Addition of a chiral boron enolate to cyclic N-acyliminium ions. Stereocontrolled synthesis of the pyrrolizidine ring system

Full text of DOI:10.1021/jo9513020

J . Org. Chem. 1996, 61, 3187-3190
3187
Ad d ition of a Ch ir a l Bor on En ola te to
Cyclic N-Acylim in iu m Ion s.
Ster eocon tr olled Syn th esis of th e
P yr r olizid in e Rin g System
Ronaldo A. Pilli* and Dennis Russowsky
Instituto de Quı´mica, Unicamp, Cx. Postal 6154,
13081-970- Campinas, SP Brasil
F igu r e 1.
Received J uly 19, 1995
Sch em e 1
The synthesis of the 1-azabicyclo[3.3.0]octane ring
system has attracted the interest of synthetic chemists
due to the diverse and important biological properties
displayed by the corresponding pyrrolizidine alkaloids.1
Among the methodologies employed for assembling
homochiral pyrrolizidine systems at the different oxida-
tion levels found in Nature,2 the intramolecular cycliza-
tion of derivatives of (S)- and (R)-malic acid have been
successfully explored.3b,c,4
As an extension of our studies on the addition of silyl
enol ethers and silyl ketene acetals to activated Schiff
bases,5 we envisaged that the substitution pattern present
in (+)-hastanecine (1a )3 or (+)-dihydroxyheliotridane
(1b )3d would be readily available through an inter-
molecular addition of carbon nucleophiles to N-acylimin-
ium ion 4 provided that good levels of diastereoselection
were achieved (Figure 1). While we reasoned that the
stereochemistry at C-8 would be directed by the steric
hindrance and/or electronic assistance provided by the
acetoxy group,6,7 the outcome of the stereogenic center
at C-1 was not clear from the outset.
Sch em e 2
During our preliminary studies, racemic succinimide
5 was prepared in 89% yield according to a previously
described procedure (Scheme 1).6 Sodium borohydride
reduction took place regioselectively, and after neutral-
ization (10% HCl, rt) and acetylation 6 was obtained as
a 1:1 mixture of stereoisomers at C-2. However, when
neutralization was carefully carried out with 1% HCl at
-23 °C, a 19:1 mixture of 6a :6b was isolated. The
stereochemistry of the diacetoxy lactams was assigned
after analysis of the 1H-NMR spectra: in the major
isomer H-5 (δ 6.28) appeared as a doublet (J H5-H4
)
49
5.5 Hz) while in the minor one it appeared as a singlet
(δ 6.02), the expected pattern for the cis and trans
stereochemistry, respectively.8
Our initial attempts focused on the addition of the silyl
ketene acetal and the silyl ketene thioacetal prepared
from 7a and 7b9 , respectively, to racemic N-acyliminium
ion 4 (Scheme 2). As previously described for Schiff
bases5 and R-ethoxypiperidines and pyrrolidines,10 nu-
cleophilic addition proceeded in the presence of trimeth-
ylsilyl trifluoromethanesulfonate (TMSOTf) to afford a
1:1 ratio of diastereoisomers 2a ,b/3a ,b, in 45% and 49%
yield, respectively.11
(1) Rizk, A. F. M., Ed. Natural Occurring Pyrrolizidine Alkaloids;
CRC: Boston, 1991.
(2) Denmark, S. E.; Thorarensen, A. J . Org. Chem. 1994, 59, 5672
and references cited therein.
(3) For total synthesis of (+)- and (-)-hastanecine (1a ), see: (a)
Aasen, A. J .; Culvenor, C. C. J .; Smith, L. W. J . Org. Chem. 1969, 34,
4137. (b) Hart, D. J .; Yang, T-K. J . Chem. Soc., Chem. Commun. 1983,
135. (c) Chamberlin, A. R.; Chung, J . Y. L. J . Org. Chem. 1985, 50,
4425. (d) Mulzer, J .; Scharp, M. Synthesis 1993, 615. For total synthesis
of (+)-dihydroxyheliotridane (1b) see, ref 3d.
(4) Choi, J .-K.; Hart, D. J . Tetrahedron 1985, 41, 3959.
(5) Pilli, R. A.; Russowsky, D. J . Chem. Soc., Chem. Commun. 1987,
1053. (b) Pilli, R. A.; Alves, C. F., unpublished results.
(6) (a) Koot, W.-J ., van Ginkel, R., Kranenburg, M., Hiemstra, H.,
Louwrier, S., Moolenaar, M. J .; Speckamp, W. N. Tetrahedron Lett.
1991, 32, 401. (b) Yoda, H., Kitayama, H., Katagiri, T.; Tanabe, K.
Tetrahedron 1992, 48, 3313.
The trans relationship between the substituents at C-7
and C-8 (hastanecine numbering system) in both dia-
stereoisomers was apparent from the splitting pattern
(7) Bernardi, A., Micheli, F., Potenza, D., Scolastico, C.; Villa, R.
Tetrahedron Lett. 1990, 31, 4949.
(9) Sudo, R., Kaneda, A.; Itoh, N. J . Org. Chem. 1967, 32, 1844.
(10) (a) Pilli, R. A., Dias, L. C.; Maldaner, A. O. Tetrahedron Lett.
1993, 34, 2729. (b) Pilli, R. A., Dias, L. C.; Maldaner, A. O. J . Org.
Chem. 1995, 60, 717.
(11) The composition of the mixture 6a /6b proved to be of no
consequence to the stereochemical outcome of the nucleophilic addition.
The same product distribution was observed when either a 1:1 or a
19:1 mixture of 6a /6b was employed.
(8) The regiochemical outcome of the reaction was correlated with
LUMO’s atomic coefficients at C-2 and C-5 (0.194 and 0.088, respec-
tively) and the transition state corresponding to the approach of the
borohydride anion to the re face of the carbonyl at C-2 was shown to
be ca. 1 kcal mol-1 more stable than the one involved in the approach
to the si face.
S0022-3263(95)01302-8 CCC: $12.00 © 1996 American Chemical Society

3188 J . Org. Chem., Vol. 61, No. 9, 1996
Notes
Sch em e 3
F igu r e 2.
F igu r e 3.
of H-7 which appeared as a doublet for 2a , 2b, and 3a (J
) 6.9, 6.3, and 6.5 Hz, respectively) and as a double
doublet for 3b (J ) 6.3 and 1.2 Hz). The stereocontrol
exerted by the substituent at C-7 was ascribed both to
the steric hindrance and to the electronic stabilization
of the N-acyliminium ion by the proximal acetoxy group.
The lack of stereochemical control in the formation of
the stereogenic center at C-1 could conceivably arise from
the intervention of the equally favored antiperiplanar (A)
and synclinal (B) approaches or to a facile enolization
involving intermediate 8 (Figure 2).
In order to improve the diastereofacial selectivity of
the nucleophile and reduce the Bro¨nsted acidity of H-1
we decided to explore the discriminating ability of chiral
boron enolates. Despite their extensive use in enantio-
selective aldol condensations12 their role in the prepara-
tion of â-amino carbonyl compounds remains to be fully
explored.13,14
Our rationale to explore the ability of the boron enolate
derived from Evans’ chiral imide 7c to control the
stereochemistry at C-1 was based on a conceivable
antiperiplanar approach of the chelated conformation of
the (Z)- enolate to (S)-4 which would accommodate the
facial preferences of both reagents (Figure 3). This
topology resembles the one proposed for the alkylation
of metal enolates of chiral oxazolidinones and has also
been postulated by Fuentes in his studies on the addition
of boron enolates to acylimines.13
of 6a /6b, prepared from (-)-5, to a CH2Cl2 solution of the
boron enolate from (+)-7c containing a 20 mol % excess
n
of Bu2BOTf afforded (-)-2c, in 53% yield, as a single
stereoisomer.16 The trans relationship of the substituents
at C-7 and C-8 was assigned after analysis of its 1H-NMR
spectrum: no coupling was observed between H-7 and
H-8 (δ 5.76 and 3.40, respectively) which appeared as
doublets (J ) 6.6 and 4.8 Hz, respectively). The stereo-
chemistry at C-1 was unambiguously established after
its conversion to the corresponding pyrrolizidine, as
depicted in Scheme 3.
Reduction of (-)-2c with excess of LiBH4 (5.0 equiv)
afforded diol (+)-9 in 67% yield and allowed recovery of
the chiral auxiliary in 72% yield after column chroma-
tography. For purification purposes and in order to avoid
unwanted reaction at the hydroxyl functionalities in the
forthcoming transformations, (+)-9 was converted to the
corresponding silyl ether (-)-10 in 64% yield after
treatment with TBDMSOTf in CH2Cl2 and 2,6-lutidine.
Lactam reduction with BH3‚Me2S afforded pyrrolidine
(-)-11, in 73% yield.
Hydrogenolysis with catalysis by Pd(OH)2, followed by
treatment of the crude amino alcohol with Ph3P in CCl4,
afforded the protected pyrrolizidine (+)-12, in 56% overall
yield. Deprotection (HF/CH3CN) gave the corresponding
After some experimentation, we developed a protocol
which allowed us to carry out the addition of a boron
enolate to an N-acyliminium ion formed in situ from the
(15) In our hands, nonreproducible results were obtained with di-
n-butylboron triflate in CH2Cl2 which is commercially available from
Aldrich. nBu2BOTf was prepared according to ref 12b and freshly
distilled before use.
(16) Reaction of the boron enolate from (+)-7c and racemic 4
was carried out under the same conditions described above to afford a
1:1 mixture of two stereoisomers: 2c as the slow eluting isomer,
n
corresponding R-acetoxy lactam and Bu2BOTf:15 addition
(12) (a) Evans, D. A., Bartroli, J .; Shih, T. L. J . Am. Chem. Soc.
1981, 103, 2127. (b) Evans, D. A., Nelson, J . V., Vogel, E.; Taber, T. R.
J . Am. Chem. Soc. 1981, 103, 3099. (c) Inoue, T.; Mukaiyama, T. Bull.
Chem. Soc. J pn. 1980, 53, 174.
and
a fast eluting isomer to which structure i was tentatively
assigned.
(13) Fuentes, L. M., Shinkai, I.; Salzmann, T. N. J . Am. Chem. Soc.
1986, 108, 4675.
(14) (a) Nagao, Y., Kumagai, T., Tamai, S., Abe, T., Kuramoto, Y.,
Taga, T., Aoyagi, S., Nagase, Y., Ochiai, M., Inoue, Y.; Fujita, E. J .
Am. Chem. Soc. 1986, 108, 4673. (b) Nagao, Y., Dai, W.-M.; Ochiai,
M., Tetrahedron Lett. 1988, 29, 6133. (c) Nagao, Y. Dai, W.-M., Ochiai,
M., Tsukagoshi, S.; Fujita, E. J . Am. Chem. Soc. 1988, 110, 289. (d)
Nagao, Y., Dai, W.-M., Ochiai, M., Tsukagoshi, S.; Fujita, E. J . Org.
Chem. 1990, 55, 1148. (e) Nagao, Y., Kumagai, T., Nagase, Y., Tamai,
S., Inoue, Y.; Shiro, M. J . Org. Chem. 1992, 57, 4232. (f) Nagao, Y.,
Nagase, Y., Kumagai, T., Kuramoto, Y., Kobayashi, S., Inoue, Y., Taga,
T.; Ikeda, H. J . Org. Chem. 1992, 57, 4238.

Notes
J . Org. Chem., Vol. 61, No. 9, 1996 3189
diol ([R]25
) +8.5 (c 0.6, EtOH) in 48% yield, which
at rt when it was quenched by addition of saturated NaHCO3
(5 mL). It was extracted with CH2Cl2 (2 × 10 mL), the organic
extracts were combined, dried over MgSO4, and concentrated
under reduced pressure. Column chromatography on silica gel
(25% ethyl acetate in hexanes) afforded 0.26 g (0.54 mmol) of a
1:1 mixture of 2a /3a , in 45% yield. Analytically pure samples
were obtained by preparative TLC (10% ethyl acetate in hex-
anes).
546
proved to be identical by 1H- and 13C-NMR with published
data for hastanecine (1a )2,3d,4 and clearly different from
those expected for dihydroxyheliotridane (1b),3d the pyr-
rolizidine which might be obtained from lactam 3c. In
particular, C-7 and C-8 appeared downfield both in CDCl3
(δ 76.80 and 77.23, respectively) and in CD3OD (δ 75.91
and 78.32, respectively) when compared with the corre-
sponding carbons (δ 71.8 and 73.2, in CD3OD) in dihy-
droxyheliotridane (1b)3d and in close agreement with the
reported values by Denmark2 (δ 76.50 and 76.78, in
CDCl3) and Mulzer3d (δ 76.8 and 77.8, in CD3OD) for (-)-
hastanecine (1a ).
2a (more polar): colorless oil, 1H-NMR: δ 1.70-1.80 (m, 1H),
1.93 (s, 3H), 2.10-2.25 (m, 1H), 2.34 (dd, J ) 18.0 and 1.2, 1H),
2.80 (ddd, J ) 18.0, 6.9 and 1.2, 1H), 3.13 (qt, J ) 4.5, 1H), 3.32-
3.44 (m, 2H), 3.47 (d, J ) 4.5, 1H), 3.92 (d, J ) 15.6, 1H), 4.35
(s, 2H), 4.97 (d, J ) 12.0, 1H), 5.04 (d, J ) 12.0, 1H), 5.13 (d, J
) 15.6, 1H), 5.46 (d, J ) 6.9, 1H), 7.2--7.40 (m, 15H); 13C-NMR:
δ 21.0, 28.6, 37.4, 42.3, 44.1, 65.4, 67.3, 67.77, 68.6, 73.1, 127.8,
127.9, 128.0, 128.9, 128.4, 128.6, 128.8, 128.9, 128.9, 135.4, 135.8,
138.3, 170.2, 172.6, 173.1.
The results described herein demonstrate the feasibil-
n
ity of Bu2BOTf promoted addition of boron enolates to
1
3a (less polar): colorless oil, H-NMR: δ 1.50-1.70 (m, 1H),
R-acetoxy lactams through participation of an intra-
molecularly chelated conformation of the nucleophile
broadening the scope of these synthetically useful species.
1.87 (s, 3H), 1.90-2.05 (m, 1H), 2.21 (dd, J ) 18.6 and 2.0, 1H),
2.80 (dd, J ) 18.6 and 6.6, 1H), 2.98 (ddd, J ) 11.2, 4.5 and 2.4,
1H), 3.28 (dt, J ) 8.7 and 4.5, 1H), 3.36-3.44 (m, 1H), 3.70 (d,
J ) 4.5, 1H), 3.88 (d, J ) 15.3, 1H), 4.39 (s, 2H), 5.01 (d, J )
15,3, 1H), 5.07 (s, 2H), 5.13 (d, J ) 6.6, 1H), 7.20-7.40 (m, 15H).
13C-NMR: δ 20.7, 26.2, 37.5, 42.3, 44.5, 64,8, 67.0, 67.8, 69.4,
73.1, 127.8, 127.9, 128.4, 128.5, 128.5, 128.6, 128.7, 128.9, 135.7,
135.8, 138.4, 170.2, 172.2, 172.7. Anal. Calcd for C28H33NO6:
C-70.15, H-6.89, N-2.92. Found: C-70.34, H-7.12, N-3.35.
(4S,5R)-N-Ben zyl-2-oxo-4-a cetoxy-5-[1-[(ter t-bu tylth io)-
ca r bon yl]-3-(ben zyloxy)p r op yl]p yr r olid in e (2b a n d 3b). To
a solution of 6a /6b (0.15 g, 0.51 mmol) in CH2Cl2 (2.5 mL) at 0
°C was added dropwise the silyl ketene thioacetal prepared from
7b19 (0.27 g, 0.80 mmol) followed by TMSOTf (0.10 mL, 0.55
mmol). The reaction was kept 15 min at 0 °C and 4 h at rt when
it was quenched with saturated NaHCO3 (5 mL). The mixture
was extracted with CH2Cl2 (2 × 10 mL), the organic phases were
combined and dried over MgSO4, and the solvent was removed
under reduced pressure. Column chromatography on silica gel
(10% ethyl acetate in hexanes) afforded 0.12 g (0.25 mmol) of a
1:1 mixture of 2b/3b, in 49% yield. Analytically pure samples
were obtained after preparative TLC (5% ethyl acetate in
hexanes).
Exp er im en ta l Section 17
nBu2BOTf was prepared according to ref 12b and distilled
immediately prior to use. (S)-Acetoxysuccinimide (5)6 and
γ-(benzyloxy)butyric acid9 were prepared according to the pub-
lished procedures. Ester 2a , thioester 2b, and oxazolidinone 2c
were prepared from γ-(benzyloxy)butyric acid using the proce-
dure developed by Steglich18 and silyl ketene acetal 2b according
to the procedure described by Gennari.19
(4S, 5S)-N-Ben zyl-2,3-d ia cetoxybu tyr ola cta m (6a ). To a
stirred solution of (S)-N-benzyl-3-acetoxysuccinimide (5)6 (6.63
g, 26.8 mmol) in ethanol (100 mL) at -23 °C was added sodium
borohydride (2.04 g, 53.7 mmol) portionwise. After the addition
was completed (5 min), the reaction was kept at -23 °C for 20
min when it was acidified with 1% HCl until pH 2-3, followed
by neutralization with saturated NaHCO3. The reaction mixture
was extracted with CH2Cl2, the organic phase was dried over
MgSO4, and filtered, and the solvent was evaporated.
The residue (5.87 g) was dissolved in CH2Cl2 and cooled to 0
°C, and Et3N (3.51 mL, 25.0 mmol), acetic anhydride (4.44 mL,
35.3 mmol), and 4-(N,N-dimethylamino)pyridine (0.20 g, 2.3
mmol) were added. The reaction was allowed to warm up to
room temperature, and after 1 h it was diluted with CH2Cl2 (20
mL) and washed with 10% HCl (20 mL), saturated NaHCO3 (20
mL) and water (2 × 30 mL).
2b (more polar): colorless oil, IR (film) 1741, 1700, 1670 cm-1
;
1H-NMR: δ 1.42 (s, 9H), 1.70 (m, 1H), 1.92 (s, 3H), 2.15 (m, 1H),
2.36 (d, J ) 18.0, 1H), 2.83 (ddd, J ) 18.0, 6.6 and 1.2, 1H),
3.25 (qt, J ) 4.8, 1H), 3.34 (d, J ) 4.2, 1H), 3.37-3.42 (m, 2H),
3.97 (d, J ) 15.6, 1H), 4.42 (s, 2H), 5.27 (d, J ) 15.6, 1H), 5.51
(d, J ) 6.3, 1H), 7.20-7.40 (m, 10H). 13C-NMR: δ 21.0, 29.2,
29.5, 37.4, 44.3, 49.2, 49.6, 65.99, 67.2, 68.7, 73.2, 127.9, 127.9,
128.0, 128.2, 128.6, 129.0, 135.7, 138.4, 170.3, 172.8, 201.9.
The organic phase was dried over MgSO4 and filtered, and
the solvent was removed under reduced pressure. The residue
was chromatographed on silica gel (230-400 mesh, 35% ethyl
acetate in hexanes) to afford 6a (6.87 g, 23.6 mmol) in 88% yield.
[R]25 546 ) -76° (c 1.0, EtOH); mp 136.5-138 °C; IR (KBr) 1745,
3b (less polar): colorless oil; IR (film) 1744, 1700, 1667 cm-1
;
1H-NMR: δ 1.43 (s, 9H), 1.60-1.70 (m, 1H), 1.89 (s, 3H), 2.00-
2.15 (m, 1H), 2.38 (dd, J ) 18.0 and 1.5, 1H), 2.85 (ddd, J )
18.0, 5.4 and 1.5, 1H), 2.98 (m, 1H), 3.30 (dt, J ) 9.4 and 4.5,
1H), 3.40 (m, 1H), 3.60 (dd, J ) 6.0 and 1.2, 1H), 3.87 (d, J )
15.0, 1H), 4.44 (d, J ) 9,3, 1H), 4.47 (d, J ) 9.3, 1H), 5.11 (d, J
) 15.0, 1H), 5.17 (dd, J ) 6.3 and 1.2, 1H), 7.20-7.40 (m, 10H).
13C-NMR: δ 20.8, 27.7, 29.6, 37.3, 44.9, 48.9, 51.7, 64.6, 67.2,
69.7, 73.2, 127.9, 128.0, 128.0, 128.6, 128.6, 128.9, 135.9, 128.3,
170.1, 172.8, 200.3. Anal. Calcd for C26H35NO5S: C-67.59,
H-7.01, N-2.81. Found: C-67.35, H-6.70, N-2.65.
1715 cm-1; H-NMR (CDCl3): δ 1.93 (s, 3H), 2.03 (s, 3H), 2.67
1
(dd, J ) 15.0 and 9.0 Hz, 1H), 2.80 (dd, J ) 15.0 and 8.4 Hz,
1H), 4.26 (d, J ) 15.0 Hz, 1H), 4.69 (d, J ) 15.0 Hz, 1H), 5.28
(dt, J ) 8.7 and 5.4 Hz, 1H), 6.28 (d, J ) 5.4 Hz, 1H), 7.23-7.35
(m, 5H). 13C-NMR (CDCl3): δ 20.5, 33.9, 44.8, 66.1, 81.6, 128.1,
128.6, 129.0, 136.1, 170.1, 170.3, 171.7; MS m/ z: 230 (14%), 229
(27%), 170 (23%), 90 (100%).
(4S,5R)-N-Ben zyl-2-oxo-4-a cetoxy-5-[1-(ca r boben zyloxy)-
3-(ben zyloxy)p r op yl]p yr r olid in e (2a a n d 3a ). To a 0.5 M
solution of LDA (4.2 mL, 2.1 mmol) in THF/hexanes at -78 °C
was added dropwise benzyl 3-(benzyloxy)butanoate (0.51 g, 1.8
mmol),16 and the reaction mixture was stirred at -78 °C for 1 h
when chlorotrimethylsilane (0.354 g, 3.0 mmol) was added. The
reaction mixture was allowed to warm up to rt when a white
solid precipitated, and after 1 h it was filtered under nitrogen
and concentrated under reduced pressure.
The residue was taken up in CH2Cl2 (3.0 mL), and a solution
of 6a /6b (0.35 g, 1.2 mmol) in CH2Cl2 (1.5 mL) followed by freshly
distilled TMSOTf (0.17 mL, 0.90 mmol) were added dropwise
at 0 °C. The reaction mixture was kept at 0 °C for 2 h and 4 h
(4S )-4-Isop r op yl-3-[(2R )-2-[(4S ,5R )-N -Be n zyl-2-oxo-4-
a ce t oxy-5-p yr r olid in yl]-4-(b e n zyloxy)b u t a n oyl]-2-oxa -
zolid in on e (2c). To a solution of 7c (0.091 g, 0.30 mmol) in
n
CH2Cl2 (1.0 mL) at 0 °C was added Bu2BOTf (0.10 g, 0.37 mmol)
followed by diisopropylethylamine (0.064 g, 0.50 mmol). The
reaction mixture was kept 45 min at 0 °C when a solution of
6a /6b (0.087 g, 0.30 mmol) in CH2Cl2 (1.0 mL) was added. After
15 min at 0 °C the reaction mixture was stirred 4 h at rt when
it was quenched with saturated NaHCO3 (5 mL). The mixture
was diluted with CH2Cl2 (10 mL), and the organic phase was
washed with 10% HCl (5 mL) and saturated NaHCO3 (5 mL)
and dried over MgSO4. Evaporation under reduced pressure,
followed by column chromatography on silica gel (25% ethyl
acetate in hexanes) afforded 0.084 g (0.16 mmol) of 2c as a
(17) For a general experimental information see ref 10b.
(18) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522.
(19) Gennari, C., Beretta, M. G., Bernardi, A., Moro, G., Scolastico,
C.; Todeschini, R. Tetrahedron 1986, 42, 893.
colorless oil, in 53% yield. [R]25 ) -16.6 (c 3.4, CH2Cl2); IR
546
(film) 1773, 1740, 1697 cm-1; 1H-NMR: δ 0.74 (d, J ) 3.4, 3H),
0.76 (d, J ) 3.4, 3H), 1.72 (m, 1H), 1.93 (s, 3H), 2.05 (m, 1H),
2.36 (d, J ) 18.0, 1H), 2.45 (m, 1H), 3.00 (dd, J ) 18.0 and 6.6,

3190 J . Org. Chem., Vol. 61, No. 9, 1996
Notes
1H), 3.05 (t, J ) 9.0, 1H), 3.40 (d, J ) 4.8, 1H), 3.60 (m, 2H),
3.80 (dd, J ) 9.0 and 3.3, 1H), 3.99 (m, 2H), 4.31 (d, J ) 11.1,
1H), 4.43 (d, J ) 11.1, 1H), 4.86 (m, 1H), 5.23 (d, J ) 15.7, 1H),
5.76 (d, J ) 6.6, 1H), 7.26-7.36 (m, 10H). 13C-NMR: δ 14.3,
17.8, 21.0, 28.7, 30.4, 37.5, 40.4, 43.6, 58.5, 62.5, 66.9, 68.8, 69.6,
72.9, 127.5, 127.7, 128.0, 128.3, 128.7, 135.4, 138.3, 154.5, 170.0,
172.6, 174.4. Anal. Calcd for C30H36N2O7: C-67.16, H-6.71,
N-5.22. Found: C-66.89, H-6.68, N-5.09.
8.4 and 5.7, 1H), 2.60 (s, br, 1H), 2.82 (t, J ) 7.6, 1H), 3.36 (d,
J ) 13.4, 1H), 3.58-3.67 (m, 3H), 3.84 (dd, J ) 9.9 and 3.9, 1H),
4.00 (d, J ) 13.4, 1H), 4.38 (d, J ) 5.4, 1H), 4.53 (s, 2H), 7.20-
7.36 (m, 10H). 13C-NMR: δ -5.6, -5.5, -4.6, -4.3, 17.8, 18.2,
25.8, 25.9, 28.7, 34.5, 38.3, 51.6, 59.8, 62.3, 68.9, 72.8, 74.2, 75.5,
126.5, 127.4, 127.7, 128.1, 128.3, 128.5, 138.7, 140.6. Anal.
Calcd for:
C34H57NO3Si2: C-69.98, H-9.78, N-2.40. Found:
C-70.14, H-9.66, N-2.56.
(4S,5R,1′R)-N-Ben zyl-2-oxo-4-h yd r oxy-5-[1′-(h yd r oxy-
m eth yl)-3′-ben zyloxy)p r op yl]p yr r olid in e (9). To a solution
of 2c (0.23 g, 0.43 mmol) in THF (1.0 mL) at 0 °C was added
LiBH4 (0.037 g, 1.7 mmol). After 5 min the reaction was allowed
to warm up and stirred 4 h at rt. The reaction was quenched
by dropwise addition of methanol (2 mL), and the solvent was
removed under reduced pressure. The residue was chromato-
graphed on silica gel to afford (S)-4-isopropyloxazolidinone (0.040
g, 0.31 mmol, 72% recovery) after elution with 50% ethyl acetate
in hexanes and (+)-9 (0.10 g, 0.29 mmol, 67% yield) as a colorless
(+)-Bis[(ter t-b u t yld im et h ylsilyl)oxy]h a st a n ecin e (12).
To a solution of (-)-11 (0.20 g, 0.32 mmol) dissolved in ethyl
acetate (8 mL) was added Pd(OH)2 (5 mg), and the mixture was
stirred 8 h under a hydrogen atmosphere (40 psi) in a Parr
apparatus. The reaction mixture was filtered over Celite, and
the solvent was removed under vacuum. The residue was
dissolved in CH3CN (4.0 mL) and Et3N (0.12 mL, 0.80 mmol),
and carbon tetrachloride (0.12 mL, 0.8 mmol) and triphen-
ylphosphine (0.20 g, 0.76 mmol) were added. The reaction
mixture was stirred 48 h at rt, the solvent was removed under
reduced pressure, and the residue was chromatographed on
silica gel (ethyl acetate:methanol:NH4OH ) 95:4:1) to afford (+)-
oil upon elution with 1% methanol in ethyl acetate. [R]25
)
546
+6.8 (c 10.0, CH2Cl2); IR (film) 3396, 3030, 1666 cm-1 1H-
;
12 (0.068 g, 0.18 mmol), in 56% overall yield. [R]25 ) +7.4 (c
NMR: δ 1.65 (m, 1H), 1.75-2.00 (m, 2H), 2.31 (dd, J ) 17.7
and 1.5, 1H), 2.70-2.90 (m, 2H), 3.30-3.60 (m, 6H), 3.90 (d, J
) 15.0, 1H), 4.35 (d, J ) 11.7, 1H), 4.38 (s, br, 1H), 4.40 (d, J )
11.7, 1H), 5.03 (d, J ) 15.0, 1H), 7.20-7.40 (m, 10H). 13C-
NMR: δ 28.5, 38.8, 40.4, 44.2, 60.5, 65.8, 69.0, 69.3, 73.6, 127.8,
128.2, 128.3, 128.8, 129.0, 136.3, 137.6, 174.2.
546
2.6, MeOH). 1H-NMR: δ 0.05 (s, 12H), 0.87 (s, 9H), 0.90 (s, 9H),
1.56-1.72 (m, 2H), 1.74-1.98 (m, 3H), 2.46 (dt, J ) 9.7 and 6.0,
1H), 2.62 (ddd, J ) 11.0, 6.7 and 4.8, 1H), 3.08 (dd, J ) 10.0
and 7.0, 1H), 3.10-3.24 (m, 2H), 3.55 (dd, J ) 10.0 and 7.0, 1H),
3.71 (dd, J ) 10.0 and 5.4, 1H), 4.02 (dd, J ) 7.8 and 3.9, 1H).
13C-NMR: δ -5.3, -4.7, -4.5, 18.0, 18.4, 25.8, 26.0, 30.3, 33.9,
46.9, 52.6, 55.0, 65.4, 75.2, 78.0; MS m/ z: 385 (M+, 2%), 227
(16%), 106 (13%), 82 (100%).
(4S,5R,1′R)-N-Ben zyl-2-oxo-4-[(ter t-bu tyld im eth ylsilyl)-
oxy]-5-[1′-[[(ter t-b u t yld im et h ylsilyl)oxy]m et h yl]-3′-(b en -
zyloxy)p r op yl]p yr r olid in e (10). To a solution of (+)-9 (0.30
g, 0.81 mmol) in CH2Cl2 (6.0 mL) at 0 °C was added 2,6-lutidine
(0.51 mL, 4.5 mmol) followed by TBDMSOTf (0.78 mL, 3.3
mmol). The reaction mixture was stirred 3 h at 0 °C when it
was diluted with CH2Cl2 (20 mL) and washed with 10% HCl (5
mL), saturated NaHCO3 (5 mL), and brine (5 mL). The organic
phase was dried over MgSO4 and concentrated under reduced
pressure, and the residue was purified by flash chromatography
(30% ethyl acetate in hexanes) to afford 0.32 g (0.54 mmol, 64%
(+)-Ha sta n ecin e (1a ). To a solution of (+)-12 (0.060 g, 0.15
mmol) in CH3CN (3.0 mL) was added 40% HF (2.0 mL), and the
mixture was stirred 48 h at rt. The reaction was quenched with
saturated NaHCO3 (10 mL) and lyophilized, and the resulting
solid was chromatographed on silica gel (CHCl3:MeOH:NH4OH
) 6:3:1) to afford (+)-1a , (0.006 g, 0.07 mmol, 48% yield) as a
white solid: mp 110 °C, [R]25 ) +8.5 (c 0.6, EtOH) (lit.3d mp
546
111 °C, [R]25D ) +9.0 (c 0.49, EtOH). 1H-NMR (CDCl3): δ 1.60-
1.76 (m, 1H), 1.84-2.02 (m, 3H), 2.09 (m, 1H), 2.50-2.61 (m,
1H), 2.64-2.76 (m, 1H), 3.10 (s, br, 2H), 3.21-3.40 (m, 3H), 3.56
(dd, J ) 10.6 and 7.5, 1H), 3.82 (dd, J ) 10.6 and 4.0, 1H), 4.14
(dd, J ) 8.5 and 5.0, 1H). 1H-NMR (CD3OD): δ 1.05-1.71 (m,
1H), 1.78-1.88 (m, 1H), 1.90-2.20 (m, 3H), 2.80 (dt, J ) 10.8
and 5.6, 1H), 2.98 (ddd, J ) 10.8, 7.4 and 2.7, 1H), 3.30-3.48
(m, 3H), 3.55 (m, 2H), 4.16 (s, br, 1H), 4.69 (s, br, 2H). 13C-
NMR (CDCl3): δ 29.7, 33.8, 46.3, 52.7, 54.9, 64.3, 76.8, 77.2.
13C-NMR (CD3OD): δ 29.9, 33.0, 46.5, 53.4, 55.8, 63.7, 75.9, 78.3.
yield) of (-)-10. [R]25 ) -1.1 (c 3.4, CH2Cl2); IR (film) 1692
546
cm-1; 1H-NMR: δ -0.04 (s, 3H), -0.02 (s, 3H), 0.00 (s, 3H), 0.02
(s, 3H), 0.83 (s, 9H), 0.86 (s, 9H), 1.57 (m, 1H), 1.74-1.90 (m,
1H), 1.93-2.20 (s, br, 1H), 2.25 (d, J ) 17.1, 1H), 2.85 (dd, J )
17.1 and 5.4, 1H), 3.36-3.52 (m, 5H), 3.84 (d, J ) 15.6, 1H),
4.37 (d, J ) 12.0, 1H), 4.43 (d, J ) 12.0, 1H), 4.48 (d, J ) 5.4,
1H), 5.12 (d, J ) 15.6, 1H), 7.22-7.33 (m, 10H). 13C-NMR: δ
-5.8, -5.6, -4.9, -4.6, 17.7, 18.1, 25.6, 25.9, 27.8, 35.9, 41.2, 43.9,
58.9, 67.1, 67.6, 69.8, 73.1, 127.5, 127.8, 127.9, 128.6, 128.7,
128.9, 136.4, 138.5, 174.5.
(2R,3S,1′R)-N-Ben zyl-2-[1′-[[(ter t-bu tyldim eth ylsilyl)oxy]-
m eth yl]-3′-(ben zyloxy)p r op yl]-3-[(ter t-bu tyld im eth ylsilyl)-
oxy]p yr r olid in e (11). To a solution of (-)-10 (0.30 g, 0.52
mmol) in THF (8.0 mL) at 0 °C was added BH3‚Me2S (10 M
solution in THF, 0.56 mL, 5.6 mmol). The reaction was stirred
16 h at rt, quenched at 0 °C with ethanol (20 mL), and the
resulting mixture was refluxed during 2 h. The solvent was
removed under vacuum, and the residue was chromatographed
on silica gel (5% ethyl acetate in hexanes) to afford (-)-11 (0.21
g, 0.38 mmol), in 73% yield.
Ack n ow led gm en t. Financial support from FINEP,
FAPESP, CNPq, SAE-Unicamp, and International Foun-
dation for Science (Sweden) is gratefully acknowledged.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H- and
13C-NMR for (-)-2c, (+)-12, and 1a (8 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
[R]25
) -31.5 (c 2.9, CH2Cl2); 1H-NMR: δ 0.029 (s, 3H),
546
0.045 (s, 6H), 0.064 (s, 3H), 0.89 (s, 9H), 0.90 (s, 9H), 1.53 (dd,
J ) 12.5 and 5.6, 1H), 1.70-1.98 (m, 4H), 2.42 (ddd, J ) 11.7,
J O9513020