, 128.2, 127.9, 77.2, 76.4, 67.7, 67.20, 67.16, 67.12, 59.6, 59.3,
9
470 J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006

Synthesis by an Organometallic Chiron Approach
A R T I C L E S
58.98, 58.89, 32.4, 31.5, 26.6, 26.5, 26.1, 25.8, 21.34, 21.27. HRMS
(FAB) calcd for C17H22NO5 ([M + H]+): 320.1498. Found: 320.1503.
(G) (()-(1R,2R,5R,6S)-6-Acetyloxy-8-azabicyclo[3.2.1]octan-2-ol
[(()-2-epi-1]. To a solution of (()-11b (189 mg, 0.59 mmol) in 16
mL of mixed solvents (EtOH/EtOAc ) 1:1) was added 20% Pd(OH)2/C
(33 mg, 0.047 mmol). The mixture was stirred overnight under a
hydrogen atmosphere and filtered through a piece of filter paper to
remove the Pd-C catalyst. The solvents were removed under vacuum
to afford (()-2-epi-1 (100 mg, 91%) as a colorless crystalline solid.
(()-2-epi-1: mp)146-148 °C. IR (cm-1): 3462 (sh, m), 3281 (br,
and 2.9 Hz, 0.4 H), 4.29 (br s, 0.6 H), 3.86-4.01 (m, 3.4 H), 3,81 (br
s, 0.6 H), 3.76-3.81 (m, 0.6 H), 3.70 (br s, 0.4 H), 2.25 (m, 1.0 H),
2.00-2.02 (m, 1.0 H), 1.91-1.97 (m, 1.0 H), 1.62-1.79 (m, 4.0 H),
1.37-1.46 (m, 1.0 H), 1.24 (s, 1.2 H), 1.20 (s, 1.8 H). 13C NMR: δ
155.2, 154.4, 137.1, 136.9, 128.5, 127.93, 127.86, 127.84, 127.66, 111.3,
111.2, 69.7, 69.0, 66.9, 66.6, 65.1, 64.9, 64.7, 64.6, 59.7, 59.2, 55.6,
55.1, 48.4, 48.0, 29.5, 28.7, 27.4, 27.0, 24.7, 24.5, 21.6, 20.8. HRMS
(FAB) calcd for C19H26NO5 ([M + H]+): 348.1811. Found: 348.1798.
Similar treatment of (+)-12 (730 mg, 2.14 mmol) with L-Selectride
(5.36 mL, 5.36 mmol) in 70 mL of THF at -78 °C afforded (-)-9b
(29 mg, 4%) [[R]25D -12.0° (c ) 1.51, CH2Cl2)] and (-)-9a (655 mg,
1
m), 1725 (s), 1656 (w). H NMR: 5.01 (dd, J ) 7.2 and 2.4 Hz, 1.0
H), 3.80 (ddd, J ) 10.0, 5.7, and 3.6 Hz, 1.0 H), 3.57 (dd, J ) 7.2 and
3.3 Hz, 1.0 H), 3.30 (br s, 1.0 H), 2.44 (dd, J ) 14.3 and 7.2 Hz, 1.0
H), 2.07-2.23 (br s, exchangeable, 2.0 H), 2.05 (s, 3.0 H), 1.91 (td, J
) 13.9 and 5.2 Hz, 1.0 H), 1.67-1.71 (m, 2.0 H), 1.58 (ddt, J ) 13.3,
9.1, and 3.3 Hz, 1.0 H), 1.18 (ddt, J ) 13.3, 10.5, and 6.2 Hz, 1.0 H).
13C NMR: δ 171.0, 78.4, 69.2, 60.8, 60.2, 33.8, 27.35, 27.17, 21.5.
HRMS (FAB) calcd for C9H16NO3 ([M + H]+): 186.1130. Found:
186.1132.
Synthesis of (-)-Bao Gong Teng A: (A) (()-(1R,5R,6S)-8-Benzyl-
oxycarbonyl-6-(1-methyl-1,1-dioxacyclopentyl)-8-azabicyclo[3.2.1]octan-
2-one [(()-12] and (+)-(1R,5R,6S)-8-Benzyloxycarbonyl-6-(1-meth-
yl-1,1-dioxacyclopentyl)-8-azabicyclo[3.2.1]octan-2-one [(+)-12]. To
a solution of (()-7 (747 mg, 2.18 mmol) in 40 mL of mixed solvents
(t-BuOH/THF ) 1:1) was added ClRh(PPh3)3 (161 mg, 0.174 mmol).
The mixture was stirred under a hydrogen atmosphere for 24 h. Brine
(1 mL) was added to quench the reaction and the solvent was removed
under vacuum. The residue was partitioned between brine and di-
chloromethane. The organic layer was separated and the aqueous layer
was extracted with dichloromethane. The organic layers were combined
and dried with sodium sulfate, and solvents were removed under
vacuum to afford an oily crude product. The crude product was further
purified by flash column chromatography to afford (()-12 (642 mg,
86%) as a colorless oil.
90%) [[R]25 -9.4° (c ) 0.90, CH2Cl2)].
D
(C) (()-(1R,2S,5R,6S)-6-Acetyl-8-benzyloxycarbonyl-8-azabicyclo-
[3.2.1]octan-2-ol [(()-10a] and (+)-(1R,2S,5R,6S)-6-Acetyl-8-ben-
zyloxycarbonyl-8-azabicyclo[3.2.1]octan-2-ol [(+)-10a]. To a solution
of (()-9a (750 mg, 2.16 mmol) in acetone (50 mL) was added
Pd(CH3CN)2Cl2 (24.6 mg, 0.173 mmol). The mixture was stirred at
ambient temperature overnight. Water (5 mL) was added to quench
the reaction and the solvent was removed under vacuum. The residue
was partitioned between brine and dichloromethane. The organic layer
was separated, and the aqueous layer was extracted with dichloro-
methane. The organic layers were combined and dried with sodium
sulfate, and solvents were removed under vacuum to afford an oily
crude product. The crude product was further purified by flash column
chromatography to afford (()-10a (648 mg, 99%) as a colorless oil.
(()-10a. TLC (Rf ) 0.18, hexanes-EtOAc 1:3). IR (cm-1): 3439
(br, m), 1695 (s). 1H NMR (50 °C): δ 7.27-7.38 (m, 5.0 H), 5.15 (s,
2.0 H), 4.55 (br s, 1.0 H), 4.46 (br s, 1.0 H), 3.79 (br s, 1.0 H), 2.91
(dd, J ) 9.1 and 5.2 Hz, 1.0 H), 2.39 (br s, 1.0 H), 2.15-2.21 (m, 4.0
H), 1.71-1.80 (m, 3.0 H), 1.51 (s, 3.0 H). 13C NMR: δ 207.1, 155.3,
154.8, 136.6, 128.6, 128.1, 127.9, 69.3, 68.8, 67.2, 59.6, 59.9, 56.3,
53.1, 52.6, 28.2, 27.1, 26.7, 24.4. HRMS (FAB) calcd for C17H22NO4
([M + H]+): 304.1549. Found: 304.1540. Calcd for C17H21LiNO4 ([M
+ Li]+): 310.1631. Found: 310.1640.
(()-12. TLC (Rf ) 0.36, hexanes-EtOAc 1:1). IR (cm-1): 1729
(sh, s), 1702 (s). 1H NMR (a 60:40 mixture of two rotamers): δ 7.31-
7.37 (m, 5.0 H), 5.15 (AB quartet, J ) 11.9 Hz, 0.8 H), 5.13 (AB
quartet, J ) 12.4 Hz, 1.2 H), 4.59 (d, J ) 8.1 Hz, 0.4 H), 4.53-4.55
(m, 1.2 H), 4.46 (br s, 0.4 H), 3.89-4.05 (m, 3.6 H), 3.76-3.82 (m,
0.4 H), 2.39-2.46 (m, 3.0 H), 2.12-2.26 (m, 2.0 H), 1.86-1.99 (m,
2.0 H), 1.29 (s, 1.8 H), 1.25 (s, 1.2 H). 13C NMR: δ 205.39, 205.34,
154.0, 153.8, 136.6, 128.6, 128.33, 128.26, 128.15, 127.8, 110.9, 67.4,
67.2, 65.30, 65.25, 65.13, 65.06, 64.98, 64.85, 55.0, 54.7, 50.1, 49.4,
33.0, 31.3, 30.9, 30.7, 30.4, 21.7, 21.3. HRMS (FAB) calcd for
C19H24NO5 ([M + H]+): 346.1654. Found: 344.1653. Calcd for C19H23-
LiNO5 ([M + Li]+): 352.1736. Found: 352.1719.
Similar treatment of (-)-9a (643 mg, 1.85 mmol) with Pd(CH3-
CN)2Cl2 (26.3 mg, 0.185 mmol) in 40 mL of acetone afforded (+)-
10a (558 mg, 99%) [[R]25 +1.5° (c ) 1.09, CH2Cl2)] as a colorless
D
oil.
(D) (()-(1R,2S,5R,6S)-6-Acetyloxy-8-benzyloxycarbonyl-8-aza-
bicyclo[3.2.1]octan-2-ol [(()-11a] and (-)-(1R,2S,5R,6S)-6-Acetyl-
oxy-8-benzyloxycarbonyl-8-azabicyclo[3.2.1]octan-2-ol [(-)-11a]. To
a solution of (()-10a (280 mg, 0.924 mmol) in 20 mL of benzene was
added m-chloroperbenzoic acid (478 mg, 2.77 mmol, recrystallized from
CH2Cl2). The reaction mixture was stirred at ambient temperature for
2 days, and an additional amount of recrystallized mCPBA (319 mg,
1.85 mmol) was added. The mixture was stirred for an additional 2
days, and then an additional amount of recrystallized mCPBA (159
mg, 0.92 mmol) was added. The mixture was stirred for another 2 days.
Brine and saturated aqueous NaHCO3 solution were added, the organic
layer was separated, and the aqueous layer was extracted with
dichloromethane (10 mL × 3). The organic layers were combined,
washed with a 1:1 mixture of brine and saturated aqueous NaHCO3
solution and then with saturated aqueous Na2S2O3 solution, and dried
with sodium sulfate. The solvents were removed under vacuum to afford
an oily crude product. The crude product was further purified by flash
column chromatography to afford (()-11a (220 mg, 75%) as a colorless
oil and the recovered starting material (()-10a (22 mg, 8%).
(()-11a. TLC (Rf ) 0.27, hexanes-EtOAc 1:1). IR (cm-1): 3451
(br, m), 1737 (sh, s), 1695 (s). 1H NMR (a 60:40 mixture of two
rotamers): δ 7.32-7.38 (m, 5.0 H), 5.14-5.23 (m, 2.0 H), 5.08 (d, J
) 6.7 Hz, 1.0 H), 4.54 (br s, 0.6 H), 4.45 (br s, 0.4 H), 4.33 (br s, 0.4
H), 4.23 (br s, 0.6 H), 3.80 (br s, 0.6 H), 3.70 (br s, 0.4 H), 2.44 (br s,
0.4 H), 2.17 (d, J ) 7.1 Hz, 0.4 H), 2.15 (d, J ) 7.1 Hz, 0.6 H), 1.95-
2.03 (m, 5.0 H), 1.87 (br s, 0.6 H), 1.59-1.68 (m, 3.0 H). 13C NMR:
δ 171.0, 156.1, 155.1, 136.8, 128.7, 128.2, 128.1, 127.8, 76.5, 75.9,
69.3, 68.8, 67.2, 60.4, 60.2, 59.4, 59.0, 35.8, 35.1, 24.7, 24.6, 24.2,
Similar treatment of a mixture of (+)-7 (800 mg, 2.33 mmol) and
ClRh(PPh3)3 (173 mg, 0.186 mmol) in 60 mL of mixed solvents (t-
BuOH/THF ) 1:1) afforded (+)-12 (684 mg, 85%) as a colorless oil,
[R]25 +26.2° (c ) 0.91, CH2Cl2).
D
(B) (()-(1R,2S,5R,6S)-8-Benzyloxycarbonyl-6-(1-methyl-1,1-di-
oxacyclopentyl)-8-azabicyclo[3.2.1]octan-2-ol [(()-9a] and (-)-
(1R,2S,5R,6S)-8-Benzyloxycarbonyl-6-(1-methyl-1,1-dioxacyclopentyl)-
8-azabicyclo[3.2.1]octan-2-ol [(-)-9a]. A solution of (()-12 (149 mg,
0.432 mmol) in THF (20 mL) was cooled to -78 °C. To this solution
was added L-Selectride (1.0 M in THF, 1.08 mL, 1.08 mmol) via
syringe. The mixture was stirred at the same temperature for 1 h. Water
(1 mL) was added to quench the reaction, and the mixture was extracted
with dichloromethane. The organic layer was dried with sodium sulfate
and concentrated under vacuum. The residue was purified by flash
column chromatography to afford (()-9b (7.4 mg, 4%) and (()-9a
(154 mg, 90%) as colorless oils.
(()-9a. TLC (Rf ) 0.2, hexanes-EtOAc 1:3). IR (cm-1): 3439 (br,
1
m), 1687 (s). H NMR (a 60:40 mixture of two rotamers): δ 7.27-
7.38 (m, 5 H), 5.164 (AB quartet, J ) 12.9 Hz, 1.2 H), 5.145 (AB
quartet, J ) 12.4 Hz, 0.8 H), 4.42-4.36 (m, 1.0 H), 4.39 (dd, J ) 7.6
9
J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006 471

A R T I C L E S
Zhang and Liebeskind
23.6, 21.2. HRMS (FAB) calcd for C19H25LiNO5 ([M + Li]+):
326.1580. Found: 326.1571.
Bao Gong Teng A benzoic acid salt (34 mg, 93%) as a colorless
crystalline solid. This product could be further purified by recrystal-
lization from benzene.
Similar treatment of (+)-10a (600 mg, 2.0 mmol) with m-chloro-
perbenzoic acid recrystallized from CH2Cl2 (2.07 g, 12.0 mmol), which
was added in three portions at 2-day intervals (first portion, 6 mmol;
second portion, 4 mmol; third portion, 2 mmol) in 42 mL of benzene
afforded (-)-11a (472 mg, 75%) as a colorless crystalline solid and
the recovered starting material (+)-10a (56 mg, 9%). (-)-11a: mp
(-)-Bao Gong Teng A Benzoic Acid Salt. mp ) 141-143 °C;
(lit.4a mp ) 138-9 °C). [R]25D -13.8° (c ) 1.32, EtOH); [R]25D -10.8°
(c ) 0.8, H2O). [lit.4b [R]28D -7.21° (c ) 0.97, H2O)]. IR (cm-1): 3416
(sh, s), 3300 (br, s), 1725 (s), 1656 (m). 1H NMR: δ 8.09 (dd, J ) 7.2
and 1.0 Hz, 2.0 H), 7.55 (dt, J ) 7.2 and 1.0 Hz, 1.0 H), 7.62 (t, J )
7.6 Hz, 2.0 H), 5.27 (br s, 3.0 H), 5.13 (dd, J ) 7.2 and 1.9 Hz, 1.0
H), 3.94 (br s, 1.0 H), 3.76 (br s, 1.0 H), 3.62 (br s, 1.0 H), 2.25 (dd,
J ) 14.8 and 7.2 Hz, 1.0 H), 2.07-2.16 (m, 1.0 H), 2.00 (s, 3.0 H),
1.98-2.02 (m, 1.0 H), 1.63-1.73 (m, 1.0 H), 1.61-1.65 (m, 2.0 H).
13C NMR: δ 173.0, 171.0, 131.5, 129.8, 128.2, 74.9, 66.8, 60.53, 60.57,
34.5, 24.0, 23.4, 21.0.
141-142 °C. [R]25 -36.3° (c ) 1.16, CH2Cl2).
D
(E) (()-(1R,2S,5R,6S)-6-Acetyloxy-8-azabicyclo[3.2.1]octan-2-ol
[(()-1] and (()-(1R,2S,5R,6S)-6-Acetyloxy-8-azabicyclo[3.2.1]octan-
2-ol [(-)-1, (-)-Bao Gong Teng A]. To a solution of (()-11a (210
mg, 0.66 mmol) in 20 mL of mixed solvents (EtOH/EtOAc ) 1:1)
was added 20% Pd(OH)2/C (40 mg, 0.057 mmol). The mixture was
stirred overnight under a hydrogen atmosphere and filtered through a
piece of filter paper to remove the Pd-C catalyst. The solvents were
removed under vacuum to afford (()-1 (109 mg, 90%) as a colorless
crystalline solid.
(()-1. mp) 86-7 °C. IR (cm-1): 3385 (sh, s), 3300 (br, s), 1725
(s), 1656 (m). 1H NMR: δ 5.14 (dd, J ) 6.7 and 2.4 Hz, 1.0 H), 3.58-
3.59 (m, 2.0 H), 3.33 (br s, 1.0 H), 2.30-2.99 (br s, exchangeable, 2.0
H), 2.18 (dd, J ) 14.3 and 6.7 Hz, 1.0 H), 2.05 (s, 3.0 H), 1.87-1.92
(m, 1.0 H), 1.80 (ddd, J ) 14.4, 7.2, and 1.7 Hz, 1.0 H), 1.50-1.60
(m, 3.0 H). 13C NMR: δ 170.9, 78.2, 67.6, 61.3, 60.7, 37.4, 25.2, 24.9,
21.4. HRMS (FAB) calcd for C9H16NO3 ([M + H]+): 186.1130.
Found: 186.1122.
Acknowledgment. This work was supported by Grant
GM522238, awarded by the National Institute of General
Medical Sciences, Department of Health and Human Services.
We acknowledge the earlier contributions of Dr. Alessandro
Moretto and Professor Helena Malinakova, who established the
use of pantolactone as an auxiliary for resolution of chiral
pyridinyl molybdenum complexes. We are grateful for the
skilled contribution of Heilam Wong, who developed the
Mukaiyama-Michael reactions mentioned in this paper as well
as a highly efficient synthesis of racemic scaffold 3. We thank
colleague Dr. Kenneth Hardcastle for his skilled and efficient
assistance with X-ray crystallography.
Similar treatment of (-)-11a (410 mg, 1.29 mmol) with 20%
Pd(OH)2/C (72 mg, 0.103 mmol) in 36 mL of mixed solvents (EtOH/
EtOAc ) 1:1) afforded (-)-1 (220 mg, 92%) as a colorless crystalline
solid: mp 76-78 °C; [R]25D -29.6° (c ) 0.97, EtOH); [R]25D -21.3°
Supporting Information Available: Experimental procedures,
synthesis, and characterization of the molybdenum complex
(-)-2 and X-ray crystallographic studies of (-)-11a (21 pages,
print/PDF); copies of 1H and 13C NMR spectra of all compounds
in addition to HPLC analysis of (()-11a, and (-)-11a (38 pages,
print/PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(c ) 1.83, H2O). [lit.6b [R]25 -7.6° (c ) 0.34, H2O)].
D
(F) (-)-Bao Gong Teng A Benzoic Acid Salts. To a solution of
(-)-1 (22 mg, 0.12 mmol) in 4 mL of mixed solvents (EtOH/CHCl3 )
1:1) was added benzoic acid (16 mg, 0.131 mmol). The mixture was
stirred at ambient temperature for 10 min. The solvents were removed
under vacuum to afford a crude product. The crude product was washed
three times with a 1:1 mixture of benzene and hexanes to afford (-)-
JA055623X
9
472 J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006