A short, organocatalytic formal synthesis of (-)-swainsonine and related alkaloids

Article abstract of DOI:10.1021/ol400566j

A short synthesis of hydroxyalkyl dihydropyrroles has been developed that involves the coupling of propargylamines with α-chloroaldehydes, followed by Lindlar reduction and a one-pot epoxide formation/opening sequence. The application of this process to the synthesis of unnatural iminosugars and a formal synthesis of (-)-swainsonine is described.

Full text of DOI:10.1021/ol400566j

ORGANIC
LETTERS
2013
Vol. 15, No. 8
1914–1917
A Short, Organocatalytic Formal
Synthesis of (ꢀ)-Swainsonine and Related
Alkaloids
Vijay Dhand, Jason A. Draper, Jarod Moore, and Robert Britton*
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada
rbritton@sfu.ca
Received March 1, 2013
ABSTRACT
A short synthesis of hydroxyalkyl dihydropyrroles has been developed that involves the coupling of propargylamines with R-chloroaldehydes,
followed by Lindlar reduction and a one-pot epoxide formation/opening sequence. The application of this process to the synthesis of unnatural
iminosugars and a formal synthesis of (ꢀ)-swainsonine is described.
Swainsonine (1) is an indolizidine alkaloid that
was originally isolated from the fungal plant pathogen
Rhizoctonia leguminicola and structurally assigned as the
piperidine 2 (Scheme 1).1 Several years later, the correct
structural assignment for 1 was reported following its
reisolation from the Australian flowering plant Swainsona
canescens,2 and it was shown to be the causative agent
of a livestock disease clinically similar to mannosidosis.2
Subsequently, it was found that swainsonine is a potent
inhibitor of lysosomal R-mannosidase3a and Golgi
R-mannosidase II,3b and 1 has been implicated as a lead
candidate for the treatment of a variety of diseases.4 Most
notably, in preclinical models, swainsonine suppressed the
growth of several carcinoma xenografts,5a and GD0039
(the HCl salt of 1) progressed as far as phase II clinical
trials for the treatment of renal cell carcinoma.5b It is not
surprising then that swainsonine has been the subject of
numerous synthetic efforts.6ꢀ9 In fact, swainsonine has
become a classic target for the demonstration of new
synthetic methods and/or strategies relevant to pyrroli-
dine, piperidine, or indolizidine synthesis.7 Presently, more
than 40 syntheses of swainsonine have been reported that
range in length from 8 to >20 steps (average approxi-
mately 14 steps), the most recent of which was a 14-step
synthesis that originates with L-glutamic acid.9s Based on
the importance of swainsonine as a biological tool and
potential therapeutic and the ongoing need for selective
Golgi R-mannosidase II inhibitors,5 we endeavored to
develop a short and flexible synthesis of 1 that does not
rely on chiral pool starting materials. Specifically, our
efforts in the synthesis of trans-epoxides10 and various
heterocycles11 from chlorohydrins suggested that optically
enriched aminoepoxides of general structure 5 should be
readily available and may well serve as precursors to the
pyrrolidine core (e.g., 6) of the indolizidine alkaloids via a
5-exo-tet epoxide opening reaction12 and subsequently
iminosugars following alkene oxidation. Elaboration of
(1) Guengerich, F. P.; DiMari, S. J.; Broquist, H. P. J. Am. Chem.
Soc. 1973, 95, 2055.
(2) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem.
1979, 32, 2257.
(3) (a) Dorling, P. R.; Huxtable, C. R.; Colegate, S. M. Biochem. J.
1980, 191, 649. (b) Elbein, A. D.; Solf, R.; Dorling, P. R.; Vosbeck, K.
Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 7393.
(4) El Nemr, A. Tetrahedron 2000, 56, 8579.
(5) (a) Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin.
Cancer Res. 1995, 1, 935. (b) Shaheen, P. E.; Stadler, W.; Elson, P.; Knox,
J.; Winquist, E.; Bukowski, R. M. Invest. New Drugs 2005, 23, 577.
(6) For early syntheses of swainsonine, see: (a) Ali, M. H.; Hough, L.;
Richardson, A. C. J. Chem. Soc., Chem. Commun. 1984, 7, 447.
(b) Schneider, M. J.; Ungemach, F. S.; Broquist, H. P.; Harris, T. M.
Tetrahedron 1983, 39, 29. (c) Adams, C. E.; Walker, F. J.; Sharpless,
B. K. J. Org. Chem. 1985, 50, 420. (d) Setoi, H.; Takeno, H.; Hashimoto,
M. J. Org. Chem. 1985, 50, 3948.
(7) For reviews of swainsonine syntheses, see: (a) Pyne, S. G. Curr.
Org. Synth. 2005, 2, 39. (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139.
(c) Nemr, A. E. Tetrahedron 2000, 56, 8579.
(8) For a large-scale synthesis of swainsonine, see: Sharma, P. K.;
Shah, R. N.; Carver, J. P. Org. Process Res. Dev. 2008, 12, 831.
r
10.1021/ol400566j
Published on Web 04/03/2013
2013 American Chemical Society

these later substances into swainsonine (1), analogues of 1,
or other inhibitors of carbohydrate-processing enzymes
(e.g., castanospermine (3)13) would then involve a second
annulation event. The development of this methodology,
as well its application in a short formal synthesis of
(ꢀ)-swainsonine (1) and several structurally related alka-
loids, are discussed below.
addition of an alkynyllithium10 derived from propargyla-
mine to an R-chloroaldehyde11e,14 followed by partial
hydrogenation. Toward this goal, R-chloroundecanal (7)
was prepared in good yield from undecanal14b and treated
with the dianion generated from the reaction of propargy-
lamine with 2 equiv of n-BuLi. Although these conditions
provided the desired chlorohydrin (not shown) as a single
stereoisomer, this compound was produced in modest
yield (22%) and proved difficult to isolate and purify by
flash chromatography. In an effort to improve the yield of
this reaction and generate a more tractable product, the
addition of lithium anions derived from a variety of
protected propargylamines to the R-chloroaldehyde 7
was explored. While reaction of the dianion derived from
commercially available N-Boc-propargylamine with 7 af-
forded the chlorohydrin 9 in improved yield (44%), addi-
tion of the monoanion 815 to this aldehyde consistently
provided the desired chlorohydrin 9 in yields >50%.16
Notably, this latter material proved stable to flash chro-
matography and underwent smooth reduction to provide
Scheme 1. Natural Products Swainsonine (1), Castanospermine
(3), and a Synthetic Strategy to Access Dihydropyrroles (e.g., 6)
As depicted in Scheme 2, our initial efforts focused on
defining a concise synthesis of 1,2-anti-chlorohydrins that
incorporate a cis-allylamine functionality. It was antici-
pated that this would be accomplished through the
Scheme 2. Synthesis of 2-Hydroxyalkyldihydropyrrole 12
(9) For syntheses of swainsonine that have been reported since the 2005
review by Pyne (ref 7a), see: (a) Martin, R.; Murruzzu, C.; Pericas, M. A.;
Riera, A. J. Org. Chem. 2005, 70, 2325. (b) Guo, H.; O’Doherty, G. A. Org.
Lett. 2006,8, 1609. (c) Tinarelli, A.; Paolucci, C. J. Org. Chem. 2006, 71, 6630.
(d) Au, C. W. G.; Pyne, S. G. J. Org. Chem. 2006, 71, 7097. (e) Ceccon,
J.; Greene, A. E.; Poisson, J.-F. Org. Lett. 2006, 8, 4739. (f) Dechamps, I.;
Pardo, D. G.; Cossy, J. Tetrahedron 2007, 63, 9082. (g) Kwon, H. Y.; Park,
C. M.; Lee, S. B.; Youn, J.-H.; Kang, S. H. Chem.;Eur. J. 2008, 14, 1023.
(h) Hakansson, A. E.; van Ameijde, J.; Horne, G.; Nash, R. J.; Wormald,
M. R.; Kato, A.; Besra, G. S.; Gurcha, S.; Fleet, G. W. J. Tetrahedron Lett.
2008, 49, 179. (i) Shi, G. F.; Li, J. Q.; Jiang, X. P.; Cheng, Y. Tetrahedron
2008, 64, 5005. (j) Alam, M. A.; Kumar, A.; Vankar, Y. D. Eur. J. Org.
Chem. 2008, 4972. (k) Tian, Y.-S.; Joo, J.-E.; Kong, B.-S.; Pham, V.-T.; Lee,
K.-Y.; Ham, W.-H. J. Org. Chem. 2009, 74, 3962. (l) Bates, R. W.; Dewey,
M. R. Org. Lett. 2009, 11, 3706. (m) Choi, H. G.; Kwon, J. H.; Kim, J. C.;
Lee, W. K.; Eum, H.; Ha, H.-J. Tetrahedron Lett. 2010, 51, 3284. (n)
Chooprayoon, S.; Kuhakarn, C.; Tuchinda, P.; Reutrakul, V.; Pohmakotr,
M. Org. Biomol. Chem. 2011, 9, 531. (o) Louvel, J.; Chemla, F.; Demont, E.;
Ferreira, F.; Perez-Luna, A. Org. Lett. 2011, 13, 6452. (p) Chen, M.-J.; Tsai,
Y.-M. Tetrahedron 2011, 67, 1564. (q) Bates, R. W.; Dewey, M. R.; Tang,
C. H.; Safii, S. b.; Hong, Y.; Hsieh, J. K. H.; Siah, P. S. Synlett 2011, 14,
2053. (r) Wardrop, D. J.; Bowen, E. G. Org. Lett. 2011, 13, 2376. (s)
Archibald, G.; Lin, C. P.; Boyd, P.; Barker, D.; Caprio, V. J. Org. Chem.
2012, 77, 7968.
the desired cis-alkenylchlorohydrin 10 in excellent yield.
After surveying conditions to promote a sequence of
reactions involving deprotection, epoxide formation, and
epoxide opening, we found that treating the alkenylchlor-
ohydrin 10 with aqueous acid effected removal of the Boc
protecting group and that direct basification of the reac-
tion mixture then promoted epoxide formation followed
immediately by epoxide opening, furnishing the dihydro-
pyrrole 12 in excellent overall yield. The relative stereo-
chemistry of the vicinal amino alcohol function in 12 was
confirmed following its conversion to the cyclic carbamate
13 and comparison of spectral data derived from 13 to that
reported for the related dihydropyrrole 14.17
(10) Kang, B.; Britton, R. Org. Lett. 2007, 9, 5083.
(11) (a) Kang, B.; Mowat, J.; Pinter, T.; Britton, R. Org. Lett. 2009,
11, 1717. (b) Draper, J. A.; Britton, R. Org. Lett. 2010, 12, 4034. (c)
Kang, B.; Chang, S.; Decker, S.; Britton, R. Org. Lett. 2010, 12, 1716. (d)
Chang, S.; Britton, R. Org. Lett. 2012, 14, 5844. (e) Britton, R.; Kang, B.
Nat. Prod. Rep. 2013, 30, 227.
(12) For examples of intramolecular epoxide opening reactions that
form 5-membered ring heterocycles, see: (a) Shankaraiah, G.; Kumar,
R. S. C.; Poornima, B.; Babu, K. S. Tetrahedron Lett. 2011, 52, 4885. (b)
White, J. D.; Hrnciar, P. J. Org. Chem. 2000, 65, 9129. (c) Medjahdi, M.;
Gonzalez-Gomez, J. C.; Foubelo, F.; Yus, M. J. Org. Chem. 2009, 74,
7859. (d) Sattely, E. S.; Cortez, G. A.; Moebius, D. C.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 8526.
(13) Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.;
Pryce, R. J.; Arnold, E.; Clardy, J. Phytochemistry 1981, 20, 811.
(14) (a) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2004, 126, 4108. (b) Halland, N.; Braunton, A.; Bachmann,
S.; Marigo, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790. (c)
Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2009, 48, 5121. (d) Dekeukeleire, S.; D’hooghe, M.;
Tornroos, K. W.; De Kimpe, N. J. Org. Chem. 2010, 75, 5934.
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2011, 133, 740.
(16) Reaction of the lithium anion derived fromN,N-bis(trimethylsilyl)-
propargylamine or N,N-bis(Boc)propargylamine with the chloroaldehyde
7 also provided the desired chlorohydrin, albeit in lower (<45%) yield.
Org. Lett., Vol. 15, No. 8, 2013
1915

compound resembles the pyrrolidine 19, which is a selec-
tive inhibitor of R-L-fucosidase.20
Scheme 3. Synthesis of Hydroxyalkyldihydropyrroles 16aꢀd
and the Protected Aminotriols 17a, 17b, and 18
Table 1. Asymmetric R-Chlorination of Aldehyde 20a
entry catalyst (mol %) conditions temp (°C) yield (%) eeb (%)
1
2
3
4
5
L-proline (20)
L-prolinamide (20)
22 (20)
A
0 to rt
0 to rt
0 to rt
ꢀ25
49
58
61
62
75
0
62
30
58
82
Ac
Bd
Be
Bf
22 (20)
22 (20)
ꢀ35
a Conditions: (A) NCS, CH2Cl2, 4 h; (B) Cu(TFA)2, LiCl, Na2S2O8,
H2O, MeCN. b Determined by chiral HPLC analysis (see the Supporting
Information for details). c 24 h. d 4 h. e 3 days. f 19 days.
Having establisheda four-step synthesisof hydroxyalkyl
dihydropyrroles, we focused on applying this process to a
short synthesis of swainsonine (1). For this purpose, it was
envisaged that a second annulation event involving dis-
placement of a primary alkyl chloride would secure the
indolizidine core of 1.21 Toward this end, L-prolinamide-
catalyzed chlorination of 5-chloropentanal (20)22 using
the procedure reported by Jørgensen14b provided the
dichloroaldehyde 21 in modest yield and enantioselectivity
(Table 1, entry 2). For comparison purposes, using iden-
tical reaction conditions the chlorination of pentanal is
complete in 4 h (>97% yield) and proceeds with much
higher enantioselectivity (85% ee).10 Unfortunately, when
repeated at 0 °C, the extended reaction time corresponded
with an erosion in enantioselectivity, presumably through
prolinamide-catalyzed racemization of the chloroaldehyde
21. Considering these challenges, we next explored the use
of MacMillan’s SOMO-activated aldehyde R-chlorination
procedure,14c as the imidazolidinone catalyst 22 does not
effect racemization of chloroaldehyde products.14c Unfor-
tunately, using these conditions (entry 3), the R-chloroal-
dehyde 21 was prepared in only modest optical purity
(30% ee). At lower temperatures, the reaction rate de-
creased substantially (e.g., entries 4 and 5); however,
racemization of the chloroaldehyde product was not ob-
served. Ultimately, chlorination at ꢀ35 °C afforded the
desired R-chloroaldehyde 21 in good yield and enantio-
selectivity (82% ee).
Asdepicted inScheme 3, thisstrategyfordihydropyrrole
synthesis was further explored through the preparation of
compounds 16aꢀd. Toward this end, the alkynyl chloro-
hydrins 15aꢀd were synthesized following addition of the
requisite Boc-protected propargylamine to 2-chloropenta-
nal or 2-chlorohydrocinnamaldehyde.14b,18 Pleasingly,
Lindlar reduction of the alkynylchlorohydrins followed
by direct treatment of the crude reduction products with
aqueous acid then base (a one-pot procedure) afforded
hydroxyalkyldihydropyrroles 16aꢀd in good overall
yield.19 Considering the brevity of the entire reaction
sequence (four steps), this strategy should serve as an
efficient means to access a wide variety of natural and
unnatural iminosugars. For example, the dihydropyrroles
16c and 16d were converted into the protected iminosugar
analogues 17a/17b and 18, respectively, via reaction with
phosgenefollowed by dihydroxylation. Therelativestereo-
chemistry of these new iminosugars was assigned based on
analysis of 1D NOESY spectra (see the Supporting In-
formation for details). Structurally, this latter spirocyclic
(20) Laroche, C.; Behr, J.-B.; Szymoniak, J.; Bertus, P.; Schutz, C.;
Vogel, P.; Plantier-Royon, R. Bioorg. Med. Chem. 2006, 14, 4047.
(21) (a) Dudot, B.; Micouin, L.; Baussanne, I.; Royer, J. Synthesis
1999, 4, 688. (b) St-Denis, Y.; Chan, T. H. J. Org. Chem. 1992, 57, 3078.
(c) Dieter, R. K.; Chen, N.; Watson, R. T. Tetrahedron 2005, 61, 3221.
(d) Dieter, R. K..; Lu, K. J. Org. Chem. 2002, 67, 847.
(22) 5-Chloropentanal is available from the oxidation of 5-chloro-1-
pentanol; see: Brodfuehrer, P. R.; Chen, B.-C.; Sattelberg, T. R.; Smith,
P. R.; Reddy, J. P.; Stark, D. R.; Quinlan, S. L.; Reid, J. G.; Thottathil,
J. K.; Wang, S. J. Org. Chem. 1997, 62, 9192.
(17) Key 1H NMR data for compounds 13 (CDCl3, 600 MHz) and 14
(CDCl3, 300 MHz). H10: δ 4.72 (13), δ 4.70 (14); H2: δ 4.72 (13), δ 4.70
(14); H5R: δ 3.75 (13), δ 3.75 (14); H5β: δ 4.42 (13), δ 4.39 (14). For
spectral data for compound 14, see: Lindsay, K. B.; Pyne, S. G. Aust. J.
Chem. 2004, 57, 669.
(18) See the Supporting Information for details.
(19) The lower overall yields for 16a and 16c reflect difficulties
associated with the isolation and purification of these substances rather
than the efficiency of the reaction sequence.
1916
Org. Lett., Vol. 15, No. 8, 2013

(<10%) of 29. As expected,23 dihydroxylation of the
indolizidine 27 provided an inseparable mixture of trihy-
droxyindolizidines 1 and 30, in which (ꢀ)-swainsonine (1)
was the major component (dr = 3:2). To improve the facial
selectivity of the dihydroxylation, the unprotected indolizi-
dine 27 was also converted into the corresponding TBS ether
28, which undergoes selective dihydroxylation (dr ∼8:1) to
provide swainsonine (1) following deprotection.24 The spec-
tral data (1H NMR, 13C NMR, MS, IR, [R]D) recorded on
the TBS ether 28 were in agreement with that reported
for this material by Pyne.9d Notably, preparation of the
indolizidine 27 in five steps from commerically available
5-chloropentanol constitutes a six-step formal synthesis of
(ꢀ)-swainsonine, the shortest of all reported routes.
Scheme 4. Formal Synthesis of (ꢀ)-Swainsonine (1)
In summary, we have developed a concise asymmetric
synthesis of hydroxyalkyldihydropyrroles and demon-
strated the utility of this process in a formal synthesis of
the R-mannosidase inhibitor swainsonine (1). While there
are more than 40 reported syntheses of swainsonine ran-
ging in length from 8 to over 20 steps (average length of 14
steps) our unique approach provides access to this poten-
tially important natural product in six steps from 5-chlor-
opentanol, does not rely on chiral pool starting materials,
and employs an organocatalytic asymmetric R-chlorina-
tion as the basis for the controlled introduction of each
stereogenic center. Based on its operational simplicity and
reliance on readily available starting materials, this pro-
cess should be adaptable to the production of a range of
indolizidine, pyrrolidine, and pyrrolizidine natural pro-
ducts, efforts that are currently ongoing in our laboratory.
With the R-chloroaldehyde 21 in hand, treatment of this
material with the lithium anion derived from the protected
propargylamine 8 afforded the 1,2-anti-chlorohydrin 23 in
good yield and diastereoselectivity (dr >20:1) (Scheme 4).
Initial attemptstoeffectdihydropyrroleformation from23
through the sequence of reactions described in Scheme 3
afforded 29 as the major product. After some experimenta-
tion, however, it was found that when both the equivalents
and rate of addition of NaOH to the alkenylchlorohydrin 25
were strictly controlled, formation of the undesired tetra-
hydrofuran 29 could be largely avoided. Thus, slow addition
of 3 equivalents of aqueous NaOH to 25 in MeOH repro-
ducibly afforded the indolizidine 27 in good yield (54% over
three steps from 23) accompanied by minor amounts
Acknowledgment. This work was supported by an
NSERC Discovery Grant to R.B., a Michael Smith Foun-
dation for Health Research Career Investigator Award to
R.B., and Graduate Fellowships to V.D., J.A.D., and J.M.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(24) (a) Buschmann, N.; Ruckert, A.; Blechert, S. J. Org. Chem. 2002,
67, 4325. (b) Mukai, C.; Sugimoto, Y.; Miyazawa, K.; Yamaguchi, S.;
Hanaoka, M. J. Org. Chem. 1998, 63, 6281.
(23) De Vicente, J.; Arrayas, R. G.; Canada, J.; Carretero, J. C.
Synlett 2000, 1, 53.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
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