Enantiospecific and stereoselective synthesis of polyhydroxylated pyrrolidines and indolizidines from trans-4-hydroxy-L-proline

Article abstract of DOI:10.1021/jo9604245

We have developed a short, efficient, and stereoselective synthesis of polyhydroxylated pyrrolidine and indolizidine glycosidase inhibitors starting from 4-hydroxy-L-proline. The regio- and stereoselective hydroxylation of an N-Pf-4-oxoproline enolate and the stereoselective reduction of the resulting keto alcohol allowed us to introduce the cis diol present in the target compounds. The different side chains needed to complete the syntheses of the target compounds were introduced by reduction of the ester group of a substituted proline or by reaction of organolithium or organomagnesium reagents with the same group followed by stereoselective reduction of the resulting ketones. Hydrogenolysis of the alcohols thus obtained gave the hydrochlorides of the desired pyrrolidine glycosidase inhibitors, which were obtained in nine steps in overall yields greater than 50%. The indolizidine glycosidase inhibitor 8-epi-swainsonine was also prepared using this approach.

Full text of DOI:10.1021/jo9604245

4748
J . Org. Chem. 1996, 61, 4748-4755
En a n tiosp ecific a n d Ster eoselective Syn th esis of P olyh yd r oxyla ted
P yr r olid in es a n d In d olizid in es fr om tr a n s-4-Hyd r oxy-L-p r olin e
Mar´ıa-J esu´s Blanco and F. J avier Sardina*
Departamento de Quı´mica Orga´nica, Universidad de Santiago de Compostela,
15706 Santiago de Compostela, Spain
Received March 1, 1996X
We have developed a short, efficient, and stereoselective synthesis of polyhydroxylated pyrrolidine
and indolizidine glycosidase inhibitors starting from 4-hydroxy-L-proline. The regio- and stereo-
selective hydroxylation of an N-Pf-4-oxoproline enolate and the stereoselective reduction of the
resulting keto alcohol allowed us to introduce the cis diol present in the target compounds. The
different side chains needed to complete the syntheses of the target compounds were introduced
by reduction of the ester group of a substituted proline or by reaction of organolithium or
organomagnesium reagents with the same group followed by stereoselective reduction of the
resulting ketones. Hydrogenolysis of the alcohols thus obtained gave the hydrochlorides of the
desired pyrrolidine glycosidase inhibitors, which were obtained in nine steps in overall yields greater
than 50%. The indolizidine glycosidase inhibitor 8-epi-swainsonine was also prepared using this
approach.
In tr od u ction
The outer envelopes of cells are charged with glyco-
proteins, which are vital for normal cell-cell communica-
tion. Several types of enzymes are responsible for the
processing of the glycoside portions of glycoproteins;
among them the glycosidases play a key function.1
Polyhydroxylated pyrrolidines and indolizidines have
attracted a great deal of interest due to their ability to
inhibit glycosidases and glycoprotein processing;2 for
instance, pyrrolidines 2-4a and indolizidine 5a (swain-
sonine) are potent inhibitors of R-mannosidases,3 while
triol 1 strongly inhibits R-galactosidase.4 Glycosidase
inhibitors have potential therapeutic value as anticancer
and antiviral agents; in particular, mannosidase inhibi-
tors have been proposed as anti-HIV agents.5
The potentially useful biological activities exhibited by
polyhydroxylated pyrrolidines and indolizidines have
prompted extensive efforts toward their syntheses, and
numerous approaches to these kinds of compounds have
been reported.2 Fleet and co-workers have published
several syntheses of enantiomerically pure 1-5 and their
analogues, starting from carbohydrate precursors that
already incorporate several of the hydroxyl groups, with
the apropriate configurations, present in the target
compounds. (S)-Glutamic acid,6 (S)-serine,7 and malic
acid8 have also served as chiral starting materials for the
synthesis of 1-5. Other approaches have made use of
the Sharpless epoxidation to induce enantioselection in
the preparation of 5a and analogues of 2-4.9 Almost all
of those approaches involve the use of sophisticated
protecting group introduction and removal sequences,
resulting in long syntheses and low overall yields. In
addition, the use of starting materials with multiple
chiral centers means that the syntheses usually lack
flexibility, often being applicable to only one or two
diastereomers of the target compound.
In this paper we present a flexible and efficient
approach to enantiomerically pure compounds 1-5 from
trans-4-hydroxyproline (6).
X Abstract published in Advance ACS Abstracts, J une 15, 1996.
(1) Warren, L. Bound Carbohydrates in Nature; Cambridge Uni-
versity Press: Cambridge, 1994.
Resu lts a n d Discu ssion
We envisioned hydroxyproline 6 as an ideal precursor
to 1-5: it already incorporates the required pyrrolidine
ring; its 4-hydroxyl group should be amenable to oxida-
tion to provide a 4-oxoproline (such as 7),10 which could,
(2) (a) Fleet, G. W. J .; Smith, P. W.; Evans, S. V.; Fellows, L. E. J .
Chem. Soc., Chem. Commun. 1984, 1240. (b) Cenci di Bello, I.; Fleet,
G.; Namgoong, S. K.; Tadano, K.-I. Biochem. J . 1989, 259, 855. (c) Eis,
M. J .; Rule, C. J .; Wurzburg, B. A.; Ganem, B. Tetrahedron Lett. 1985,
26, 5397. (d) Naruse, M.; Aoyagi, S.; Kibayashi, C. J . Org. Chem. 1994,
59, 1358. (e) Kim, N.-S.; Kang, C. H.; Cha, J . K. Tetrahedron Lett. 1994,
35, 3489. (f) Chen, Y.; Vogel, P. J . Org. Chem. 1994, 59, 2487. (g) Ryu,
Y.; Kim, G. J . Org. Chem. 1995, 60, 103. (h) Miller, S. A.; Chamberlin,
A. R. J . Am. Chem. Soc. 1990, 112, 8100.
(6) (a) Ikota, N.; Hanaki, A. Chem. Pharm. Bull. 1987, 35, 2140. (b)
Ikota, N.; Hanaki, A. Heterocycles 1987, 26, 2369.
(3) (a) Winchester, B.; Al Daher, S.; Carpenter, N. C.; Cenci di Bello,
I.; Choi, S. S.; Fairbanks, A. J .; Fleet, G. W. J . Biochem. J . 1993, 290,
743. (b) Farr, R. A.; Holland, A. K.; Huber, E. W.; Peet, N. P.;
Weintraub, P. M. Tetrahedron 1994, 50, 1033.
(4) (a) Fleet, G. W. J .; Nicholas, S. J .; Smith, P. W.; Evans, S. V.;
Fellows, L. E.; Nash, R. J . Tetrahedron Lett. 1985, 26, 3127. (b) Austin,
G. N.; Baird, P. D.; Fleet, G. W. J .; Peach, J . M.; Smith, P. W.; Watkin,
D. J . Tetrahedron 1987, 43, 3095.
(7) Burley, I.; Hewson, A. T. Tetrahedron Lett. 1994, 35, 7099.
(8) Leeper, F. J .; Howard, S. Tetrahedron Lett. 1995, 36, 2335.
(9) (a) J a¨ger, V.; Hu¨mmer, W. Angew. Chem., Int. Ed. Engl. 1990,
29, 1171. (b) Adams, C. E.; Walker, F. J .; Sharpless, K. B. J . Org. Chem.
1985, 50, 420.
(10) In related syntheses of kainoids, 4-oxoprolines have been used
for the introduction of carbon appendages at C-3 of the proline ring:
(a) Gill, P.; Lubell, W. D. J . Org. Chem. 1995, 60, 2658. (b) Baldwin,
J . E.; Rudolph, M. Tetrahedron Lett. 1994, 33, 6163. (c) Sharma, R.;
Lubell, W. D. J . Org. Chem. 1996, 61 , 202.
(5) Trost, B. M.; Van Vranken, D. L. J . Am. Chem. Soc. 1991, 113,
6317, and references therein.
S0022-3263(96)00424-0 CCC: $12.00 © 1996 American Chemical Society

Synthesis of Polyhydroxylated Pyrrolidines and Indolizidines
J . Org. Chem., Vol. 61, No. 14, 1996 4749
Sch em e 1
followed by oxidation of the resulting enolate with
MoOPH led to ketoalcohol 8a (82%) as a sole reaction
product.12,13 The configuration of the newly introduced
chiral center was assigned by reduction of the 4-keto
group of 8a with NaBH4 (quantitative) and acetylation
of the resulting diol (9a ) to give diacetate 9b (52%); NOE
experiments performed on 9b showed that H2, H3, and
H4 were all syn to each other, thus confirming the
configurations depicted in Scheme 1.
The transformation of 8a into 9a allowed us to deter-
mine the configuration at C3 and also to demonstrate
that the 4-keto group could be stereoselectively reduced
(anti to the 3-hydroxy group) to provide the desired cis
3,4-diol system present in 1-5.
Carbamoylation of 8a with both (S)- and (R)-phenyl-
ethyl isocyanate (quantitative) allowed us to establish its
enantiomeric purity. 1H NMR analysis of the resulting
diastereomeric carbamates 8b,c showed that 8a had a
ratio of enantiomers (er) > 99.5/0.5, indicating that the
hydroxylation conditions employed did not affect the
chiral center of the N-Pf-oxoproline 7.
Once we had secured a method to prepare the all-cis-
3,4-dihydroxyproline 9a , we turned our attention to the
problem of introducing the appropriate side chains at C2.
The simplest of our targets, R-galactosidase inhibitor 1,
should be easily accessible by reduction of either 8a or
9a , and, in fact, it was efficiently obtained by exhaustive
reduction of keto alcohol 8a with LiEt3BH (91%)14 fol-
lowed by hydrogenolysis of the resulting triol 10 (quan-
titative). In this way, 1‚HCl, which showed spectral
properties identical to those reported in the literature,4a
was prepared in six steps from hydroxyproline 6 with a
61% overall yield.
Sch em e 2
The synthesis of the rest of the desired glycosidase
inhibitors, 2-5, called for a more demanding strategy
since it required both flexibility (to introduce the different
carbon appendages) and stereocontrol (to produce the
correct configurations at the C2′′ chiral centers). We
thought that the sequence of transformations: ester 9
to ketone (11) to alcohol (13 or 14) could offer the
opportunity to fulfill both objectives. The attractiveness
of this synthetic scheme was further increased by our
serendipitous discovery that the reaction of organo-
lithium reagents with certain N-(9-phenylfluoren-9-yl)-
amino esters afforded the corresponding enantiomerically
pure amino ketones in high yields.15 We thus decided to
explore the reaction of N-Pf proline ester 9c, prepared
from 9a in 97% yield (2,2-dimethoxypropane, cat. PPTS),
with organolithium reagents.
The reaction of 9c with MeLi was used to optimize the
experimental conditions to provide the ketones 11a -c.
Surprisingly, when 9c was treated with 120 mol % of
MeLi (THF, -78 °C, 90 min) no reaction occurred; only
when the amount of MeLi was raised over 200 mol %
(220 mol %, -78 °C, 105 min) was ketone 11a formed in
good yield (88%), along with tertiary alcohol 12 (10%).
in turn, be manipulated to introduce the cis-3,4-diol
moiety of the target compounds; and finally, it possesses
a carboxymethyl group attached at C-2 that could be
elongated to give the various side chains present in 1-5.
Our approach to compounds 1-5 from 6 is shown in
Schemes 1 and 2. We faced first the introduction of the
3-hydroxy group by hydroxylation of a suitably protected
4-oxoproline enolate. We chose the 9-phenylfluoren-9-
yl as the N-protecting group since we expected that it
would steer both the enolate formation (away from C-2
and C-5) and the selective hydroxylation (from the Si
face, away from the phenyl ring).11,12 In the event,
treatment of prolinone 7, prepared in three steps (82%
yield) from trans-4-hydroxy-L-proline (6), with NaHMDS
(11) Molecular mechanics and semiempirical calculations on various
N-Pf-∆3,4 dehydroproline model systems showed that the CO2Me group
is locked in an axial position and that one of the ortho hydrogens of
the phenyl ring of the Pf group effectively blocks the Re face of the
3,4
∆
double bond.
(12) Blanco, M. J .; Sardina, F. J . Tetrahedron Lett. 1994, 35, 8493.
(13) The rest of the material isolated from this reaction was mostly
unreacted ketone 7.
(14) The use of DIBAL, Red-Al, or LiAlH4 led to the formation of
small amounts of the C4 epimer of 10.
(15) Ferna´ndez-Meg´ıa, E.; Iglesias-Pintos, J . M.; Sardina, F. J .
Unpublished results.

4750 J . Org. Chem., Vol. 61, No. 14, 1996
Blanco and Sardina
Sch em e 3
We attributed the lack of reactivity of equimolar amounts
of MeLi toward the carboxymethyl group of 9a to a
complexation of the organometallic reagent with the
dioxolane group of 9c. In order to break this complex-
ation we used HMPA (300 mol %), and indeed, some
alkylation was seen even with 100 mol % of MeLi: 11a
was obtained in 25% yield, along with 60% of recovered
9a and traces of 12. The best results were, however,
obtained when LiClO4 (500 mol %) was used to saturate
all possible coordination sites of 9a (and perhaps to
activate the carboxy group): 125 mol % of MeLi afforded
(-78 °C, 2 h) 90-97% yields of ketone 11a unac-
companied by alcohol 12. When these optimized condi-
tions were applied to the reaction of 9c with LiCH2-
OMOM16 the desired ketone 11b was obtained in 79%
yield; no trace of the corresponding tertiary alcohol was
detected.
Sch em e 4
To introduce the side chain required for the synthesis
of indolizidines 5a ,b we deemed that a Grignard reagent
would be a far easier nucleophile to prepare than the
corresponding organolithium species; thus, we decided
to study the feasibility of preparing the ketones 11 by
the reaction of 9c with organomagnesium nucleophiles.
When 9c was treated with MeMgBr (300 mol %, -40 °C)
methyl ketone 11a was isolated in 75% yield, accompa-
nied by 25% of recovered 9c. In this case the addition of
LiClO4 did not affect the outcome of the reaction. When
(CH2O)2CHCH2CH2MgBr17 was substituted for MeMgBr
(300 mol %, -40 to -5 °C) as the nucleophile, ketone 11c
was isolated in 96% yield; no trace of the corresponding
tertiary alcohol was detected.
in good to excellent yields. Analysis of the chemical shifts
of H-2 and the hydrogens on the side chains of O-
mandelates 15 allowed us to assign the configuration
shown in Scheme 3 to alcohols 13a ,b,d . The configura-
tion of alcohol 13c was established by correlation with
8-epi-swainsonine 5b, as discussed below.
Hydrogenolysis in an acidic media (Pd/C (10%), MeOH-
HCl) of 13a ,b,d and 14a ,b,d was all that was needed to
obtain the desired glycosidase inhibitors 2-4 (as the
corresponding hydrochlorides) in quantitative yields.
Pyrrolidine 3a ‚HCl exhibited spectral properties identical
to those reported in the literature,21 as did compounds
2a ‚HCl22 and 2b‚HCl.4a
We believe that the success of these transformations
results from the interplay of several factors: the electron-
poor nature of the carboxyl group of 9c (R,â,γ-trisubsti-
tuted by electron-withdrawing groups) and the presence
of Li+ complexing substituents at C3 and N.18 In this
respect it is worthy of note that N-Pf-proline gives mainly
the corresponding tertiary alcohol when treated with
MeLi (150 mol %, 500 mol % of LiClO4, 2 h).
Fluoro ketone 11d was prepared in 65% yield (87%
based on recovered starting material) by fluorination of
the kinetic enolate of methyl ketone 11a (NaHMDS, 150
mol %, THF, -78 °C) with (PhSO2)2NF (160 mol %).19
The last synthetic hurdle in our approach to the
glycosidase inhibitors 2-5 was the stereoselective reduc-
tion of ketones 11 to the alcohols (13 or 14) with the
appropriate configuration at the side chain. The results
of the reactions of ketones 11a -d with several hydrides
are shown in Scheme 2. Methyl ketone 11a could be
stereoselectively reduced to provide alcohols 13a or 14a
with complete stereocontrol. The rest of the ketones
could be reduced stereoselectively, but the degree of
stereocontrol was not absolute. The configurations of the
newly created stereogenic centers in 13a ,b,d were de-
termined by application of the empirical method for the
establishment of the absolute configuration of secondary
alcohols developed by Trost and co-workers.20 Thus,
13a ,b,d were esterified with both (R)- and (S)-O-meth-
ylmandelic acids ((COCl)2, DMF) to give esters 15a ,b,d
The indolizidine glycosidase inhibitor 8-epi-swainso-
nine (5b) was obtained in 94% yield by treatment of 13c
with aqueous HCl (5%) followed by hydrogenolysis (Pd/C
(10%), MeOH, HCl), with concomitant reductive cycliza-
tion of the resulting crude N-Pf-amino aldehyde (Scheme
4). The triacetate of 5b showed spectral and physical
properties identical to those reported in the literature.23
Con clu sion s
We have developed a short, efficient, and stereoselec-
tive synthesis of polyhydroxylated pyrrolidine and in-
dolizidine glycosidase inhibitors starting from 4-hydroxy-
L-proline. The regio- and stereoselective hydroxylation
of a N-Pf-4-oxoproline enolate and the stereoselective
reduction of the resulting keto alcohol allowed us to
introduce the cis diol present in the target compounds.
(16) Generated in situ from the reaction of Bu3SnCH2OMOM with
nBuLi: J ohnson, C. R.; Medich, J . R. J . Org. Chem. 1988, 53, 4131.
(17) Bu¨chi, G.; Wu¨est, H. J . Org. Chem. 1969, 34, 1122.
(18) Posner, G. H.; Lentz, C. M. J . Am. Chem. Soc. 1979, 101, 934.
(19) Differding, E.; Ofner, H. Synlett 1991, 187.
(20) Trost, B. M.; Belletire, J . L.; Godleski, S.; McDougal, P. G.;
Balkovec, J . M.; Baldwin, J . J .; Christy, M. E.; Ponticello, G. S.; Varga,
S. L.; Springer, J . P. J . Org. Chem. 1986, 51, 2370.
(21) Stevens, C. L.; Glinski, R. P.; Taylor, K. G.; Blumbergs, P.;
Gupta, S. K. J . Am. Chem. Soc. 1970, 92, 3160.
(22) Bashyal, B. P.; Fleet, G. W. J .; Gough, M. J .; Smith, P. W.
Tetrahedron 1987, 43, 3083.
(23) Tadano, K.-I.; Iimura, Y.; Hotta, Y.; Fukabori, C.; Suami, T.
Bull. Chem. Soc. J pn. 1986, 59, 3885.

Synthesis of Polyhydroxylated Pyrrolidines and Indolizidines
J . Org. Chem., Vol. 61, No. 14, 1996 4751
(2 × 250 mL), and the combined organic layers were washed
with brine (350 mL), dried, filtered, and evaporated to an oil,
which was chromatographed (silica 70-230 mesh) with EtOAc/
hexane 1:4 as eluant to give 5.26 g (100%) of 7. Recrystalli-
zation from Et2O/hexane provided 7 as a white solid: mp 136-
The different side chains needed to complete the synthe-
ses of the target compounds were introduced by reduction
of the ester group of a susbtituted proline or by reaction
of organolithium or organomagnesium reagents with the
same group followed by stereoselective reduction of the
resulting ketones. Hydrogenolysis of the alcohols thus
obtained gave the hydrochlorides of the desired pyrroli-
dine glycosidase inhibitors, which were obtained in nine
steps in overall yields greater than 50%. The indolizidine
glycosidase inhibitor 8-epi-swainsonine was also prepared
using this approach.
138 °C; [R]25 ) -64.2° (c 1.42, Cl3CH); IR (NaCl) 3057, 1756,
D
1728, 1266; 1H NMR (Cl3CD) δ 2.28 (dd, J ) 2.8, 19.0 Hz, 1H),
2.45 (dd, J ) 9.0, 17.9 Hz, 1H), 3.20 (s, 3H), 3.48 (d, J ) 17.9
Hz, 1H), 3.76 (dd, J ) 3.1, 8.6 Hz, 1H), 3.77 (d, J ) 17.8 Hz,
1H), 7.23-7.48 (m, 11H), 7.71 (m, 2H); 13C NMR (Cl3CD) δ
41.6, 51.5, 55.2, 58.2, 76.0, 120.1, 120.3, 125.5, 126.9, 127.0,
127.6, 127.7, 128.0, 128.6, 128.8, 128.9, 140.3, 140.9, 141.8,
145.3, 146.5, 173.1, 212.9. Anal. Calcd for C25H21O3N: C, 78.3;
H, 5.5; N, 3.6. Found: C, 78.0; H, 5.6; N, 3.6.
Exp er im en ta l Section
(2S,3S)-3-Hyd r oxy-4-oxo-N-(9′-p h en ylflu or en -9′-yl)p yr -
r olid in e-2-ca r boxylic Acid Meth yl Ester (8a ). A solution
of 7 (1.47g, 3.82 mmol) in THF (37 mL) was added dropwise
(in 25 min) to a stirred solution of NaHMDS (5.7 mL, 5.7 mmol,
150 mol %, 1.0 M in THF) in THF (13 mL) at -78 °C; the
resulting solution was stirred for 1.5 h at -78 °C, and then
MoOPH (1.77 g, 4.08 mmol, 175 mol %) was added and the
stirring was continued for 2.5 h from -78 to -15 °C. The
reaction was quenched at -15 °C with saturated Na2SO3 (2
mL). The resulting suspension was allowed to reach room
temperature. The suspension was partitioned between H2O
(30 mL) and Et2O (40 mL); the organic phase was washed with
HCl (30 mL, 5% aqueous) and brine (40 mL); the aqueous
phase was reextracted with Et2O (2 × 40 mL), and the
combined organic layers were dried and concentrated to give
a residue that was purified by column chromatography (hex-
ane/EtOAc, 2/1) to give 1.26 g (82%) of 8a and 55 mg (4%) of
7. The compound 8a was recrystallized as a colorless solid
from EtOAc/hexane: mp 180-182 °C; [R]25D ) -199.8 (c 1.04,
Gen er a l Meth od s. All the reactions were carried out
under an atmosphere of dry argon, unless otherwise noted.
Tetrahydrofuran (THF) was distilled from sodium/benzophe-
none inmediately before use; methylene chloride, triethy-
lamine, CH3CN, pyridine, DMF, and trimethylsilyl chloride
were distilled from CaH2; methanol was distilled from mag-
nesium and acetone from CaCO3. Column chromatography
was performed with 230-400 (low-pressure chromatography)
and 70-230 (gravity chromatography) mesh silica gel. Thin-
layer chromatography (TLC) was done on silica 60/F-254
aluminium-backed plates (E. Merck). Melting points are
uncorrected.
(2S,4R)-4-Hyd r oxyp yr r olid in e-2-ca r boxylic Acid Meth -
yl Ester Hyd r och lor id e (6a ). Thionyl chloride (7.8 mL,
106.8 mmol, 140 mol %) was added dropwise to a suspension
of trans-4-hydroxy-L-proline (6) (10.0 g, 76.3 mmol) in MeOH
(52 mL) at 0 °C. The bath was removed, and the solution was
allowed to stir at room temperature for 74 h and then
concentrated. The residual oil was triturated with ether, and
the resulting white crystalline solid was filtered, washed with
cold ether, and dried to give 13.9 g (100%) of 6a , which was
recrystallized from MeOH/EtOAc to give 6a as colorless
needles: 1H NMR (MeOD-d4) δ 2.20 (m, 1H), 2.42 (m, 1H),
3.31 (m, 1H), 3.44 (d, J ) 11, 8 Hz, 1H), 3.86 (s, 3H), 4.61 (m,
2H); 13C NMR (MeOD-d4) δ 38.6, 54.0, 55.0, 59.5, 70.6, 170.7.
(2S,4R)-4-H yd r oxy-N-(9′-p h en ylflu or en -9′-yl)p yr r oli-
d in e-2-ca r boxylic Acid Meth yl Ester (6b). A mixture of
6a (2.20 g, 12.1 mmol) and chlorotrimethylsilane (3.8 mL, 30.3
mmol, 250 mol %) in CH2Cl2 (30 mL) in a Morton flask at 0 °C
was treated with triethylamine (5.9 mL, 42.4 mmol, 350 mol
%) and allowed to reach room temperature. The mixture was
stirred while refluxing for 1 h, cooled to 0 °C, treated with
MeOH (0.74 mL, 18.2 mmol, 150 mol %) in CH2Cl2 (3,3 mL),
allowed to warm to room temperature for 1 h, and then treated
with PfBr (5.05 g, 15.7 mmol, 130 mol %), triethylamine (1.7
mL, 12.1 mmol, 100 mol %), and Pb(NO3)2 (3.6 g, 10.9 mmol,
90 mol %). The mixture was stirred at room temperature for
96 h, filtered, and evaporated. The remaining solid was
redissolved in MeOH (40 mL) and citric acid (4 g) was added;
the mixture was vigorously stirred for 1 h. Solvent was
evaporated, and the remaining solid was chromatographed
with EtOAc/hexane 1/1 as eluant to provide 3.84 g (82%) of
6b as a white foam: [R]25D ) +143.2 (c 1.37, Cl3CH); IR (CH3-
1
Cl3CH); IR (NaCl) 3592, 1769, 1741; H NMR (Cl3CD) δ 3.13
(s, 3H), 3.65 (d, J ) 17.7 Hz, 1H), 3.88 (d, J ) 17.8 Hz, 1H),
3.95 (d, J ) 7.9 Hz, 1H), 4.41 (d, J ) 7.9 Hz, 1H), 7.21-7.44
(m, 11 H), 7.66-7.75 (m, 2H); 13C NMR (Cl3CD) δ 51.3, 51.8,
61.9, 74.9, 75.1, 120.2, 120.3, 125.2, 126.6, 126.8, 127.7, 127.9,
128.1, 128.7, 129.0, 139.9, 141.1, 141.3, 145.2, 146.7, 171.0,
211.8. Anal. Calcd for C25H21O4N: C, 75.2; H, 5.3; N, 3.5.
Found: C, 75.2; H, 5.4; N, 3.5.
(2S,3S,4′′R)- a n d (2S,3S,4′′S)-3-[(P h en yleth yl)ca r ba m -
oyl]-4-oxo-N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e-2-ca r -
boxylic Acid Meth yl Ester . (8b, 8c). (R)-Ph(CH3)CHNCO
(36 µL, 0.255 mmol, 200 mol %) was added to a suspension of
8a (51 mg, 0.128 mmol) and CuBr‚SMe2 (79 mg, 0.384 mmol,
300 mol %) in THF (3 mL). Stirring was continued for 5 h at
rt, and then AcOEt (2 mL) was added. The reaction mixture
was washed with a solution of NH4Cl/NH3 pH ) 8 (2 × 10
mL). The aqueous layer was extracted with AcOEt (2 × 15
mL). The combined organic layers were washed consecutively
with H2O (15 mL) and brine (25 mL), dried, and concentrated.
The residue was purified by column chromatography (EtOAc/
hexane 1/3) to afford 70 mg (100%) of 8c as a white foam. 8c:
[R]25 ) -116° (c 1.39, Cl3CH); IR (NaCl) 3343, 1775, 1734;
D
1H NMR (Cl3CD) δ 1.38 (d, J ) 6.9 Hz, 3H), 3.19 (s, 3H), 3.52
(d, J ) 17.7 Hz, 1H), 3.86 (d, J ) 17.7 Hz, 1H), 4.15 (d, J )
8.0 Hz, 1H), 4.73 (m, 1H), 5.10 (d, J ) 7.4 Hz, 1H), 5.41 (d, J
) 8.0 Hz, 1H), 7.25-7.75 (m, 18 H); 13C NMR (Cl3CD) δ 22.1,
51.0, 51.4, 52.0, 60.5, 74.2, 75.2, 120.2, 120.3, 125.3, 125.9,
126.5, 126.7, 127.5, 127.7, 127.9, 128.3, 128.6, 128.7, 129.0,
139.5, 141.0, 141.4, 142.5, 144.8, 146.5, 153.7, 170.4, 206.7.
Anal. Calcd for C34H30O5N2: C, 74.7; H, 5.5; N, 5.1. Found:
C, 74.9; H, 5.6; N, 5.1. In an analogous way, 8b was prepared
1
Cl) 3619, 3019, 1735; H NMR (Cl3CD) δ 1.81 (m, 1H), 1.98
(m, 1H), 2.93 (dd, J ) 5.3, 10.6 Hz, 1H), 3.24 (s, 3H), 3.30 (dd,
J ) 5.8, 9.0 Hz, 1H), 3.60 (dd, J ) 5.2, 10.0 Hz, 1H), 4.51 (q,
J ) 5.4 Hz, 1H), 7.12-7.76 (m, 13 H); 13C NMR (Cl3CD) δ 39.9,
51.3, 56.8, 59.3, 70.3, 119.8, 120.1, 126.4, 127.1, 127.2, 127.3,
127.6, 128.3, 128.4, 128.7, 139.9, 141.5, 142.7, 146.1, 147.2,
175.9. Anal. Calcd for C25H23O3N: C, 77.9; H, 6.0; N, 3.6.
Found: C, 77.6; H, 6.2; N, 3.4.
using (S)-Ph(CH3)CHNCO. 8b: [R]25 ) -136.5° (c 1.07, Cl3-
D
1
CH), IR (NaCl) 3396, 1773, 1723; H NMR (Cl3CD) δ 1.41 (d,
J ) 6.8 Hz, 3H), 3.10 (s, 3H), 3.52 (d, J ) 17.5 Hz, 1H), 3.86
(d, J ) 17.8 Hz, 1H), 4.10 (d, J ) 8.1 Hz, 1H), 4.75 (m, 1H),
5.14 (d, J ) 7.5 Hz, 1H), 5.43 (d, J ) 8.0 Hz, 1H), 7.16-7.74
(m, 18 H); 13C NMR (Cl3CD) δ 22.1, 50.9, 51.3, 52.1, 60.4, 74.1,
75.3, 120.2, 120.3, 125.4, 125.8, 126.6, 126.8, 127.5, 127.7,
127.9, 128.4, 128.7, 128.8, 129.1, 139.6, 141.2, 141.4, 142.9,
145.0, 146.6,; 153.7, 170.5, 207.1. Anal. Calcd for
(2S)-4-Oxo-N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e-2-ca r -
boxylic Acid Meth yl Ester (7). DMSO (5.0 mL, 71.09 mmol,
520 mol %) was added to a solution of oxalyl chloride (3.1 mL,
35.76 mmol, 260 mol %) in CH2Cl2 (60 mL) at -60 °C. After
being stirred for 5 min, a solution of 6b (5.3 g, 13.75 mmol) in
CH2Cl2 (90 mL) was added. The mixture was stirred for 30
min at -60 °C, treated with 44 mL of triethylamine, and
allowed to reach room temperature. NaHCO3 (saturated) (200
mL) was added, the aqueous layer was extracted with CH2Cl2
C
34H30O5N2: C, 74.7; H, 5.5; N, 5.1. Found: C, 74.4; H, 5.6;
N, 5.1.

4752 J . Org. Chem., Vol. 61, No. 14, 1996
Blanco and Sardina
(2R,3S,4R)-3,4-Dih ydr oxy-2-(h ydr oxym eth yl)-N-(9′-ph e-
n ylflu or en -9′-yl)p yr r olid in e (10). LiEt3BH (1.3 mL, 1.19
mmol, 500 mol %, 0.89 M in THF) was added to a solution of
8a (95 mg, 0.238 mmol) in THF (1.9 mL) at -78 °C. The
reaction mixture was stirred 45 min at -78 °C and 2 h at rt.
The reaction was worked up with a solution of H2O2 (30%, 1.5
mL) in aqueous LiOH (5%) at 0 °C in order to break up the
intermediate boronate ester. After that, the bath was removed
and the stirring was continued for 2 h at rt. The reaction
mixture was cooled to 0 °C again, and Na2SO3 (saturated) (1
mL) was added and stirred for 15 min. The resulting suspen-
sion was partitioned between Na2SO3 (saturated) (30 mL) and
CH2Cl2 (3 × 25 mL). The combined organic layers were
washed with brine (40 mL), dried, and concentrated. The
residue was purified by column chromatography (70-230 mesh
silica gel, AcOEt/hexane 1/1.6) to give 81 mg (91%) of 10.
Recrystallization from AcOEt/hexane resulted in colorless
by chromatography on silica gel (AcOEt/hexane 1/4) to afford
28 mg (52%) of 9b as a white foam: [R]25 ) +174.9 (c 1.33,
D
Cl3CH); IR (NaCl) 2958, 1748, 1750, 1449; 1H NMR (Cl3CD) δ
2.00 (s, 3H), 2.03 (s, 3H), 3.36 (s, 3H), 3.40 (d, J ) 6.9 Hz,
1H), 3.45 (d, J ) 6.6 Hz, 2H), 5.00 (td, J ) 4.8, 6.6 Hz, 1H),
5.22 (dd, J ) 4.8, 6.9 Hz, 1H), 7.12-7.75 (m, 13H); 13C NMR
(Cl3CD) δ 20.6, 20.7, 51.3, 51.4, 51.5, 62.0, 71.0, 72.3, 119.8,
120.2, 125.7, 127.2, 127.3, 127.5, 128.4, 128.5, 128.6, 129.1,
139.5, 141.7, 142.7, 145.7, 146.8, 169.7, 170.3, 171.1. Anal.
Calcd for C29H27O6N: C, 71.7; H, 5.6; N, 2.9. Found: C, 71.6;
H, 5.8; N, 2.8.
(2S,3S,4R)-3,4-(Isop r op ylid en ed ioxy)-N-(9′-p h en ylflu o-
r en -9′-yl)pyr r olidin e-2-car boxylic Acid Meth yl Ester (9c).
A solution of 9a [(310 mg, 0.772 mmol) in DMF (2.1 mL) and
acetone (0.7 mL)] and 2,2-dimethoxypropane (0.242 mL, 1.93
mmol, 250 mol %) was stirred with PPTS (14 mg, 0.05 mmol,
7 mol %) at 5 °C for 24 h. The mixture was partitioned
between brine (5 mL) and CH2Cl2 (3 × 5 mL). The combined
organic layer was concentrated, the oily residue was redis-
solved in Et2O (10 mL), and the organic layer was washed with
H2O (2 × 5 mL). The combined organic layers were dried,
filtered, and evaporated. The residue was purified by chro-
matography (EtOAc/hexane 1/5) to afford 330 mg (97%) of 9c
as a white foam: [R]25D ) 32.9° (c 1.21, Cl3CH); IR (NaCl) 2953,
1767, 1453; 1H NMR (Cl3CD) δ 1.24 (s, 3H), 1.47 (s, 3H), 3.21
(dd, J ) 5.5, 11.5 Hz, 1H), 3.32 (s, 3H), 3.38 (d, J ) 7.2 Hz,
1H), 3.54 (dd, J ) 2.9, 11.5 Hz, 1H), 4.61 (m, 2H), 7.15-7.72
(m, 13H); 13C NMR (Cl3CD) δ 25.2, 26.0, 50.8, 53.5, 65.5, 76.1,
79.3, 80.6, 113.5, 119.6, 120.1, 126.2, 127.1, 127.2, 127.3, 127.5,
127.6, 128.4, 128.7, 139.7, 141.3, 142.3, 146.0, 147.2, 171.1.
Anal. Calcd for C28H27O4N: C, 76.2; H, 6.2; N, 3.2. Found:
C, 75.9; H, 6.2; N, 3.0.
needles: mp 174 °C dec; [R]25 ) +313.6 (c 1.06, Cl3CH); IR
D
(NaCl) 3287, 1451, 1121; 1H NMR (Cl3CD) δ 2.60 (dd, J ) 4.3,
11.0 Hz, 1H), 2.69 (dd, J ) 4.2, 8.0 Hz, 1H), 3.21 (dd, J ) 5.1,
11.9 Hz), 3.32 (dd, J ) 2.7, 11.9 Hz, 1H), 3.36 (d, J ) 11.1 Hz,
1H), 3.87 (dd, J ) 4.9, 8.0 Hz, 1H), 3.97 (m, 1H), 7.19-7.75
(m, 13H); 13C NMR (Cl3CD) δ 55.4, 59.8, 59.9, 70.9, 73.4, 76.6,
120.1, 120.2, 125.5, 125.9, 127.4, 127.5, 127.9, 128.0, 128.5,
128.6, 128.9, 139.1, 141.8, 142.2, 146.5, 148.9. Anal. Calcd
for C24H23O3N: C, 77.2; H, 6.2; N, 3.7. Found: C, 76.9; H,
6.5; N, 3 .6.
(2R,3S,4R)-3,4-Dih yd r oxy-2-(h yd r oxym et h yl)p yr r oli-
d in e Hyd r och lor id e (1‚HCl). Pd/C (17 mg, 30 wt %, 10%)
and HCl (concd) (0.1 mL) were added to a solution of 10 (58
mg, 0.16 mmol) in deoxygenated MeOH (2 mL). The flask was
purged with argon and then evacuated (vacuum) and pres-
surized (H2) three times. The reaction mixture was mechani-
cally shaken under 52 psi of H2 for 10 h. The catalyst was
removed by filtration, and the filtrate was evaporated. The
residue was washed with toluene to give a clear yellow oil that
was recrystallized from methanol/AcOEt to afford 26 mg of
(2S,3S,4R)-2-(1′′-Oxoeth yl)-3,4-(isop r op ylid en ed ioxy)-
N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e (11a ). MeLi (0.38
mL, 0.62 mmol, 1.6 M in ether, 150 mol %) was added dropwise
to a stirred solution of 9c (182 mg, 0.41 mmol) and LiClO4
(219 mg, 2.06 mmol, 500 mol %) in THF (5.5 mL) at -78 °C.
The resulting yellow solution was stirred for 2.5 h, and then
a few drops of H3PO4 (10%) were added. The suspension was
partitioned between H2O (7 mL) and CH2Cl2 (10 mL). The
aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The
combined organic layers were dried and concentrated to give
a residue that was purified by column chromatography (hex-
ane/EtOAc 5/1) to give 155 mg (89%) of 11a as a white foam:
1‚HCl (100%) as a white solid: mp 157-159 °C; [R]20
)
D
+19.0° (c 0.60, H2O); IR (KBr) 3392, 2940, 1550, 1450; 1H NMR
(D2O) δ 3.07 (dd, J ) 12.1, 7.3 Hz, 1H), 3.40 (dd, J ) 7.3, 12.1
Hz, 1H), 3.62 (m, 1H), 3.75 (dd, J ) 8.2, 12.1 Hz, 1H), 3.86
(dd, J ) 5.1, 12.1 Hz, 1H), 4.21 (t, J ) 4.1 Hz, 1H), 4.36 (dt, J
) 4.1, 7.3 Hz, 1H); 13C NMR (D2O, ref dioxane) δ 10.0, 13.3,
12.1, 13.1, 12.5. Anal. Calcd for C5H11O3NCl: C, 35.6; H, 6.6;
N, 8.3. Found: C, 35.3; H, 6.8; N, 8.0.
[R]22 ) 206.4° (c 1.22, Cl3CH); IR (NaCl) 2955, 1734, 1712;
D
(2S,3S,4R)-3,4-Dih yd r oxy-N-(9′-p h en ylflu or en -9′-yl)-
p yr r olid in e-2-ca r boxylic Acid Meth yl Ester (9a ). NaBH4
(13 mg, 0.426 mmol, 200 mol %) was added to a solution of 8a
(85 mg, 0.213 mmol) in MeOH/THF (1/1, 2.2 mL) at -78 °C;
the resulting suspension was stirred for 4 h at -78 °C, and
then the reaction was quenched with a few drops of H3PO4
(10%) and allowed to reach room temperature. The suspension
was partitioned between H2O (10 mL) and Cl3CH (10 mL). The
aqueous phase was extracted with Cl3CH (2 × 10 mL), and
the combined organic layers were washed with brine (20 mL),
dried, and concentrated to give a residue that was purified by
column chromatography (hexanes/EtOAc 1/1) to give 79 mg
(92%) of 9a as a white foam: [R]25D ) +223.3° (c 1.39, Cl3CH);
IR (CH3Cl), 3021, 1722, 1217; 1H NMR(Cl3CD) δ 2.83 (br d, J
) 8.8 Hz, 1H), 2.97 (dd, J ) 2.8, 10.4 Hz, 1H), 3.18 (d, J ) 9.0
Hz, 1H), 3.31 (s, 3H), 3.41 (d, J ) 10.4 Hz, 1H), 3.94 (m, 2H),
4.11 (d, J ) 11.8 Hz, 1H), 7.12-7.77 (m, 13H); 13C NMR (Cl3-
CD) δ 51.9, 53.0, 62.6, 71.9, 72.7, 75.4, 120.0, 120.3, 126.4,
126.8, 127.2, 127.3, 127.5, 127.6, 128.4, 128.5, 128.9, 139.3,
140.9, 141.8, 144.5, 147.5, 175.8. Anal. Calcd for C25H23O4N:
C, 74.8; H, 5.8; N, 3.5. Found: C, 74.5; H, 5.8; N, 3.4.
(2S,3S,4R)-3,4-Dia cetoxy-N-(9′-p h en ylflu or en -9′-yl)p yr -
r olid in e-2-ca r boxylic Acid Meth yl Ester (9b). To a sus-
pension of 9a (45 mg, 0.112 mmol) and DMAP (cat.) in Ac2O
(0.5 mL) was added pyridine (0.5 mL), and the mixture was
stirred at rt for 3 h. A few drops of NaHCO3 (saturated) were
added to the reaction mixture, which was partitioned between
NaHCO3 (saturated) (10 mL) and AcOEt/hexane (15 mL). The
aqueous layer was reextracted with AcOEt/hexane (2 × 15
mL), and the combined organic layers were washed with brine
(30 mL), dried, and concentrated. The residue was purified
1H NMR (Cl3CD) δ 1.20 (s, 3H), 1.48 (s, 3H), 1.97 (s, 3H), 3.21
(d, J ) 6.9 Hz, 1H), 3.36 (dd, J ) 6.7, 12.6 Hz, 1H), 3.51 (dd,
J ) 3.8, 12.9 Hz, 1H), 4.55 (m, 2H), 7.11-7.74 (m, 13H); 13C
NMR (Cl3CD) δ 24.9, 26.4, 28.6, 55.4, 71.1, 77.1, 79.8, 81.5,
113.1, 119.9, 120.2, 125.9, 126.9, 127.4, 127.5, 127.6, 127.9,
128.5, 128.7, 128.9, 139.5, 141.7, 142.7, 146.5, 148.2, 208.2.
Anal. Calcd for C28H27O3N: C, 79.0; H, 6.4; N, 3.3. Found:
C, 78.8; H, 6.4; N, 3.0. Compound 12 was isolated in order to
be identified. Flash chromatography (hexanes/AcOEt 7/1)
afforded 12 as a white foam. 12: [R]25 ) 312.6° (c 1.4, Cl3-
D
1
CH); IR (NaCl) 3579, 2935, 1449; H NMR (Cl3CD) δ 0.94 (s,
3H), 1.15 (s, 3H), 1.30 (s, 3H), 1.48 (s, 3H), 2.63 (d, J ) 7.9
Hz, 1H), 3.43 (dd, J ) 6.2, 14.3 Hz, 1H), 3.62 (m, 2H), 3.82 (t,
J ) 8.0 Hz, 1H), 4.79 (dd, J ) 14.2, 7.7 Hz, 1H), 7.06-7.73
(m, 13H); 13C NMR (Cl3CD) δ 23.4, 25.5, 27.3, 30.2, 55.6, 67.4,
74.0, 78.5, 81.9, 83.4, 114.3, 119.5, 120.4, 125.5, 127.3, 127.3,
127.5, 127.6, 128.3, 128.5, 129.2, 139.8, 141.8, 143.5, 148.5,
148.6. Anal. Calcd for C29H31O3N: C, 78.9; H, 7.1; N, 3.2.
Found: C, 78.5; H, 7.2; N, 2.9.
(2S,3S,4R)-2-[2′′-(Met h oxym et h oxy)-1′′-oxoet h yl]-3,4-
(isop r op ylid en ed ioxy)-N-(9′-p h en ylflu or en -9′-yl)p yr r oli-
d in e (11b). n-BuLi (0.410 mL, 0.567 mmol, 1.4 M in hexane,
250 mol %) was added to a stirred solution of Bu3SnCH2OMOM
(207 mg, 0.567 mmol, 250 mol %) in THF (3.5 mL) at -78 °C
over a period of 2 min while the temperature was maintained
below -65 °C. Stirring was continued for no more than 5
min,16 at which time a solution of 9c (100 mg, 0.227 mmol)
and LiClO4 (121 mg, 1.14 mmol, 500 mol %) in THF (4 mL)
was added dropwise. The resulting yellow solution was stirred
for 2 h at -78 °C, and then the reaction was quenched by the
addition of saturated NH4Cl solution (0.25 mL). The suspen-

Synthesis of Polyhydroxylated Pyrrolidines and Indolizidines
J . Org. Chem., Vol. 61, No. 14, 1996 4753
sion was partitioned between H2O (10 mL) and CH2Cl2 (10
mL). The aqueous layer was extracted with CH2Cl2 (2 × 10
mL), and the combined organic layers were dried and evapo-
rated. The crude product was purified by chromatography
(hexane/EtOAc 4/1) to give 87 mg (79%) of 11b: [R]22D ) 120.2°
(c 1.31, Cl3CH); IR (NaCl) 2942, 1737, 1449; 1H NMR (Cl3CD)
δ 1.19 (s, 3H), 1.43 (s, 3H), 3.29 (s, 3H), 3.47 (m, 3H), 3.82 (d,
J ) 17.3 Hz, 1H), 4.17 (d, J ) 17.3 Hz, 1H), 4.48 (dd, J ) 6.6,
obtained: mp 183-184 °C; [R]25 ) -21.0° (c 0.50, MeOH);
D
1
IR (KBr) 3600, 3100, 2930, 2815, 2450, 1550; H NMR (D2O)
δ 1.14 (d, J ) 6.4 Hz, 3H), 3.00 (dd, J ) 8.6, 11.6 Hz, 1H),
3.26 (br d, J ) 8.3 Hz, 1H), 3.43 (dd, J ) 8.5, 11.9 Hz, 1H),
4.05 (m, 1H), 4.21 (t, J ) 3.1 Hz, 1H), 4.33 (dt, J ) 3.8, 8.5
Hz, 1H); 13C NMR (D2O ref dioxane) δ 20.5, 48.3, 64.2, 67.0,
70.8, 71.2. Anal. Calcd for C6H14O3NCl: C, 39.2; H, 7.7; N,
7.6. Found: C, 38.9; H, 7.9; N, 7.3.
9.0 Hz, 2H), 4.56 (d, J ) 4.4 Hz, 2H), 7.12-7.73 (m, 13H); 13
C
(2R,3S,4R,1′′S)-2-[1′′-H yd r oxy-2′′-(m et h oxym et h oxy)-
eth yl]-3,4-(isop r op ylid en ed ioxy)-N-(9′-p h en ylflu or en -9′-
yl)p yr r olid in e (14b). By following the same procedure
described above for 13a (using LiEt3BH), 200 mg (100%) of
NMR (Cl3CD) δ 25.1, 26.3, 55.2, 55.4, 67.8, 71.5, 77.1, 80.2,
81.4, 96.1, 113.6, 119.8, 120.1, 125.8, 126.9, 127.4, 127.5, 127.9,
128.0, 128.5, 128.6, 128.9, 139.4, 141.6, 142.7, 146.8, 148.3,
205.9. Anal. Calcd for C30H31O5N: C, 74.2; H, 6.5; N, 2.9.
Found: C, 74.0; H, 6.7; N, 2.7.
14b was obtained as a white foam: [R]25 ) 91° (c 0.95, Cl3-
D
1
CH); IR (NaCl) 3495, 2936, 1447; H NMR (Cl3CD) δ 1.23 (s,
(2R,3S,4R,1′′R)-2-(1′′-Hydr oxyeth yl)-3,4-(isopr opyliden e-
d ioxy)-N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e (14a ). K-Se-
lectride (0.71 mL, 0.7 mmol, 1.0 M in THF, 150 mol %) was
added to a stirred solution of 11a (200 mg, 0.47 mmol) in THF
(4 mL). The stirring was continued for 14h at room temper-
ature. The reaction mixture was partitioned between H2O (20
mL) and CH2Cl2 (30 mL). The aqueous layer was extracted
with CH2Cl2 (2 × 30 mL), and the combined organic layers
were dried and evaporated. The crude product was purified
by chromatography (70-230 mesh silica gel, hexane/EtOAc
3H), 1.60 (s, 3H), 2.62 (t, J ) 5.7 Hz, 1H), 2.89 (dd, J ) 6.2,
12.9 Hz, 1H), 3.16 (d, J ) 13.0 Hz, 1H), 3.33 (m, 1H), 3.34 (s,
3H), 3.82 (m, 3H), 4.23 (t, J ) 6.2 Hz, 1H), 4.58 (m, 1H), 4.60
(s, 2H), 7.22-7.69 (m, 13H); 13C NMR (Cl3CD) δ 24.6, 26.1,
55.2 (2C), 62.9, 69.2, 70.6, 76.7, 79.1, 82.7, 96.6, 113.1, 119.7,
120.2, 125.5, 127.0, 127.4, 127.8, 128.2, 128.5, 128.6, 140.3,
140.4, 143.0, 146.1, 148.8. Anal. Calcd for C30H33O5N: C, 73.9;
H, 6.8; N, 2.9. Found: C, 73.5; H, 7.1; N, 2.7.
(2R,3S,4R,1′′R)-2-[1′′-H yd r oxy-2′′-(m et h oxym et h oxy)-
eth yl]-3,4-(isop r op ylid en ed ioxy)-N-(9′-p h en ylflu or en -9′-
yl)p yr r olid in e (13b). NaBH4 (34 mg, 0.86 mmol, 250 mol
%) was added to a solution of 11b (167 mg, 0.34 mmol) in THF/
MeOH (1/1, 6 mL) at room temperature; the resulting suspen-
sion was stirred for 20h and quenched with AcOEt (0.2 mL).
The suspension was partitioned between H2O (25 mL) and
CH2Cl2 (3 × 25 mL). The combined organic layers were
washed with brine, dried, and evaporated to give a residue
that was purified by column chromatography (hexanes/EtOAc
6/1) to afford both epimers in a 3/1 ratio, 120 mg (14b) and 40
mg (13b) (yield 95%); [R]25D ) 199.4° (c 1.8, Cl3CH); IR (NaCl)
3732, 2925, 1453; 1H NMR (Cl3CD) δ 1.15 (s, 3H), 1.43 (s, 3H),
2.58 (t, J ) 7.7 Hz, 1H), 3.12 (dd, J ) 6.5, 10.3 Hz, 1H), 3.25
(s, 3H), 3.31 (m, 1H), 3.57 (m, 2H), 3.77 (m, 3H), 4.44 (d, J )
6.4 Hz, 1H), 4.52 (d, J ) 6.4 Hz, 1H), 4.70 (m, 1H), 7.21-7.75
(m, 13H); 13C NMR (Cl3CD) δ 24.4, 25.6, 54.2, 55.0, 61.3, 67.4,
70.3, 77.3, 81.3, 81.7, 96.6, 114.2, 119.8, 120.5, 125.1, 126.5,
127.0, 127.6, 128.0, 128.4, 128.6, 128.7, 129.3, 139.4, 141.5,
142.8, 148.1, 148.5. Anal. Calcd for C30H33O5N: C, 73.9; H,
6.8; N, 2.9. Found: C, 74.1; H, 6.9; N, 2.9.
5/1) to give 200 mg (100%) of 14a as a white foam: [R]25
)
D
1
214.0° (c 0.63, Cl3CH); IR (NaCl) 3523, 2931, 1450; H NMR
(Cl3CD) δ 1.18 (d, J ) 6.5 Hz, 3H), 1.22 (s, 3H), 1.55 (s, 3H),
2.36 (t, J ) 6.6 Hz, 1H), 3.19 (d, J ) 5.2 Hz, 2H), 3.65 (br s,
1H), 3.73 (m, 1H), 4.02 (t, J ) 6.6 Hz, 1H), 4.62 (m, 1H), 7.15-
7.73 (m, 13H); 13C NMR (Cl3CD) δ 20.9, 24.5, 25.9, 55.0, 66.2,
66.6, 77.1, 80.2, 83.1, 113.5, 119.7, 120.3, 125.4, 127.3 (3C),
127.4, 127.5, 127.8, 128.3 (2C), 128.5, 128.8, 139.8, 141.1,
143.4, 147.5, 148.9. Anal. Calcd for C28H29O3N.1.5 H2O: C,
74.0; H, 7.1; N, 3.1. Found: C, 74.1; H, 6.7; N, 2.7.
(2R,3S,4R,1′′S)-2-(1′′-Hydr oxyeth yl)-3,4-(isopr opyliden e-
d ioxy)-N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e (13a ). LiEt3-
BH (1.47 mL, 1.30 mmol, 1.0 M in THF, 150 mol %) was added
dropwise to a stirred solution of 11a (370 mg, 0.87 mmol) in
THF (7 mL) at 0 °C. The stirring was continued at 0 °C for 3
h, and then AcOEt (0.25 mL) was added. The reaction mixture
was partitioned between H2O (35 mL) and CH2Cl2 (35 mL).
The aqueous layer was extracted with CH2Cl2 (2 × 40 mL),
and the combined organic layers were dried and evaporated.
The crude product was purified by chromatography (70-230
mesh silica gel, hexane/EtOAc 5/1) to give 370 mg (100%) of
13a as a white foam: [R]25D ) 254.2° (c 0.51, Cl3CH); IR (NaCl)
3557, 2932, 1448; 1H NMR (Cl3CD) δ 0.98 (d, J ) 5.9 Hz, 3H),
1.15 (s, 3H), 1.42 (s, 3H), 2.36 (t, J ) 7.6 Hz, 1H), 3.25 (m,
1H), 3.48 (dd, J ) 6.9, 13.9 Hz, 1H), 3.73 (m, 2H), 4.67 (c, J )
7.0 Hz, 1H), 7.19-7.75 (m, 13H); 13C NMR (Cl3CD) δ 20.6, 24.4,
25.5, 54.1, 64.2, 66.7, 77.3, 81.2, 81.9, 113.9, 119.7, 120.4, 125.1,
126.6, 127.0, 127.3, 127.6, 128.0, 128.2, 128.5, 128.7, 129.2,
139.5, 141.3, 143.1, 148.0, 148.8. Anal. Calcd for
C28H29O3N‚0.5H2O: C, 77.0; H, 6.9; N, 3.2. Found: C, 77.0;
H, 7.3; N, 2.8.
(2R ,3S ,4R ,1′′S )-2-(1′′,2′′-D ih y d r o x y e t h y l)-3,4-d ih y -
d r oxyp yr r olid in e h yd Roch lor id e (2a ‚HCl). Pd/C (18 mg,
10%) and concd HCl (0.1 mL) were added to a solution of
14b (58 mg, 0.12 mmol) in deoxygenated MeOH (2 mL). The
flask was purged with argon and then evacuated (vacuum) and
pressurized (H2) three times. The reaction mixture was
mechanically shaken under 52 psi of H2 for 13 h. The catalyst
was removed by filtration, and the filtrate was evaporated.
The residue was washed with toluene to give a yellow oil that
was recrystallized from ethanol/ether to afford 24 mg of 2a ‚
HCl (100%) as a white solid: mp 146-148 °C; IR (KBr) 3300,
1
3100, 2940, 2800, 2450, 1550; H NMR (D2O) δ 3.03 (dd, J )
8.9, 11.9 Hz, 1H), 3.45 (dd, J ) 8.9, 11.8 Hz, 2H), 3.55 (m,
2H), 3.96 (m, 1H), 4.23 (t, J ) 2.6 Hz, 1H), 4.35 (dt, J ) 3.8,
8.2 Hz, 1H), 13C NMR (D2O ref dioxane) δ 48.4, 63.4, 64.1, 68.4,
71.0, 71.2. Anal. Calcd for C6H14O4NCl: C, 36.1; H, 7.1; N,
7.0. Found: C, 36.0; H, 6.9; N, 6.9.
(2R,3S,4R,1′′S)-2-(Hyd r oxyeth yl)-3,4-d ih yd r oxyp yr r o-
lid in e Hyd r och lor id e (3b‚HCl). Pd/C (37 mg, 30 wt %, 10%)
and concd HCl (0.2 mL) were added to a solution of 13a (122
mg, 0.285 mmol) in deoxygenated MeOH (4 mL). The flask
was purged with argon and then evacuated (vacuum) and
pressurized (H2) three times. The reaction mixture was
mechanically shaken under 52 psi of H2 for 10 h. The catalyst
was removed by filtration, and the filtrate was evaporated.
The residue was washed with toluene to give a yellow oil which
was recrystallized from ethanol/ether to afford 52 mg of 3b‚
(2R ,3S ,4R ,1′′R )-2-(1′′,2′′-Dih yd r oxye t h yl)-3,4-d ih y-
d r oxyp yr r olid in e Hyd r och lor id e (2b‚HCl). By following
the same procedure described above, 13 mg of 2b‚HCl (100%)
was obtained as a white solid: mp 168-170 °C; IR (KBr) 3390,
1
3090, 2935, 2755, 2460, 1578; H NMR (D2O) δ 3.02 (dd, J )
HCl (100%) as a white solid: mp 185-187 °C; [R]25 ) 15.1°
8.4, 11.5 Hz, 1H), 3.43 (m, 3H), 3.62 (dd, J ) 3.1, 12.2 Hz,
1H), 3.98 (m, 1H), 4.14 (t, J ) 3.6 Hz, 1H), 4.35 (dt, J ) 3.9,
8.1 Hz, 1H), 13C NMR (D2O ref dioxane) δ 47.6, 64.2 (2C), 69.3,
70.9, 71.5. Anal. Calcd for C6H14O4NCl: C, 36.1; H, 7.1; N,
7.0. Found: C, 36.0; H, 6.8; N, 6.8.
D
(c 0.40, MeOH); IR (KBr) 3600, 3110, 2940, 2775, 2500, 1560;
1H NMR (D2O) δ 1.13 (d, J ) 6.3 Hz, 3H), 2.99 (dd, J ) 8.5,
11.8 Hz, 1H), 3.28 (dd, J ) 3.1, 9.3 Hz, 1H), 3.39 (dd, J ) 8.4,
12.2 Hz, 1H), 4.01 (m, 1H), 4.11 (t, J ) 3.2 Hz, 1H), 4.34 (dt,
J ) 3.9, 8.5 Hz, 1H); 13C NMR (D2O ref DMSO) δ 20.8, 47.7,
65.5, 68.5, 71.0, 71.5. Anal. Calcd for C6H14O3NCl: C, 39.2,
H, 7.7, N, 7.6. Found: C, 39.1; H, 7.4; N, 7.4.
(2R,3S,4R,1′′R)-2-(Hyd r oxyeth yl)-3,4-d ih yd r oxyp yr r o-
lid in e Hyd r och lor id e (3a ‚HCl). By following the same
procedure described above, 50 mg (100%) of 3a ‚HCl was
(2S,3S,4R)-2-[4′′-(1,3-Dioxola n yl)-1′′-oxobu tyl]-3,4-(iso-
p r op ylid e n e d ioxy)-N -(9′-p h e n ylflu or e n -9′-yl)p yr r oli-
d in e (11c). A solution of 3-(1,3-dioxolane)-1-propyl bromide
(328 mg, 1.81 mmol, 250 mol %) in THF (2.9 mL) was added
to a suspension of magnesium (120 mg) in THF (1 mL) over a
period of 30 min at 30-35 °C. Stirring was continued for 2 h

4754 J . Org. Chem., Vol. 61, No. 14, 1996
Blanco and Sardina
at 35-40 °C, and then the Grignard reagent was cooled at -40
°C and a solution of 9c (320 mg, 0.73 mmol, 100 mol %) in
THF (2.9 mL) was added. Stirring was continued for 3.5 h
from -40 to -5 °C. The reaction was quenched with a few
drops of H2O, and it was allowed to reach room temperature.
The suspension was partitioned between H2O (30 mL) and
CH2Cl2 (35 mL). The aqueous layer was extracted with CH2-
Cl2 (2 × 30 mL). The combined organic layers were dried and
evaporated to give a residue that was purified by chromatog-
raphy (70-230 mesh silica gel, EtOAc/hexane 1/4) to provide
358 mg (96%) of 11c as a white foam. Recrystallization from
and Cl3CH (2 × 10 mL). The combined organic layers were
washed consecutively with saturated CuSO4 solution (2 × 10
mL) and H2O (2 × 10 mL), dried, and concentrated. The
residue was purified by flash chromatography (Cl3CH/MeOH
2%) to give 15 mg (94%) of 5b: [R]25 ) -17.4° (c 0.80, Cl3-
D
CH); 1H NMR (Cl3CD) δ 1.18-2.28 (m, 6H), 2.03 (s, 3H), 2.05
(s, 3H), 2.14 (s, 3H), 2.43 (dd, J ) 6.6 Hz, 11.0 Hz, 1H), 3.24
(m, 2H), 5.23-5.43 (m, 3H); 13C NMR (Cl3CD) δ 19.6, 20.5,
20.7, 21.5, 29.6, 53.1, 59.0, 66.1, 66.6, 69.8, 71.9, 170.1, 170.3
(2C).
(2S,3S,4R)-2-(2′′-Flu or o-1′′-oxoeth yl)-3,4-(isopr opyliden e-
d ioxy)-N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e (11d ). A so-
lution of 11a (145 mg, 0.336 mmol) in THF (4.5 mL) was added
dropwise to a stirred solution of NaHMDS (0.5 mL, 0.5 mmol,
150 mol %, 1.0 M in THF) in THF (0.9 mL) at -78 °C; the
resulting solution was stirred for 1.5 h at -78 °C, and then
this solution was added via cannula to a precooled (-78 °C)
solution of (PhSO2)2NF (170 mg, 0.54 mmol, 160 mol %) in THF
(3 mL). The resulting mixture was stirred at -78 °C for 3 h
and quenched with saturated NH4Cl solution. The suspension
was partitioned between H2O (15 mL) and CH2Cl2 (2 × 25 mL).
The organic layer was washed with brine, dried, and evapo-
rated to afford a residue, which was purified by chromatog-
raphy (hexanes/EtOAc 6/1) to give 87 mg (60%) of 11d , 37 mg
(26%) of 11a , and 7 mg (5%) of the corresponding difluoro
Et2O provided 11c as a white solid: mp ) 178-180 °C; [R]25
D
) 117.9° (c 1.18, Cl3CH); IR (NaCl) 2934, 1698, 1086; 1H NMR
(Cl3CD) δ 1.17 (s, 3H), 1.41 (s, 3H), 1.68 (dt, J ) 4.8, 7.6 Hz,
2H), 2.03 (dt, J ) 7.5, 18.0 Hz, 1H), 2.62 (dt, J ) 7.7, 18.0 Hz,
1H), 3.37 (m, 2H), 3.49 (dd, J ) 3.5, 12.2 Hz, 1H), 3.88 (m,
4H), 4.53 (m, 2H), 4.78 (t, J ) 4.7 Hz, 1H), 7.09-7.72 (m, 13H);
13C NMR (Cl3CD) δ 25.1, 26.3, 27.2, 35.4, 55.3, 64.8 (2C), 70.3,
77.1, 80.1, 81.5, 103.8, 113.5, 119.8, 120.1, 125.7, 126.9, 127.4,
127.7, 127.9, 128.5 (2C), 128.8, 139.4, 141.5, 142.9, 147.1,
148.4, 208.4. Anal. Calcd for C32H33O5N: C, 75.1; H, 6.5; N,
2.7. Found: C, 74.9; H, 6.5; N, 2.7.
(2R,3S,4R,1′′S)- a n d (2R,3S,4R,1′′R)-2-(4′′-[1,3-Dioxol-
a n yl)-1′′-h yd r oxybu tyl]-3,4-(isop r op ylid en ed ioxy)-N-(9′-
p h en ylflu or en -9′-yl)p yr r olid in e (13c a n d 14c). LiEt3BH
(0.90 mL, 0.90 mmol, 1.0 M in THF, 200 mol %) was added
dropwise to a stirred solution of 11c (225 mg, 0.44 mmol) in
THF (3.9 mL) at 0 °C. The stirring was continued at 0 °C for
18 h, and then AcOEt (0.25 mL) was added. The reaction
mixture was partitioned between H2O (35 mL) and CH2Cl2 (35
mL). The aqueous layer was extracted with CH2Cl2 (2 × 40
mL), and the combined organic layers were dried and evapo-
rated. The crude product was purified by chromatography
(230-400 mesh silica gel, hexane/EtOAc 2/1) to afford both
epimers in a 4/1 ratio, 166 mg (13c) and 42 mg (14c) (yield
compound: [R]22 ) 143.8 (c 0.53, Cl3CH); IR (NaCl) 2936,
D
1744, 1449; 1H NMR (Cl3CD) δ 1.20 (s, 3H), 1.44 (s, 3H), 3.45
(m, 3H), 4.65 (m, 4H), 7.15-7.75 (m, 13H); 13C NMR (Cl3CD)
δ 25.0, 26.1, 55.0, 67.9, 76.9, 80.1, 81.0, 84.9 (d, J ) 182.5 Hz),
113.6, 119.9, 120.3, 125.9, 126.8, 127.4, 127.6, 127.9, 128.0,
128.6, 128.8, 129.0, 139.5, 141.7, 142.4, 146.3, 148.1, 204.2 (d,
J ) 17.5 Hz). Anal. Calcd for C28H26O3NF‚2H2O: C, 70.1; H,
6.3; N, 2.9. Found: C, 70.2; H, 6.6; N, 2.5. Difluoro com-
pound: [R]22 ) 78.6° (c 1.31, Cl3CH); IR (NaCl) 3068, 1763,
D
1490, 1449; 1H NMR (Cl3CD) δ 1.14 (s, 3H), 1.34 (s, 3H), 3.27
(dd, J ) 6.0 Hz, 12.5 Hz, 1H), 3.44 (dd, J ) 3.7, 12.5 Hz, 1H),
3.79 (d, J ) 7.5 Hz, 1H), 4.57 (m, 2H), 5.26 (t, J ) 53.7 Hz,
1H), 7.10-7.73 (m, 13H); 13C NMR (Cl3CD) δ 25.1, 25.8, 54.6,
66.6, 76.8, 80.5, 81.2, 109.3 (t, J ) 252.5 Hz), 114.2, 119.8,
120.1, 120.3, 124.8, 125.5, 125.9, 127.0, 127.2, 127.4, 127.6,
127.9, 128.1, 128.2, 128.4, 128.6, 128.7, 129.0, 129.1, 139.5,
139.7, 141.5, 142.4, 143.4, 146.7, 148.0, 150.7, 197.0 (t, J )
25.0 Hz).
92%) as a white foam. 13c: [R]25 ) 183.2° (c 0.81, Cl3CH);
D
1
IR (NaCl) 3600, 2936, 1449; H NMR (Cl3CD) δ 1.14 (s, 3H),
1.24 (m, 1H), 1.41 (s, 3H), 1.61 (m, 3H), 2.44 (t, J ) 7.9 Hz,
1H), 3.29 (dd, J ) 4.7, 14.2 Hz, 1H), 3.57 (m, 2H), 3.81 (m,
5H), 4.71 (m, 2H), 7.18-7.75 (m, 13H); 13C NMR (Cl3CD) δ
24.3, 25.6, 28.9, 29.9, 54.0, 64.4, 64.6, 64.7, 67.1, 77.3, 81.5,
81.9, 104.8, 114.1, 119.7, 120.4, 125.0, 126.5, 127.1, 127.5,
127.9, 128.4, 128.6, 128.7, 129.2, 139.4, 141.5, 142.9, 148.2,
148.6. Anal. Calcd for C32H35O5N: C, 74.8; H, 6.9; N, 2.7.
(2R,3S,4R,1′′S)-2-(2′′-F lu or o-1′′-h yd r oxyeth yl)-3,4-(iso-
p r op ylid e n e d ioxy)-N -(9′-p h e n ylflu or e n -9′-yl)p yr r oli-
d in e (14d ). The ketone 11d was reduced with K-Selectride
following the same procedure as used for 11a . The crude
product was purified by chromatography (70-230 mesh silica
gel, hexane/EtOAc 4/1) to give 190 mg (95%) of 14d as a white
Found: C, 74.7; H, 6.9; N, 2.7. 14c: [R]25 ) 143.6° (c 0.83,
D
1
Cl3CH); IR (NaCl) 3600, 2933, 1449; H NMR (Cl3CD) δ 1.25
(s, 3H), 1.43 (m, 2H), 1.60 (s, 3H), 1.80 (m, 2H), 2.41 (t, J )
5.7 Hz, 1H), 3.05 (dd, J ) 6.1, 13.0 Hz, 1H), 3.23 (dd, J ) 3.1,
12.9 Hz, 1H), 3.39 (br s, 1H), 3.60 (br s, 1H), 3.92 (m, 4H),
4.23 (t, J ) 6.3 Hz, 1H), 4.60 (m, 1H), 4.83 (t, J ) 4.6 Hz, 1H),
7.19-7.74 (m, 13H); 13C NMR (Cl3CD) δ 24.6, 26.1, 29.2, 30.4,
55.2, 64.8, 64.8, 65.6, 70.2, 76.9, 79.3, 82.9, 104.6, 113.0, 119.6,
120.2, 125.7, 127.3, 127.4, 127.5, 127.7, 128.2, 128.4, 128.7,
139.8, 141.0, 143.4, 147.1, 148.4. Anal. Calcd for
C32H35O5N‚0.25H2O: C, 74.2; H, 6.9; N, 2.7. Found: C, 74.1;
H, 7.2; N, 2.3.
foam: [R]25 ) 283.1° (c 0.65, Cl3CH); IR (NaCl) 3491, 2956,
D
1449; 1H NMR (Cl3CD) δ (500 MHz) 1.23 (s, 3H), 1.58 (s, 3H),
2.60 (t, J ) 6.2 Hz, 1H), 3.06 (dd, J ) 6.4, 13.3 Hz, 1H), 3.21
(dd, J ) 3.2, 13.3 Hz, 1H), 3.85 (m, 2H), 4.12 (m, 1H), 4.24
(ddd, J ) 47.9, 6.4, 9.3 Hz, 1H), 4.61 (m, 1H), 4.65 (ddd, J )
48.8, 9.4, 5.2 Hz, 1H), 7.09-7.71 (m, 13H); 13C NMR (Cl3CD)
δ 24.5, 25.9, 55.1, 62.1 (d, J ) 4.6 Hz), 69.0 (d, J ) 18.6 Hz),
76.9, 79.7, 82.9, 85.5 (d, J ) 171.0 Hz), 113.5, 119.9, 120.4,
125.4, 126.9, 127.1, 127.5, 127.7, 127.9, 128.4, 128.7, 128.9,
140.1, 140.8, 142.9, 146.6, 148.5. Anal. Calcd for
C28H28O3NF.3.25H2O: C, 66.7; H, 6.9; N, 2.8. Found: C, 66.8;
H, 6.5; N, 2.4.
(1S,2R,8S,8aR)-1,2,8-Tr iacetoxyh ydr oin dolizidin e, 8-epi-
Sw a in son in e Tr ia ceta te (5b). HCl (aqueous, 5%, 0.3 mL)
was added to a solution of 13c (50 mg, 0.12 mmol) in THF (1
mL). The solution was stirred at room temperature overnight.
The mixture was partitioned between a solution of KH2PO4/
NaOH (pH ) 7, 10 mL) and CH2Cl2 (3 × 15 mL). The
combined organic layers were washed with brine, dried,
filtered, and evaporated. The crude product (32 mg, 0.08
mmol) was dissolved in deoxygenated MeOH (1 mL), and Pd/C
(10 mg, 30 wt %, 10%) was added. The flask was purged with
argon and then evacuated (vacuum) and pressurized (H2) three
times. The reaction mixture was mechanically shaken under
52 psi of H2 for 3 h, and AcOH (0.1 mL) was added (to obtain
pH ) 5) and hydrogenated for 36 h at 52 psi. The catalyst
was removed by filtration, and the filtrate was evaporated.
The residue was washed with toluene to give a yellow oil that
was acetylated using Ac2O (1 mL), DMAP (cat.), and pyridine
(1 mL) during 48 h at room temperature. A few drops of
saturated NaHCO3 solution were added to the reaction mix-
ture, which was partitioned between NaHCO3 solution (5 mL)
(2R,3S,4R,1′′R)-2-(2′′-F lu or o-1′′-h yd r oxyeth yl)-3,4-(iso-
p r op ylid e n e d ioxy)-N -(9′-p h e n ylflu or e n -9′-yl)p yr r oli-
d in e (13d ). NaBH4 (15 mg, 0.38 mmol, 250 mol %) was added
to a solution of 11d (70 mg, 0.15 mmol) in THF/MeOH (1/1, 1
mL) at room temperature; the resulting suspension was stirred
overnight and quenched with a few drops of H3PO4 solution
(10%). The suspension was partitioned between H2O (10 mL)
and CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with brine, dried, and evaporated to give a residue
that was purified by column chromatography (hexanes/EtOAc
6/1) to afford both epimers in a 2/1 ratio, 41 mg (14d ) and 19
mg (13d ) (yield 90%): [R]25D ) 212.5° (c 0.4, Cl3CH); IR (NaCl)
3590, 2990, 1456; 1H NMR (Cl3CD) δ 1.18 (s, 3H), 1.45 (s, 3H),
2.60 (t, J ) 7.8 Hz, 1H), 3.32 (dd, J ) 4.6, 14.2 Hz, 1H), 3.59
(dd, J ) 7.0, 14.2 Hz, 1H), 3.84 (m, 3H), 4.09 (ddd, J ) 48.2,

Synthesis of Polyhydroxylated Pyrrolidines and Indolizidines
J . Org. Chem., Vol. 61, No. 14, 1996 4755
9.4, 5.7 Hz, 1H), 4.44 (ddd, J ) 47.2, 9.4, 1.7 Hz, 1H), 4.72 (dt,
J ) 4.7, 7.1 Hz, 1H), 7.22-7.78 (m, 13H); 13C NMR (Cl3CD) δ
24.4, 25.6, 54.3, 60.4 (d, J ) 10.0 Hz), 67.4 (d, J ) 18.2 Hz),
77.3, 81.1, 81.6, 85.6 (d, J ) 169.5 Hz), 114.2, 119.9, 120.6,
125.1, 126.3, 127.0 (2C), 127.7, 128.0, 128.5, 128.8 (2C), 129.4,
139.4, 141.5, 142.7, 147.8, 148.3. Anal. Calcd for
C28H28O3NF‚0.5H2O: C, 74.0; H, 6.4; N, 3.1. Found: C, 73.8;
H, 6.4; N, 3.0.
O-Meth ylm a n d ela tes of (2R,3S,4R,1′′S)-2-(1′′-Hyd r oxy-
eth yl)-3,4-(isop r op ylid en ed ioxy)-N-(9′-p h en ylflu or en -9′-
yl)p yr r olid in e (15a ). The alcohol 13a was treated with (S)-
O-methylmandelic acid and (R)-O-methylmandelic acid,
following the same procedure described above to afford 52 mg
(96%) of (S)15a as a white foam: [R]25 ) 153.0° (c 1.05, Cl3-
D
1
CH); IR (NaCl) 2938, 1744, 1451; H NMR (Cl3CD) δ 1.13 (s,
3H), 1.21 (d, J ) 6.1 Hz, 3H), 1.50 (s, 3H), 2.49 (t, J ) 6.7 Hz,
1H), 2.99 (dd, J ) 6.7, 13.0 Hz, 1H), 3.12 (dd, J ) 4.4, 13.0
Hz, 1H), 3.34 (s, 3H), 3.79 (t, J ) 6.3 Hz, 1H), 4.38 (m, 1H),
4.63 (s, 1H), 4.79 (m, 1H), 7.18-7.69 (m, 18H); 13C NMR (Cl3-
CD) δ 17.7, 25.0, 26.6, 55.5, 57.1, 63.8, 71.2, 77.1, 79.0, 82.0,
82.7, 112.6, 119.7, 120.1, 125.3, 127.1, 127.2, 127.4, 127.6,
127.8, 128.2, 128.4, 128.5, 128.5, 128.6, 136.5, 139.7, 140.8,
143.7, 148.6, 169.7. Anal. Calcd for C37H37O5N.0.5H2O: C,
76.0; H, 6.6; N, 2.4. Found: C, 75.7; H, 6.5; N, 2.4. The
corresponding compound (R)-15a was obtained (82%) as a
(2R,3S,4R,1′′S)-2-(2′′-F lu or o-1′′-h yd r oxyeth yl)-3,4-d ih y-
d r oxyp yr r olid in e Hyd r och lor id e (4a ‚HCl). By following
the same procedure as 13a , 14d afforded 16 mg (100%) of 4a ‚
HCl as a white solid: mp 168-170 °C; [R]22 ) 62.8° (c 0.5,
D
MeOH); IR (KBr) 3600, 3285, 2690, 1550, 1100; 1H NMR
(MeOD-d4) δ 3.19 (m, 1H), 3.58 (m, 2H), 4.36 (m, 2H), 4.47 (br
s, 1H), 4.60 (dd, J ) 4.4, 47.2 Hz, 2H); 13C NMR (MeOD-d4) δ
48.7, 63.8 (d, J ) 4.1 Hz), 66.9 (d, J ) 20.4 Hz), 71.5 (2C),
85.6 (d,
J
) 170.4 Hz). Anal. Calcd for C6H13O3-
NClF‚1.5H2O: C, 31.5; H, 7.1; N, 6.1. Found: C, 31.6; H, 7.0;
N, 6.1.
white foam: [R]25 ) -5.19° (c 1.08, Cl3CH); IR (NaCl) 1756,
D
1455; 1H NMR (Cl3CD) δ 0.96 (d, J ) 6.1 Hz, 3H), 1.19 (s, 3H),
1.55 (s, 3H), 2.61 (dd, J ) 5.7, 8.0 Hz, 1H), 2.69 (dd, J ) 6.3,
12.8 Hz, 1H), 3.07 (dd, J ) 3.2, 12.9 Hz, 1H), 3.33 (s, 3H),
4.05 (t, J ) 6.4 Hz, 1H), 4.42 (dt, J ) 3.2, 6.7 Hz, 1H), 4.50 (s,
1H), 5.08 (m, 1H), 7.19-7.69 (m, 18H); 13C NMR (Cl3CD) δ
18.0, 25.0, 26.3, 55.3, 56.9, 65.4, 70.9, 76.9, 78.6, 81.9, 82.0,
112.6, 119.7, 120.0, 125.3, 126.3, 127.2, 127.2, 127.5, 127.5,
128.1, 128.3, 128.4, 128.5, 128.5, 136.5, 139.5, 140.8, 144.4,
146.2, 150.1, 169.1. Anal. Calcd for C37H37O5N.0.5H2O: C,
76.0; H, 6.6; N, 2.4. Found: C, 76.0; H, 6.4; N, 2.2.
(2R,3S,4R,1′′R)-2-(2′′-F lu or o-1′′-h yd r oxyeth yl)-3,4-d ih y-
d r oxyp yr r olid in e Hyd r och lor id e (4b‚HCl). By following
the same procedure as described above, 20 mg (100%) of 4b‚
HCl was obtained as a white solid: mp 140-143 °C; [R]25
)
D
-8.0° (c 0.4, MeOH); IR (KBr) 3600, 3387, 2700, 2450, 1560,
1
1090; H NMR (MeOD-d4) δ 3.10 (m, 1H), 3.55 (m, 2H), 4.15
(m, 2H), 4.27 (br s, 1H), 4.53 (br d, J ) 49.0 Hz, 2H); 13C NMR
(MeOD-d4) δ 48.5, 65.1 (d, J ) 6.1 Hz), 71.4 (d, J ) 20.5 Hz),
72.1 (2C), 86.0 (d, J ) 179.0 Hz). Anal. Calcd for C6H13O3-
NClF: C, 35.7; H, 6.5; N, 7.0. Found: C, 35.6; H, 6.5; N, 6.9.
O-Meth ylm a n d ela tes of (2R,3S,4R,1′′R)-2-(2′′-Flu or o-1′′-
h ydr oxyeth yl)-3,4-(isopr opyliden edioxy)-N-(9′-ph en ylflu -
or en -9′-yl)p yr r olid in e (15d ). (R)-O-Methylmandelic acid (9
mg, 0.06 mmol, 110 mol %) was added to a white suspension
prepared by slow addition of oxalyl chloride (5 µL, 0.06 mmol,
100 mol %) to DMF (6 µL, 0.08 mmol, 135 mol %) in acetonitrile
(0.5 mL) at 0 °C. After 10 min, a solution of 13d (25 mg, 0.06
mmol) in pyridine (0.15 mL) was added slowly, and the
resultant mixture was stirred at 0 °C for 2.5 h. The pale yellow
reaction mixture was diluted with ether (20 mL), the organic
layer was washed twice with saturated aqueous cupric sulfate
solution (2 × 5 mL) and dried over sodium sulfate, and the
solvent was removed in vacuo to give a yellow oil. Purification
by chromatography (silica 70-230 mesh, hexanes/AcOEt, 3/1)
O-Meth ylm a n d ela tes of (2R,3S,4R,1′′R)-2-[1′′-Hyd r oxy-
2′′-(m et h oxym et h oxy)et h yl]-3,4-(isop r op ylid en ed ioxy)-
N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e (15b). By following
the same procedure, (S)-15b (88%) was obtained as a white
foam from 13b: [R]25D ) 105.8° (c 1.7, Cl3CH); IR (NaCl) 2999,
1756, 1452; 1H NMR (Cl3CD) δ 1.09 (s, 3H), 1.48 (s, 3H), 2.57
(dd, J ) 6.0, 7.4 Hz, 1H), 3.08 (dd, J ) 6.8, 13.2 Hz, 1H), 3.13
(dd, J ) 5.4, 13.2 Hz, 1H), 3.28 (s, 3H), 3.35 (s, 3H), 3.56 (t, J
) 6.2 Hz, 1H), 3.68 (dd, J ) 7.7, 11.3 Hz, 1H), 3.87 (d, J )
10.6 Hz, 1H), 4.33 (c, J ) 6.4 Hz, 1H), 4.43 (d, J ) 6.6 Hz,
1H), 4.46 (d, J ) 6.5 Hz, 1H), 4.71 (s, 1H), 4.89 (t, J ) 7.3 Hz,
1H), 7.17-7.71 (m, 18H); 13C NMR (Cl3CD) δ 25.0, 26.7, 55.1,
55.8, 57.2, 61.2, 68.1, 74.3, 77.5, 79.3, 81.6, 82.9, 96.5, 112.9,
119.9, 120.2, 125.5, 127.1, 127.2, 127.4, 127.7, 127.8, 127.9,
128.4, 128.5, 128.6, 128.8, 136.8, 139.7, 141.5, 143.6, 147.5,
148.5, 169.9. Anal. Calcd for C39H40O7N: C, 73.8; H, 6.4; N,
gave 28 mg (85%) of (R)-15d as a white foam: [R]22 ) 43.5°
D
(c 0.92, Cl3CH); IR (NaCl) 2940, 1757, 1453; 1H NMR (Cl3CD)
δ 1.20 (s, 3H), 1.53 (s, 3H), 2.76 (t, J ) 6.5 Hz, 1H), 2.88 (dd,
J ) 6.2, 12.9 Hz, 1H), 3.17 (dd, J ) 3.4, 13.0 Hz, 1H), 3.40 (s,
3H), 4.04 (t, J ) 6.0 Hz, 1H), 4.49 (m, 3H), 4.70 (s, 1H), 5.00
(m, 1H), 7.23-7.72 (m, 18H); 13C NMR (Cl3CD) δ 24.9, 26.4,
55.6, 57.3, 61.3 (d, J ) 8.1 Hz), 73.5 (d, J ) 20.2 Hz), 77.2,
78.9, 81.4, 82.7, 83.4 (d, J ) 169.3 Hz), 112.8, 120.0, 120.4,
125.6, 127.0, 127.2, 127.4, 127.5, 127.8, 127.9, 128.5, 128.6,
128.7, 128.8, 136.4, 140.2, 140.9, 143.6, 146.7, 148.6, 169.8.
By following the same procedure using (S)-O-methylmandelic
acid, 24 mg (89%) of (S)-15d was obtained as a white foam:
2.2. Found: C, 73.5; H, 6.6; N, 2.1. (R)-15b (85%): [R]25
)
D
27.8° (c 1.0, Cl3CH); IR (NaCl) 2934, 1752, 1452; 1H NMR (Cl3-
CD) δ 1.18 (s, 3H), 1.52 (s, 3H), 2.78 (dd, J ) 6.1, 8.7 Hz, 1H),
3.01 (s, 3H), 3.05 (dd, J ) 7.1, 13.4 Hz, 1H), 3.24 (dd, J )
13.4, 3.8 Hz, 1H), 3.38 (dd, J ) 6.2, 11.3 Hz, 1H), 3.44 (s, 3H),
3.49 (d, J ) 9.7 Hz, 1H), 3.96 (t, J ) 7.3 Hz, 1H), 3.96 (d, J )
6.6 Hz, 1H), 4.00 (d, J ) 6.5 Hz, 1H), 4.52 (m, 1H), 4.74 (s,
1H), 5.14 (t, J ) 6.5 Hz, 1H), 7.21-7.70 (m, 18H); 13C NMR
(Cl3CD) δ 24.8, 26.2, 54.8, 55.0, 57.2, 60.8, 68.3, 72.9, 77.5,
78.0, 81.9, 82.7, 96.4, 113.4, 119.8, 120.2, 125.4, 127.0, 127.2,
127.3, 127.3, 127.6, 127.7, 128.0, 128.5, 128.7, 136.7, 140.2,
140.8, 144.0, 147.6, 149.6, 169.7. Anal. Calcd for C39H40O7N:
C, 73.8; H, 6.4; N, 2.2. Found: C, 73.5; H, 6.6; N, 2.1.
[R]25 ) 103.3° (c 0.9, Cl3CH); IR (NaCl) 2937, 1760, 1453; 1H
D
NMR (Cl3CD) δ 1.09 (s, 3H), 1.50 (s, 3H), 2.44 (t, J ) 5.0 Hz,
1H), 2.80 (dd, J ) 6.4, 12.5 Hz, 1H), 3.08 (dd, J ) 3.8, 12.4
Hz, 1H), 3.33 (s, 3H), 3.48 (t, J ) 5.7 Hz, 1H), 4.21 (m, 1H),
4.67 (s, 1H), 4.72 (m, 3H), 7.21-7.76 (m, 18H); 13C NMR (Cl3-
CD) δ 25.0, 26.7, 56.2, 57.2, 62.2 (d, J ) 8.9 Hz), 74.6 (d, J )
21.4 Hz), 77.0, 77.9, 80.8, 82.4, 83.5 (d, J ) 166.9 Hz), 112.1,
119.9, 120.2, 120.5, 125.7, 127.0, 127.3, 127.5, 127.6, 127.7,
128.0, 128.5, 128.6, 128.6, 128.8, 129.3, 136.7, 139.9, 141.4,
143.2, 146.5, 147.4, 169.6. Anal. Calcd for C37H36O5NF: C,
74.8; H, 6.1; N, 2.4. Found: C, 74.5; H, 6.2; N, 2.1.
Ack n ow led gm en t. We thank the CICYT (Spain,
Grant No. SAF93-0767) and the Xunta de Galicia (Grant
No. XUGA20908B94) for financial support. M.J .B.
thanks the Xunta de Galicia (Spain) for a fellowship.
We thank Prof. Rafael Suau (University of Ma´laga,
Spain) for the elemental analyses.
J O9604245