Asymmetric synthesis of polyfunctionalized pyrrolidines and related alkaloids

16 Pages·2017·0.23 MB·English

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Faculty of Science - Papers (Archive) Faculty of Science, Medicine and Health
2004
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Stephen G. Pyne
University of Wollongong, [email protected]
Andrew S. Davis
University of Wollongong
Nicole Gates
University of Wollongong
Joseph Hartley
University of Wollongong
Karl Lindsay
University of Wollongong
See next page for additional authors
Follow this and additional works at: https://ro.uow.edu.au/scipapers
Part of the Life Sciences Commons, Physical Sciences and Mathematics Commons, and the Social
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Pyne, Stephen G.; Davis, Andrew S.; Gates, Nicole; Hartley, Joseph; Lindsay, Karl; Machan, Theeraphan;
and Tang, Minyan: Asymmetric synthesis of polyfunctionalized pyrrolidines and related alkaloids 2004.
https://ro.uow.edu.au/scipapers/5317
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This account describes our recent studies on the development of a general method of preparing
polyfunctionalized pyrrolidine, indolizidine, pyrrolizidine and pyrrolo[1,2-a]azepines and their related
alkaloids.
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Life Sciences | Physical Sciences and Mathematics | Social and Behavioral Sciences
PPuubblliiccaattiioonn DDeettaaiillss
Pyne, S. G., Gates, N., Hartley, J., Lindsay, K., Machan, T. & Tang, M. (2004). Asymmetric synthesis of
polyfunctionalized pyrrolidines and related alkaloids. Synlett: accounts and rapid communications in
synthetic organic chemistry, 15 2670-2680.
AAuutthhoorrss
Stephen G. Pyne, Andrew S. Davis, Nicole Gates, Joseph Hartley, Karl Lindsay, Theeraphan Machan, and
Minyan Tang
This journal article is available at Research Online: https://ro.uow.edu.au/scipapers/5317
1 ACCOUNT
Asymmetric Synthesis of Polyfunctionalized Pyrrolidines and
Related Alkaloids

Stephen G. Pyne*, Andrew S. Davis, Nicole J. Gates, Joseph P. Hartley, Karl B. Lindsay, Theeraphan Machan and
Minyan Tang
Department of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522, Australia
Fax: [phone]
E-mail: [email protected]

Received: The date will be inserted once the manuscript is accepted.

Abstract: This account describes our recent studies on the Scheme 1. Retrosynthetic analysis of croomine (1).
development of a general method of preparing polyfunc-
tionalized pyrrolidine, indolizidine, pyrrolizidine and pyr- Me
rolo[1,2-a]azepines and their related alkaloids.
O
H a. [O]
Key words: Vinyl epoxides, aminolysis, oxazolidinones, a O N Me b. N-alkylation
ring-closing metathesis, pyrrolidines, indolizidine, pyrroli- H H O
b
zidine and pyrrolo[1,2-a]azepines, Petasis reaction. a O

croomine 1
Introduction
In early 2000, we started a project concerned with Me RCM
developing a general synthesis of polyfunctional HO
H
pyrrolidines with the initial intention of developing
HO Me
a synthesis of the Stemona alkaloid, croomine 1. N
This project was given to a fresh PhD student, Karl H H H OH
OH
Lindsay, who was keen to tackle a challenging OP1
natural product target. Our general retro-synthetic
2
analysis is outlined in Scheme 1. The key reactions
Me
of this analysis were the ring-closing metathesis
(RCM) reaction of the diene 3 and the regioselec- PO
H
tive aminolysis of the vinyl epoxides 4 or 7 with the
HO Me
chiral allylic amines 5 and 6, respectively. At the N
H
start of this project the regioselective ring-opening H HO
OP
of vinyl epoxides with ammonia and benzyl and
cyclohexyl amine had been reported by Somfai’s OP1
group.1,2 However, the regioselectivity of the ami- 3
nolysis of more complex chiral vinyl epoxides and
Me
more hindered amines was uncertain at the time,
and required closer examination. The RCM reaction PO O H H
was well established as a versatile and efficient + H N Me
process for making heterocyclic rings.3,4 While both H 2 OH
these key reactions had been well documented, we OP
thought that their application in tandem appeared to 5
be a novel way to allow ready access to our target 4 OP1
molecule.
OR
Me
In the first year of Karl’s project we realized that
OH
this tandem-methodology could also be applied to PO
the synthesis of the more relatively simpler polyhy- + Me
H
droxylated indolizidine and pyrrolizidine alkaloids H NH2 O H
like swainsonine 8 and australine 9 (Schemes 2 and
OP
3, respectively). Thus Karl temporarily stopped 7
6 OP1
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2 ACCOUNT
working on croomine and then focused on the syn- Scheme 4. Asymmetric Synthesis of trans-vinyl
thesis of swainsonine 8. epoxides.
In early 2001, Minyan Tang joined my research PMBO
group as a PhD student and she was given the task (CH2)n REDAL OH
of synthesizing australine 9 and its epimers. These CH OH
2 (CH2)n OPMB
target molecules required access to both chiral 10
11
trans- and cis-vinyl epoxides.
O 1. Swern or O
SAE OH TPAP
Scheme 2. Retrosynthetic analysis of swainsonine
(8). (CH2)n OPMB 2. CH2=PPh3(CH2)n OPMB
12 13 [92-94% ee]
HO HO
H OH H [n = 0,1,2]
RCM
OH
N N Scheme 5. Asymmetric Synthesis of cis-vinyl
epoxides
8 N-alkylation

HO
H epoxide O
aminolysis PMBO
OH
(CH2)n Lindlar
HN H N CH OH
2 2 (CH2)n OPMB
10
HO PO 14
O O
OH 1. Swern or
Scheme 3. Retrosynthesis of australine (9). SAE TPAP
HO H OH HO H (CH2)n OPMB 2. CH =PPh (CH2)n OPMB
RCM 2 3
15 16
OH [82% ee, n = 0]
N N
[n = 0,1,2]

9 OH N-alkylation OR
Initial vinyl epoxide-ring opening studies using
HO H epoxide O allyl amine employed the methodology reported by
aminolysis Somfai.1 In a typical reaction this involved heating
a solution of the vinyl epoxide (e.g. 17, Scheme 6)
HN in the presence of allyl amine (10 equiv) and p-
HO PO TsOH.H2O (0.1 equiv) in a sealed tube for 3 days at
OR 105oC. Surprizingly these seemingly harsh condi-
H N
2 tions provided the desired 1,2-amino alcohols (e.g.
18) in good to excellent yields.5 Furthermore these
OR
reactions were highly regioselective and gave the

expected S 2 products. We latter found that these
N
Tandem Vinyl Epoxide Aminolysis/Ring-closing reactions were accelerated by changing the protic
Metathesis acid catalyst p-TsOH.H O for the Lewis acid cata-
2
In order to test our proposed synthetic strategy, lyst LiOTf (1-1.5 equiv) without any detrimental
Karl and Minyan prepared a number of chiral vinyl effects on the regioselectivities or chemical yields.
epoxides using the Sharpless asymmetric epoxida- With the combination of LiOTf and microwave
tion (SAE) to introduce the epoxide functions on E- heating2 then these aminolysis reactions were com-
and Z-allylic alcohols. These were readily obtained plete after 1 h of heating at 110oC.5 The purchase of
from the differentially protected propargyl alcohols a microwave reactor in 2002 allowed us to perform
10, by either REDAL reduction to the E-allylic aminolysis reactions of vinyl epoxides using
alcohols (Scheme 4) or Lindlar reduction to give aqueous ammonia2 which was difficult to perform
the Z-allylic alcohols (Scheme 5). The resulting in a sealed tube and often resulted in only cleavage
epoxy alcohols were then converted to chiral vinyl of primary OTBS groups on the vinyl epoxide.
epoxides via TPAP or Swern oxidation followed by Prior to this purchase we had to prepare amino
Wittig olefination. alcohols like 22 in two steps, first vinyl epoxide
aminolysis with allyl amine followed by regioselec-

tive N-deallylation with Pd(0) and N,N-
dimethylbarbituric acid (NDMBA) (Scheme 7).6
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3 ACCOUNT
Scheme 6 sive product by treating 25 with triphosgene under
basic conditions (Scheme 9).8
HO
O p-TsOH.H O (0.1 equiv)
2 Scheme 9
sealed tube
105oC, 3 days
OPMB HN
OR HO HO
17[92% ee]
mircowave, LiOTf, OPMB (Boc) O
2
+
NH2 105oC, 1 h 18 HN Et3N, DMAP BocN
(88%) PMBO PMBO

OBn OBn
Scheme 7 25 26 (71%)
+
allyl amine HO triphosgene PMBO H
O p-TsOH.H2O (0.1 equiv) Et3N
sealed tube, O
(79%) N
(CH2)2 OPMB 105oC, 3 days (CH2)2 HN
O OBn
19 (87%)
OPMB 27 (15%)

28% aqueous NH 20
3
The RCM reaction of 26 gave the expected 2,5-
microwave,
1. TBSCl, imidazole (77%)
110oC, 30 min 2. Pd(PPh ) , NDMBA, dihydropyrrole 28 but upon treatment with
34 TBSOTf, for the purpose of preparing the corres-
(98%) 60oC, 3 h (97%)
ponding secondary TBS ether, we obtained the
OH
OTBS oxazolidinoe 29 in 42 % yield (Scheme 10).7
Scheme 10
(CH2)2 NH2 (CH2)2 NH2 HO TBSOTf H
PMBO
OPMB RCM 2,6-lutidine
OPMB 26 O
21 22 PMBO BocN (42%) N

OBn O
28
With 1,2-amino alcohols in hand we were in a posi- BnO
tion to attempt RCM reactions. These were first 29
Since all Minyan’s reactions were producing oxazo-
converted to their corresponding N-Boc derivatives
lidinones we thought we should ‘go with the flow’
and not unexpectedly their RCM reactions pro-
ceeded readily using Grubbs’ 1st generation catalyst and use the oxazolidinone as a protectiong group
for the 1,2-amino alcohol moiety. Fortunately this
(benzylidene bis(tricyclohexylphosphine)-
proved to be a viable protecting group and allowed
dichlororuthenium, Grubbs’ I, 5-10 mol%) and high
us to perform much more diastereoselective syn-
dilution in dichloromethane solution at reflux for
18-20 h (Scheme 8).5 dihydroxylations on the resulting pyrrolo[1,2-
c]oxazol-3-ones (e.g. 29).8
Scheme 8
At about this time Nicole Gates joined my group in
(Boc) O HO RCM HO H 2002 to start a laboratory based 3rd year chemistry
2
Et N Grubbs' I subject. Her project initially involved the synthesis
18 3
of the 3-allyl-4-vinyloxazolidinones 30a,b and an
(98%) BocN (96%) BocN
examination of their RCM reactions. Compound
30a had been prepared before, however it was
OPMB OPMB
claimed to not undergo the RCM reaction with
23 24 Grubbs’ I catalyst in benzene at RT.3a We had
All Routes Lead to Oxazolidinones
thought that by running this reaction in refluxing
When Minyan attempted to protect the amino group dichloromethane then we would obtained the pyrro-
of more hindered amino alcohols like 25 we found lo[1,2-c]oxazol-3-one 31 (Scheme 11). In the
that DMAP was required to enhance the rate of event, heating a dilute dichloromethane solution of
reaction. Under these conditions we obtained a 30a and Grubbs’ I catalyst (10 mol%) at reflux for
mixture of the desired N-Boc derivative 26 (71%) 24 h resulted in only 50% conversion to 31 by GC
and the oxazolidinone 27 (15%) (Scheme 9).7 The analysis.9 Indeed the RCM reaction of 30a was
oxazolidinone 27 could be obtained as the exclu- slow compared to that of dienes like 23. However a
yield of 73% could be obtained for 31, after 24 h,
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4 ACCOUNT
when the more reactive, and expensive, Grubbs’ II with addition of the osmium reagent to the less hindered
catalyst (10 mol%) was employed.9 The styrene -face of 36. Approach to the -face being hindered by
derivative 30b underwent a RCM reaction under the pseudo-axial allylic protons H8a and H3 (Scheme
the same conditions to give 31 in 82% yield.9 14).10-13
Scheme 11
R Scheme 13
RCM
Grubbs' II HO H HO H OH
K OsO .H O
O O 2 4 2
N (73-82%) N NMO OH
BocN BocN
O O
30a, R = H 31
30b, R = Ph OPMB OPMB
24 34
The more heavily substituted 3-allyl-4-
vinyloxazolidinones like 32 were even more slug-
2 steps
gish in their RCM reactions than 30a and 30b. For
example, the RCM reaction of 32 required a total BnO
H
catalyst (Grubbs’ I) loading of 40 mol% and heat-
ing for 48 h. The yield of the pyrrolo[1,2-c]oxazol-
3-one 33, however was an acceptable 73% (Scheme HN
12).8
OH 35
Scheme 12
Ph P, CBr
3 4
Et3N
(97%)
PMBO PMBO
RCM RO RO
H H OH
H Grubb's I H K2OsO4.H2O
(40 mol%) NMO OH
O N CH2Cl2 O N N N
36 37
O OBnreflux 48 h O OBn a, R = Bn, b, R = H, a, dr = 67 : 33
(73%)
32 33 c, R = TIPS, d, R = TBS b, dr = 60 : 40
c, dr = 20 : 80
d, 88 : 12 or ca 1 : 1
Syn-Dihydroxylation Reactions of 2,5-
Scheme 14
dihydropyrroles, indolizidines and pyrrolo[1,2-
c]oxazol-3-ones RO H8a
H
RO H 
Syn-dihydroxylation (DH) of 2-substituted-2,5- 3
dihydropyrroles like 24 with catalytic potassium os- N
mate.dihydrate (K OsO .2H O) and stoichiometric N H
2 4 2
NMO in acetone-water is a highly diastereoselective 36
reaction (dr >98 : <2) with the C-2 substituent acting as 36 OsO4
the stereochemical control element (Scheme 13).10 Syn-
dihydroxylations of indolizidines 36a-d were less diate- RO
OH
H
reoselective under similar conditions. For example, we
OsO
found the DH reaction of 36a gave a 67 : 33 mixture of 4
OH
diastereomers in favour of the diastereomer 37a, having N
the same absolute stereochemistry as swainsonine (8).
Other investigators have found similar diastereoselectiv- 37
ities for the DH reactions of 36b-d (Scheme 13).11-13
The DH reaction of Minyan’s pyrrolo[1,2-c]oxazol-
Surprizingly, the TIPS derivative 36c is reported to un-
3-one 33 using K OsO .2H O/NMO was highly
2 4 2
dergo DH to give a mixture in favour of 1,2-diepi-37c
diastereoselective (dr >95 : <5) and gave the pure
(structure not shown). The diastereoselectivities of 6,7-,-diol 38 in 82% yield (Scheme 15).8
these reactions are greatly enhanced using the Sharpless
asymmetric DH conditions. Under these conditions
using AD-mix- the diastereoselectivities for the DH of
36a by us10 and 36d by Blechert’s group13 were en-
hanced to 98 : 2 and 95 : 5, respectively. The stereo-
chemical outcomes for these reactions were consistent
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5 ACCOUNT
Scheme 15 compounds have attracted the attention of synthetic
chemists resulting in many total syntheses of these
PMBO PMBO
and related compounds.14,15
OH
H H
K OsO .H O In 2002 we reported Karl’s successful synthesis of
2 4 2
NMO 1 (-)-swainsonine 8 from the deprotection of the diol
O O 6 OH
N N 37a and (+)-1,2-diepi-swainsonine by intramolecu-
(82%)
lar N-alkylation of the activated primary alcohol of
O OBn O OBn 35 after removal of the N-Boc and O-PMB groups
33 38 (Scheme 17).10 In principle, the tandem vinyl epox-

ide aminolysis/RCM method could allow the syn-
The DH reaction of Nicole’s pyrrolo[1,2-c]oxazol- thesis of all possible stereoisomers of swainsonine.
3-one 31 using K OsO .2H O/NMO was also high- For example, we also reported the synthesis of (+)-
2 4 2
ly diastereoselective (dr >95 : <5) and gave the 1,2,8-triepi-swainsonine 42 by starting from the cis-
pure 6,7-,-diol 39 in 76% yield (Scheme 16). vinyl epoxide 16 (n = 1). Karl also extended his
This diol resulted from attack of the oxidizing agent method to the preparation of the novel 1H-
from the concave face of the molecule (Figure 1) pyrrolo[1,2-a]azepine analogue 44 of swainsonine
due to the pseudo-axial allylic protons H5 and by starting with 43 the homologue of 41 (Scheme
H7a that sterically hinder the -face to attack by the 17).16
osmium reagent (Figure 1).9 This argument is simi- Scheme 17
lar to that proposed to account for the facial selec-
BnO
tivity of DH reactions on the related indolizines 36 H OH HO H OH
(Scheme 14). Thus the C-5 -benzyloxymethyl
OH
OH
substituent in 33 was not entirely responsible for
N
N
the facial selectivity in the DH reaction of 33.
37a
Scheme 16 8
OH HO HO
H K OsO .H O H H OH H OH
2 4 2
NMO
O O OH OH 8 1 OH
N (76%) N BocN N 3
O O
OPMB 40
31 39
35
Figure 1
HO HO
H H OH
H7a
OsO4 OH
X HN N
1 H5 PMBO 42
41
N
O
HO HO
O H H OH
OH
OsO4 HN N
Figure 1. Stereochemical model of 31 (Spartan PC
43
44
OPMB
AM1).

In 2003 Karl developed an alternative synthesis of (-)-
Asymmetric Synthesis of Swainsonine and Epi-
swainsonine that was inspired by the success of Nicole
austalines
and Minyan’s DH reactions of the pyrrolo[1,2-c]oxazol-
Polyhydroxylated indolizidines (e.g. (-)- 3-ones 31 and 33, respectively.17 Base catalysed cycliza-
swainsonine 8) and pyrrolizidine natural products tion of 24 gave the pyrrolo[1,2-c]oxazol-3-one 45. With
(e.g. australine 9) are potent glycosidase inhibitors 45 in hand, Karl next examined its DH reactions. To this
and have potential applications as anti-cancer, anti- end 45 was treated with K OsO .2H O/NMO in ace-
2 4 2
viral and anti-retroviral drugs. These interesting tone-water, which gave a 3 : 1 inseparable mixture of
biological properties coupled with the polyfunc- the diols 46 and 6,7-diepi-46 (structure not shown) in
tional and stereochemically rich nature of these
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6 ACCOUNT
85% yield. A pure sample of the major diol 46 was )-7-epiaustraline 51 required us to invert the stereo-
isolated by careful crystallisation from hot dichlorome- chemistry at C-1 (australine numbering) in the diol
thane and petroleum spirit. This crystallisation was not 38. This was achieved in a regioselective manner
necessary however, because benzylation of the mixture via ring-opening of the derived cyclic sulfate 49
of diols, gave the corresponding bis-benzyl ethers 47 with cesium benzoate. The regioselectivity being
and 6,7-diepi-47 (structure not shown) in quantitative controlled by the C-3 (australine numbering) ben-
yield, and these were readily separable by column zyloxymethyl group in 49 (Scheme 19). In 2004 we
chromatography. Conducting the same DH reaction at reported Minyan’s synthesis of the natural product
0oC resulted in an improved diastereoselectivity and (+)-1-epiaustraline 53 and her attempted synthesis
yield (3.5 : 1 and 92%, respectively). Thus the diaste- of australine 9 (Scheme 20).19 Starting with the cis-
reoselectivities for the DH reaction of 46 were similar to vinyl epoxide 16 (n = 0) we prepared the C-4 epi-
those found for the DH reactions of indolizidine 36. mer of 25 which eventually provided the diol 52.
These DH reactions however were far less diastereose- This was readily converted to the alkaloid (+)-1-
lective than those of the unsubstituted pyrrolo[1,2- epiaustraline 53. Compound 52 was converted to
c]oxazol-3-one 31. The C-1 -substituent present in 45 the amino tetraol 56 using similar chemistry as
is most likely responsible for this reduced -face diaste- shown in Scheme 19. Cyclization of 56 was antic-
reoselectivity. With the aim of increasing the steric bulk ipated to give 57, the O-benzyl ether of our target
of the oxidant, and perhaps the diastereoselectivity, the australine 9 (Scheme 20). Unexpectantly, the cycli-
DH reaction was repeated in the presence of the coordi- zation of 56 under the Mitsunobu reaction condi-
nating ligand pyridine (10 equiv.). Unfortunately, the tions, that had provided 48, 51 and 53, failed to
use of pyridine extended the reaction time to 7 d and work in this case. Unfortunately we had run out of
resulted in a significant reduction in the diastereoselec- time and compound to try this cyclization again as
tivity to 1.5 : 1. When AD-mix- was used at RT the Minyan had to commence the writing of her PhD
reaction did not go to completion within 6 d, and the thesis in March 2004. The reasons why this mole-
diastereoselectivity was only slightly improved (3.7 : 1). cule failed to cyclize are not clear, however this
step had been a relatively low yielding process in
Surprisingly, when AD-mix- was used a 20 : 1 ratio of
our synthesis of 48, 51 and 53. In contrast, we have
diastereoisomers was obtained, albeit at low conversion
had relatively little difficulty preparing analogous
after 6 days at RT, giving a 46% yield of product diols
5,6- and 5,7-bicyclic heterocyclic systems (c.f.
46 and 6,7-diepi-46 (and 45% recovered starting ma-
Schemes 13 [conversion of 35 to 36a] and 17) by
terial). We attribute the disparencies between the  and
formation of the heterocyclic 6- or 7-membered
 AD-mixes to be a result of a matched/mismatched
situation.18 ring using the Appel cyclization conditions (Ph3P,
CBr , Et N).20 Unfortunately this method has not
4 3
Conversion of 47 into (-)-swainsonine 8 proved to be
been successful in our hands to prepare pyrrolizi-
relatively straight forward (Scheme 19).
dines.
Scheme 18

OH
H PMBO H H

NaH, toluene 1
O
BocN 50oC 3 N
O
OPMB

24 45

PMBO HH OR
K OsO .2H O
2 4 2
NMO O OR
N
O
BnBr, NaH 46, R = H
Bu NI, THF 47, R = Bn
4

(-) swainsonine (8)

In 2003 we reported Minyan’s synthesis of (+)-1,7-
diepiaustraline 48 and (-)-7-epiaustraline 51 and
from the diol 38 (Scheme 18).8 The synthesis of (-

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7 ACCOUNT
Scheme 19 py that the required 1,2-amino alcohols required
seven synthetic steps from commercially available
PMBO
alkynes. A novel one-pot, three-component method
H OH HO H OH of preparing 1,2-amino alcohols is the Petasis reac-
7 1 tion (boronic acid-Mannich reaction).21 Indeed
O OH OH
N 5 N 3 Nicole used the Petasis reaction in her synthesis of
the 1,2-amino alcohol 30b (Scheme 21).
O OBn 48 OH
38
Scheme 21
Ph
PMBO Ph
PMBO HO CHO (HO) B
H O SO2 PhDCMOF2Cs H OBz 2 EtOH, RT HO HN
H N (98%)
2
O O O OH 58
N N
Ph
O OBn O OBn triphosgene
Et N
49 50 3
O
(71%) N
HO OH
H
O
30b
OH
N
To test this method for alkaloid synthesis we tar-
OH
51 geted the synthesis of the polyhydroxylindolizidine

alkaloid, uniflorine A 59 which was isolated in
Scheme 20 2000 from the leaves of the tree Eugenia uniflora
L.22-24 The water-soluble extract of these leaves has
been used as an antidiabetic agent in Paraguayan
PMBO
traditional medicine. Uniflorine A was found to be
H OH HO H OH an inhibitor of the -glucosidases, maltase and
7 1 sucrase, with IC values of 12 and 3.1 M, respec-
O OH OH 50
N 5 N 3 tively. The structure of uniflorine A was deduced
from NMR analysis to be that shown as structure
O OBn 53 OH 59.22 The proposed structure of uniflorine A is
52
similar to that of castanospermine 60, except for the
stereochemistry at C-1 and the extra hydroxyl subs-
titution at C-2 (Figure 2).
PMBO
PMBO
PhCO Cs
H O SO2 DMF2 H OBz Figure 2
O O O OH HO OH HO OH
N N H H
HO HO
O OBn O OBn 88a 1 OH
54 55 N N
HO HO
5 3
HO H OH HO H OH 59 60
In April 2003 Andrew Davis joined our group as a new
OH OH
HN N PhD student to work on the synthesis of uniflorine A and
related alkaloids. Our retrosynthetic analysis of 59
HO
56 OBn 57 OBn (Scheme 22) suggested that the target compound could
be acquired from the precursor 61 using a RCM reaction
and N-alkylation to prepare the 5- and 6-membered rings
of 59, respectively.25 The 1,2-anti amino alcohol 61
Synthesis of 1,2-amino alcohols and Putative
would be expected to be readily obtained from the Peta-
Uniflorine A using the Petasis Reaction
sis reaction of L-xylose, allylamine and (E)-styrene bo-
While we had successfully demonstrated the tan- ronic acid, followed by chemo- and regioselective N-
dem aminolysis of vinyl epoxides/RCM stategy in and O-protection reactions.
the synthesis of several alkaloids, we were not hap-
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8 ACCOUNT
downfield peaks in the 1H NMR, perhaps consistent with
the amine salt. The 1H NMR of the hydrochloride salt of
Scheme 22. Retrosynthetic analysis of 59
synthetic 59 however, did not match the literature spectral
data either. We therefore concluded that the structure
HO assigned to uniflorine A was not correct.25
HO
OH H
HO H [RCM] HO Ph Scheme 23
OH RN L-xylose
N HO EtOH, RT
HO [N-alkylation] R1O (HO) B Ph H2N
2 (73%)
61
59
HO HO
Petasis H
Reaction HO Ph HO Ph RCM
CHO (HO) B
2
RN (86%)
HO
HO H N
2 R1O
HO
62, R = R1 = H
(Boc) O,Et N
2 3 63, R = Boc, R1 = H
TrCl/py
In the event, the requisite Petasis reaction gave the desired 64, R = Boc, R1 = Tr
amino-tetraol 62 in 73% yield as a single diastereomer
after purification by ion-exchange chromatography
(Scheme 23). The amino-tetraol 62 was converted to its N-
HO RO
Boc derivative 63 (51 % yield) and then the primary H H OR
HO RO
alcohol was regioselectively protected as its O-trityl DH
compound 64 (68 % yield). A RCM reaction of 64 using N (88%) N OR
Grubbs’ I catalyst (10 mol %) smoothly gave the 2- HO Boc RO Boc
TrO TrO
substituted-2,3-dihydropyrrole 65 in 86% yield. Syn-
dihydroxylation of 65 furnished the pentaol 66 as a single 65 BnBr, NaH, 66, R = H
Bu NI, THF 67, R = Bn
diastereomer in 88% yield. The stereochemical outcome of 4
(76%)
this DH reaction was expected due to the stereodirecting
effect of the C-2 substituent in 65 and was later confirmed
from the single crystal X-ray analysis of the pentaacetate BnO OBn BnO OBn
H H
derivative of 59 (70). The pentaol 66 was readily converted TFA BnO BnO
+
to its penta-O-benzyl derivative 67 in 76% yield under OBn OBn
HN N
standard conditions. Selective liberation of the secondary BnO BnO
amino and primary hydroxyl groups of 67 was achieved by HO
exposure of 67 to TFA in the presence of anisole, as a 68 (37%) 69 (54%)
cation scavenger, at RT. Surprisingly, this reaction gave a PPh , CBr
3 4
mixture of the desired amino-alcohol 68 (37%) and the
(54%)
indolizidine 69 (54%) (Scheme 23). When this reaction
was performed at 0oC a mixture of 68 and the mono- RO OR
H
deprotected trityl derivative of 67 was obtained. Treatment RO
PdCl , H
of this compound or 68 with TFA/anisole at RT gave only 2 2 OR
a very poor yield (<5% from 1H NMR analysis) of 69 after (63%) RO N
2 days. We suggested that 69 arises by cyclization of an
59, R = H
incipient amide anion A with activation of the O-trityl Ac2O,py 70, R = Ac
group by protonation by TFA, as shown in Scheme 24.

The amino-alcohol 68 underwent smooth cyclization to
give the same indolizidine 69 using Ph3P/CBr4/Et3N Scheme 24
(54%). Debenzylation of 11 under hydrogenolysis condi-
tions using PdCl2/H2 gave 59 in 63% after ion-exchange BnO H OBn
chromatography and then recrystallization in a total of 8 TFA BnO
synthetic steps from L-xylose. The structure of 59 was 67 OBn 69
N
unequivocally established by a single-crystal X-ray study BnO
of its pentaacetate derivative 70. The 1H and 13C NMR O O But
TrO
data for synthetic 59, however did not match with those
reported for uniflorine A; the latter showed many more H A
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