Diastereoselective synthesis of polyfunctional-pyrrolidines via vinyl epoxide aminolysis/ring-closing metathesis: Synthesis of chiral 2,5-dihydropyrroles and (1R,2S,7R,7aR)-1,2,7-trihydroxypyrrolizidine

Article abstract of DOI:10.1055/s-2002-25337

This paper describes an efficient and diastereoselective method for preparing 2-substituted-2,5-dihydropyrroles in racemic and optically active form via acid catalysed or microwave assisted aminolysis of vinyl epoxides with allyl amine followed by ring-cl

Full text of DOI:10.1055/s-2002-25337

LETTER
731
Diastereoselective Synthesis of Polyfunctional-Pyrrolidines via Vinyl Epoxide
Aminolysis/Ring-Closing Metathesis: Synthesis of Chiral 2,5-Dihydropyrroles
and (1R,2S,7R,7aR)-1,2,7-Trihydroxypyrrolizidine
D
iastereoselective
a
Synthesis
o
r
f
Polyfu
l
nctional-Pyrr
B
olidines . Lindsay, Minyan Tang, Stephen G. Pyne*
Department of Chemistry, University of Wollongong, Wollongong, NSW, 2522, Australia
Fax +61(2)42214287; E-mail: stephen_pyne@uow.edu.au
Received 19 February 2002
readily be obtained from regioselective ring-opening of
Abstract: This paper describes an efficient and diastereoselective
method for preparing 2-substituted-2,5-dihydropyrroles in racemic
and optically active form via acid catalysed or microwave assisted
aminolysis of vinyl epoxides with allyl amine followed by ring-
vinyl epoxides 6 with allylic amines 5 to give the dienes
4, which upon N-protection and ring-closing metathesis
should furnish the desired pyrrolidines 3. The regioselec-
closing metathesis. Using this method, (1R,2S,7R,7aR)-1,2,7-trihy- tive ring opening of vinyl epoxides with ammonia and
benzyl and cyclohexyl amine has been reported7 while the
droxypyrrolizidine could be prepared by elaboration of a chiral 2-
substitited-2,5-dihydropyrrole.
ring-closing metatheses (RCM) reaction is well docu-
Key words: 2,5-dihydropyrroles, vinyl epoxide, aminolysis, ring-
closing metathesis
mented as a versatile and efficient process for making het-
erocyclic rings.8–10 We report here an efficient method for
preparing poly-functionalised pyrrolidines of the type 3
using the above strategy and the synthesis of the trihy-
Polyhydroxylated pyrrolizidine and indolizidine alkaloids droxypyrrolizidine (16), the ring-contracted analogue of
[e.g swainsonine (1)] are well known potent glycosidase 1,2-di-epi-swainsonine, and the C,D-ring analogue 19 of
enzyme inhibitors.1,2 Some of these alkaloids exhibit anti- croomine (2).
viral and anti-HIV activity by effectively inhibiting the
enzymatic processing of glycoproteins.3 While many of
Me
HO
OH
H
these alkaloids and their derivatives have been prepared
for structure-activity studies there is still a need for new
synthetic methods to prepare a variety of analogues to al-
low a better understanding of the structural requirements
for glycosidase inhibition and to develop more potent, se-
lective and less toxic drugs.4 Structurally related mole-
cules are found in the stemona family of alkaloids. These
compounds have been isolated from the roots of the Ste-
mona and Croomine species that have been used as tradi-
tional medicines by the Chinese and Japanese to treat
respiratory diseases such as bronchitis, pertussis, and tu-
berculosis and have also found use as anthelmintic
agents.5 These alkaloids have novel polycyclic structures,
as is illustrated by the representative member croomine
(2). Their unique structural features coupled with their in-
teresting biological properties have stimulated the devel-
opment of new synthetic methodology and synthetic
strategies for the synthesis of these alkaloids.6 The struc-
tural similarity between 1 and 2 is highlighted in
Scheme 1. A central structural feature of these alkaloids is
a poly-functionalised pyrrolidine ring with one (at C-2, in
the case of 1) or two (at C-2 and C-5, in the case of 2) ap-
pended hydroxy-alkyl substituents.
O
H
A
OH
C
N
Me
O
D
N
H
H
O
B
O
(-)-swainsonine (1)
(+)-croomine (2)
n = 0
n = 1
R1
R2
*
H
*
*
N
*
H
R
HO
OH
(3) n = 0,1
n
ring-closing
metathesis
epoxide
aminolysis
R1
R1
R2
*
H
*
H
*
O
*
*
*
N
NH2
*
*
R2
H
n
R
HO
HO
OH
(4) n = 0,1
n
(6) cis or trans
(5) n = 0,1
Our general retro-synthetic analysis, illustrated for swain-
sonine (1) and croomine (2) is shown in Scheme 1. The
key poly-functionalised pyrrolidines of the type 3 should
Scheme 1
Enantiomerically enriched trans- or racemic cis-vinyl ep-
oxides 7 were readily prepared using literature proce-
dures.7a,11 Using the conditions described by Somfai,7 the
vinyl epoxides 7 were heated at 110 °C in a sealed tube
in an excess of allyl amine (20 equiv) in the presence of
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
1437-2096,E;2002,0,05,0731,0734,ftx,en;D03102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

732
K. B. Lindsay et al.
LETTER
p-TsOH (0.1–0.2 equiv) for 4 days (Scheme 2, Table). Protection of the amino group of 8a–d as its N-Boc deriv-
Despite the seemingly harsh reaction conditions these re- ative followed by a ring-closing metathesis reaction at
actions cleanly provided the required amino alcohols 8 in high dilution in refluxing dichloromethane, using com-
excellent yields (Table).12 In the case of 7a two regioiso- mercially available benzylidene bis(tricyclohexylphos-
meric products were obtained that were readily separated phine)-dichlororuthenium (Grubbs’ catalyst), provided
by column chromatography as single diastereomers, while the 2,5-dihydropyrroles 9a–c in high overall yields (Ta-
the reactions of 7b–d were essentially regioselective (< ble).13
5% of the other regioisomer could be detected on a large
In some initial studies we have studied some aminolysis
scale synthesis) and diastereomerically pure 8b–d were
reactions of rac-7d using microwave heating.7b We have
obtained in excellent yields.
found that by using 1 mole equivalent of lithium triflate in
acetonitrile14 that good to excellent yields of aminolysis
products can be obtained using 1–2 mole equivalents of
NH2
O
allyl amines under microwave heating conditions
R
(Scheme 3).15 Thus treatment of rac-7d under these con-
R
N
pTsOH, 110 °C
H
(7)
OH
4 days
ditions at 120 °C for 1 h gave 8d in 92% yield using only
2 mole equivalents of allyl amine. The microwave–lithi-
um triflate assisted reaction of a 1:1 mixture of the more
complex allyl amine rac-11 and rac-7d, a model study for
the key reaction in our proposed croomine (7) synthesis,
gave a 1:1 mixture of the diastereomeric amino-diols 12a
and 12b in 65% yield.
(8)
1. (Boc)2O
2. RCM
H4
O
R
Ph
H5
N
N
Boc
OH
(10)
(9)
O
Scheme 2
Optically active 9b (ee 94% based on that of 7b) was con-
verted to the known (1R,2S,7R,7aR)-1,2,7-trihydroxy-
The relative stereochemistry of 8a was established by pyrrolizidine (16) according to Scheme 4. Catalytic cis-
conversion (triphosgene, Et3N) to its corresponding 4,5- dihydroxylation of 9b with osmium tetroxide/N-methyl-
cis-oxazolidinone derivative 10. 1H NMR analysis of this morpholine N-oxide,16 gave the expected diol 13 in 79%
compound showed a typical cis-coupling constant for J4,5 yield. The stereochemistry of the produced diol being
of 8.5 Hz7 thus establishing that product 8a arises from 7a completely controlled by the C2 substituent of the 2,5-di-
via an inversion reaction at the allylic stereogenic centre.
hydropyrrole 9b. Treatment of 13 with trifluoroacetic acid
Table Synthesis of 8 and 9 According to Scheme 2
Vinyl Epoxide 7
Amino alcohol 8, yield [%]
Pyrrolidine 9, yield [%]c
trans-(2S,3S)-(7a) R = Ph
Ph
Ph
OH
N
H
Boc
OH
N
H
H
(9a)d [86]
(8a) [65]a
trans-(2R,3R)-(7b) R = -(CH2)2OPMB
cis-(2R*,3S*)-(7c) R = -(CH2)3OTBS
cis-(2R*,3S*)-(7d) R = -(CH2)4OPMB
(CH2)2OPMB
OH
(CH2)2OPMB
OH
N
H
Boc
N
H
H
(9b) [87]
(8b) [90]
(CH2)3OTBS
OH
(CH2)3OTBS
OH
N
Boc
H
N
H
H
(9c) [89]b
(8c) [93]b
(CH2)4OPMB
OH
(CH2)4OPMB
OH
N
Boc
H
N
H
H
(9d) [77]b
(8d) [88]b
a A 2:1 mixture of 8a and its regioisomer were formed in 97% combined yield.
b Racemic product formed from racemic 7.
c Overall yield from 8.
d [ ]D22 +131 (c 0.14, CHCl3).
Synlett 2002, No. 5, 731–734 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective Synthesis of Polyfunctional-Pyrrolidines
733
a
ether, H2 (1 atm), 89%] of the alkene group of 8c, fol-
lowed by primary alcohol deprotection (Bu4NF–THF,
89%) and oxidative cyclization with TPAP–NMO (4 Å
mol. sieves, CH2Cl2, 94%)23 gave compound 19 with the
correct relative stereochemistry as the C,D-ring system of
croomine (2).
NH2
( 2 equiv)
rac-(8d)
rac-(7d)
rac-(7d)
+
[92%]
b
a
(CH2)4OPMB
OH
rac-(7d)
H2N
H
rac-(11) [98%]
H
a-c
N
Boc
OTBS
N
Boc
H
R
R
R
+
R
O
H
OH
rac-(8c)
N
H
N
O
rac-(19)
H
H
H
H
H
HO
OH
HO
OH
rac-(12a)
rac-(12b)
Scheme 5 Reagents: a) Pd/C, H2 (1 atm), petroleum ether (91%). b)
Bu4NF, THF (89%). c) TPAP, NMO, 4 Å mol. sieves, CH2Cl2 (94%).
[65%, dr = 1 : 1, R = (CH2)4OPMB]
Scheme 3 Microwave heating
Reagents: a) LiOTf (1 equiv), MeCN, 120 °C, 1 h, microwave hea-
ting. b) Concd aqueous NH3, 110 °C, 20 min, microwave heating.
In conclusion, we have demonstrated that the aminolysis
of vinyl epoxides with allyl amine followed by N-protec-
tion and RCM efficiently gives functionalised 2,5-dihy-
dropyrroles 9. These compounds are potentially valuable
precursors for the synthesis of more complex alkaloids,
including chiral polyhydroxylated pyrrolizidine and in-
dolizidine alkaloids and stemona alkaloids.
using anisole17 (10 equiv) as a carbocation scavenger gave
the amino alcohol 14 in 90% yield after purification by
ion-exchange chromatography. Initially we attempted cy-
clisation of the tri-O-benzyl derivative 15 of 14 in an at-
tempt to produce the pyrrolizidine 18 using either Ph3P,
CBr4, Et3N18 or Mitsunobu conditions,19 however, none of
the desired product was obtained from a complex product
mixture. However, the less sterically demanding, unpro-
tected tetrol 14 could be cyclised to 16 under Mitsunobu
conditions using pyridine as solvent.20 The product was
difficult to purify and the crude reaction mixture was thus
treated with Ac2O–pyridine to provide the triacetate 17 in
poor overall yield (18%). The triacetate 17 could be con-
verted to its triol 16 upon base (K2CO3–MeOH) treatment.
The 1H and 13C NMR spectra of 16 and 17 were identical
to that of the previously synthesised compound.21,22
Acknowledgement
We thank the University of Wollongong for PhD scholarships to
KBL and MT, the Australian Research Council for financial support
and Prof. Carretero (Universidad Autónoma de Madrid) for kindly
providing copies of the 1H and 13C NMR spectra of compounds 16
and 17.
References
(1) Denmark, S. E.; Hurd, A. R. J. Org. Chem. 2000, 65, 2875;
and references cited therein.
(2) Denmark, S. E.; Herbert, B. J. Org. Chem. 2000, 65, 2887;
and references cited therein.
(3) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem.
Soc. 1998, 120, 7359; and references cited therein.
(4) Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato,
A.; Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1.
HO
OH
a
b
OPMB
(9b)
N
Boc
H
OH
(5) Goetz, M.; Edwards, O. E. In The Alkaloids, Vol. IX;
Manske, R. H. F., Ed.; Academic Press: New York, 1976,
545–551.
(6) Hinman, M. M.; Heathcock, C. H. J. Org. Chem. 2001, 66,
7751; and references cited therein.
(7) (a) Lindstrom, U. M.; Somfai, P. Synthesis 1998, 109.
(b) Lindstrom, U. M.; Olofsson, B.; Somfai, P. Tetrahedron
Lett. 1999, 40, 9273.
(13)
OR
RO
OR
H
RO
d
OR
OH
c
N
N
H
H
OR
(16) R = H
(17) R = Ac
(18) R = Bn
(14) R = H
(15) R = Bn
(8) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(9) For the application of the ring-closing metathesis reaction to
the synthesis of aza-sugars see: (a) Huwe, C. M.; Blechert,
S. Tetrahedron Lett. 1995, 36, 1621. (b) Overkleeft, H. S.;
Pandit, U. K. Tetrahedron Lett. 1996, 37, 547. (c) Huwe, C.
M.; Blechert, S. Synthesis 1997, 61. (d) White, J. D.;
Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem. Soc. 1998, 120,
7359. (e) Lindstrom, U. M.; Somfai, P. Tetrahedron Lett.
1998, 39, 7173. (f) Ovaa, H.; Stragies, R.; van der Marcel,
G. A.; van Boom, J. H.; Blechert, S. Chem. Commun. 2000,
1501. (g) Subramanian, T.; Lin, C.-C. Tetrahedron Lett.
2001, 42, 4079. (h) Klitze, C. F.; Pilli, R. A. Tetrahedron
Lett. 2001, 42, 5605.
Scheme 4 Reagents: a) OsO4 (5 mol%), NMO (2 equiv), acetone–
water (9:6), r.t., 24 h (79%), b) TFA (120 equiv), anisole (10 equiv),
CH2Cl2, r.t., 2.5 h; ion- exchange chromatography (90%). c: (i)
DEAD (1.2 equiv), Ph3P (1.2 equiv), pyridine, 0 °C, 18 h; (ii) Ac2O–
pyridine (18% overall for 14). d) K2CO3/MeOH, r.t., 1.5 h (100%).
The racemic 2,5-dihydropyrrole 8c could be readily
converted to the bicyclic butyrolactone 19, a model for
the C,D-ring system of croomine (2), as shown in
Scheme 5. Catalytic hydrogenation [Pd/C, petroleum
Synlett 2002, No. 5, 731–734 ISSN 0936-5214 © Thieme Stuttgart · New York

734
K. B. Lindsay et al.
LETTER
(10) For the application of the ring-closing metathesis reaction to
the synthesis of 2,5-dihydropyrroles from dienes see:
(a) Huwe, C. M.; Velder, J.; Blechert, S. Angew. Chem. Int.
Ed. Engl. 1996, 35, 2376. (b) Fursterner, A.; Picquet, M.;
Bruneau, C.; Dixneuf, P. H. Chem Commun 1998, 1315.
(c) Cerezo, S.; Cortes, J.; Moreno-Manas, M.; Pleixats, R.;
Roglans, A. Tetrahedron 1998, 54, 14869. (d) Furstner, A.;
Ackermann, L. Chem. Commun. 1999, 95. (e) Bujard, M.;
Briot, A.; Gouverneur, V.; Mioskowski, C. Tetrahedron
Lett. 1999, 40, 8795. (f) Furstner, A.; Liebl, M.; Hill, A. F.;
Wilton-Ely, J. D. E. T. Chem. Commun. 1999, 601.
H), 4.09 (m,1 H), 3.93–3.89 (m,1 H), 3.82 (m, 2 H), 3.80 (s,
3 H), 3.73–3.57 (m, 2 H), 1.76 (br s, 2 H); 13C NMR (75
MHz, CDCl3) CO not observed, 159.00 (C), 134.96 (CH),
129.98 (CH), 129.12 (CH), 118.38 (CH2), 116.27 (CH2),
113.65 (CH), 80.14 (C), 72.84 (CH2), 70.06 (CH), 68.32
(CH2), 65.11 (CH), 55.21 (CH3), 50.12 (CH2), 33.93 (CH2),
28.42 (CMe3); [ ]D25 -19.2 (c 2.4 CHCl3); MS (CI +ve) m/z
392 (M + 1+); HRMS (CI +ve) Calcd for C22H34NO5 (MH+)
392.244. Found: 392.244. RCM: Grubbs’ Catalyst (0.219 g,
0.266 mmol) was added to a solution of the above N-Boc
derivative (1.039 g, 2.634 mmol) in dry DCM (500 mL)
under nitrogen. The mixture was heated to reflux for 24 h.
The solution was cooled and the solvent was removed in
vacuo to give a brown oil which was purified by column
chromatography (gradient elution with 20–55% EtOAc–
petroleum ether) to give 9b as a clear oil (0.877 g, 91%). 1H
NMR (300 MHz, CDCl3) 7.25 (d, 2 H, J = 8.4 Hz), 6.86 (d,
2 H, J = 8.4 Hz), 5.80 (apparent dd,1 H, J = 1.5, 6.3 Hz), 5.64
(apparent dd,1 H, J = 2.1, 6.3 Hz), 4.85 (d,1 H, J = 8.4 Hz),
4.83–4.80 (m,1 H), 4.44 (s, 2 H), 4.19 (dd,1 H, J = 2.1, 15.6
Hz), 4.04–3.97 (m,1 H), 3.87 (apparent t,1 H, J = 9.6 Hz), 3.8
(s, 3 H), 3.71–3.56 (m, 2 H), 1.69–1.53 (m, 2 H), 1.48 (s, 9
H); 13C NMR (75 MHz, CDCl3) 158.91(CO), 156.14 (C),
130.39 (C), 129.25 (CH), 127.12 (CH), 126.53 (CH), 113.62
(CH), 80.50 (C), 72.84 (CH2), 71.33 (CH), 71.51 (CH),
67.87 (CH2), 55.26 (CH3), 54.68 (CH2), 31.79 (CH2), 28.48
(CH3); [ ]D23 -80.3 (c 2.4 CHCl3); MS (CI +ve) m/z 364 (M
+ 1+); HRMS (CI +ve) Calcd for C20H30NO5 (MH+) 364.212.
Found: 364.199.
(g) Ackermann, L.; Furstner, A.; Weskamp, T.; Kohl, F. J.;
Hermann, W. A. Tetrhedron Lett. 1999, 40, 4787.
(h) Ahmed, M.; Barrett, A. G. M.; Braddock, D. C.; Cramp,
S. M.; Procopiou, P. A. Tetrahedron Lett. 1999, 40, 8657.
(i) Evans, P. A.; Robinson, J. E. Org. Lett. 1999, 1, 1929.
(j) Hunt, J. C. A.; Laurent, P.; Moody, C. J. Chem. Commun.
2000, 1771.
(11) These were prepared from the corresponding (E)- or (Z)-
allylic alcohols via epoxidation (Sharpless AE or m-CPBA),
oxidation (Swern or TPAP/NMO) and Wittig olefination
using procedures from ref.7a and the following references:
(a) Hayashi, N.; Fujiwara, K.; Murai, A. Tetrahedron 1997,
53, 12425. (b) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P.
K.; Hwang, C. K. J. Am. Chem. Soc. 1989, 111, 5330.
(c) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C. K.;
Duyyan, M. E.; Veale, C. A. J. Am. Chem. Soc. 1989, 111,
5321. (d) Díez-Martin, D.; Kotecha, N. R.; Ley, S. V.;
Mantegani, S.; Menéndez, J. C.; Organ, H. M.; White, A. D.
Tetrahedron 1992, 48, 7899.
(14) Chini, M.; Crotti, P.; Giovani, E.; Macchina, F.; Pineschi, M.
Synlett 1992, 303.
(15) Reactions were performed on a Milestone, ETHOS SEL
microwave labstation in sealed teflon vessels with strict
control of the internal reaction temperature.
(16) Mukai, C.; Sugimoto, Y.-I.; Miyazawa, K.; Yamaguchi, S.;
Hanaoka, M. J. Org. Chem. 1998, 63, 6281.
(17) Medeiros, E. F. D.; Herbert, J. M.; Taylor, R. J. K. J. Chem.
Soc. Perkin Trans. 1 1991, 2725.
(18) (a) Mulzer, J.; Dehmlow, H. J. Org. Chem. 1992, 57, 3194.
(b) Casiraghi, G.; Ulgheri, F.; Spanu, P.; Rassu, G.; Pinna,
L.; Gasparri, F. G.; Belicchi, F. M.; Pelosi, G. J. Chem. Soc.,
Perkin Trans. 1 1993, 2991.
(12) (3S,4R)-3-Allylamino-6-(4-methoxybenzyloxy)-1-hexen-4-ol
(8b): (2R,3R)-3-[2-(4-Methoxybenzyloxy)ethyl]-2-
ethenyloxirane (7b) (1.647 g, 6.98 mmol) was dissolved in
allylamine (11.5 mL, 153.56 mmol), then pTsOH.H2O (355
mg, 1.87 mmol) was added. The mixture was heated at 110
°C under nitrogen in a sealed tube for 4 d. After cooling, all
volatiles were removed in vacuo to give a red solid that was
purified by column chromatography (gradient elution from
0–12.5% MeOH–CH2Cl2) to give the title compound (1.83
g, 90%) as a pale yellow solid. Mp 61.5–62.5 °C. 1H NMR
(300 MHz, CDCl3) 7.24 (d, 2 H, J = 9.0 Hz), 6.86 (d, 2 H,
J = 9.0 Hz), 5.94–5.81 (m,1 H), 5.71 (ddd,1 H, J = 8.4, 10.5,
17.4 Hz), 5.22 (dd,1 H, J = 1.8, 10.5 Hz), 5.19–5.18 (m,1 H),
5.13–5.12 (m,1 H), 5.08 (dd,1 H, J = 1.2, 9.9 Hz), 4.43 (s, 2
H), 3.85 (dt,1 H, J = 3.3, 6.6 Hz), 3.79 (s, 3 H), 3.69–3.56
(m, 2 H), 3.28 (apparent dd,1 H, J = 6.0, 13.8 Hz), 3.12
(apparent dd,1 H, J = 6.3, 14.4 Hz), 3.07 (dd,1 H, J = 3.3, 8.4
Hz), 1.80–1.61 (m, 2 H); 13C NMR (75 MHz, CDCl3)
159.00 (C), 136.40 (CH), 136.04 (CH), 130.05 (C), 129.18
(CH), 118.28 (CH2), 116.00 (CH2), 113.67 (CH), 72.84
(CH2), 71.38 (CH), 68.27 (CH2), 65.18 (CH), 55.25 (CH3),
49.55 (CH2), 32.76 (CH2); [ ]D25+2.0 (c 2.3 CHCl3); MS (CI
+ve) m/z 292 (M–1+. 100%); HRMS (CI +ve) Calcd for
C17H26NO3 (MH+) 292.191. Found: 292.194.
(19) Misunobu, O. Synthesis 1981, 1.
(20) (a) Bernotas, R. C.; Cube, R. V. Tetrahedron Lett. 1991, 32,
161. (b) Chen, Y.; Vogel, P. J. Org. Chem. 1994, 59, 2487.
(21) de Vincente, J.; Arrayás, R. G.; Carretero, J. C. Tetrahedron
Lett. 1999, 40, 6083.
(22) 17: 1H NMR (300 MHz, CDCl3) 5.40 (ddd,1 H, J = 2.1, 4.2,
4.5 Hz), 5.12 (m,1 H), 4.99 (dd,1 H, J = 4.5, 7.8 Hz), 3.50
(dd,1 H, J = 2.1, 7.8 Hz), 3.27 (dd,1 H, J = 2.1, 11.7 Hz), 3.21
(ddd,1 H, obscured), 2.87 (dd,1 H, J = 4.2, 11.7 Hz), 2.71
(ddd,1 H, J =6.0, 9.0, 11.1 Hz), 2.07 (s, 3 H), 2.05 (s, 3 H),
2.02 (s, 3 H), 1.95–1.86 (m, 2 H); 13C NMR (75 MHz,
CDCl3) 170.34 (CO), 170.11 (CO), 170.07 (CO), 77.13
(CH), 74.09 (CH), 73.16 (CH), 71.58 (CH), 57.12 (CH2),
52.91 (CH2), 30.54 (CH2), 21.11 (CH3), 20.94 (CH3), 20.75
(CH3); [ ]D25 +5.0 (c 0.8 CHCl3); 16: 1H NMR (300 MHz,
D2O) 4.23–4.15 (m, 2 H), 3.86 (dd,1 H, J = 4.2, 6.3 Hz),
3.10 (dd,1 H, J = 1.8, 6.3 Hz), 3.04–2.98 (m, 2 H), 2.71 (dd,1
H, J = 4.2, 11.7 Hz), 2.61 (apparent quint,1 H), 2.08–1.95
(m,1 H), 1.77–1.67 (m,1 H); 13C NMR (75 MHz, D2O)
77.78 (CH), 77.64 (CH), 77.41 (CH), 74.81 (CH), 60.51
(CH2), 54.85 (CH2), 35.13 (CH2).
(13) N-Boc Protection: To a solution of 8b (1.17 g, 4.01 mmol)
in dry THF (70 mL) were added triethylamine (0.98 mL,
7.00 mmol) and di-tert-butyldicarbonate (1.53 g, 7.00
mmol) under nitrogen. The mixture was stirred at r.t. for 24
h. All volatiles were then removed in vacuo to give a yellow
oil which was purified by column chromatography (gradient
elution from 20–40% EtOAc–petroleum ether) to give the N-
Boc derivative of 8b (1.507 g, 96%) as a yellow oil. 1H NMR
(300 MHz, CDCl3) 7.24 (d, 2 H, J = 8.4 Hz), 6.87 (d, 2 H,
J = 8.4 Hz), 6.08 (ddd,1 H, J = 6.9, 9.9, 17.1 Hz), 5.85–5.72
(m,1 H), 5.30–5.21 (m, 2 H), 5.16–5.06 (m, 2 H), 4.44 (s, 2
(23) Griffith, W. P.; Ley, S. P. Aldrichimica Acta 1990, 23, 13.
Synlett 2002, No. 5, 731–734 ISSN 0936-5214 © Thieme Stuttgart · New York