Asymmetric synthesis of anti-1,2-amino alcohols via the borono-Mannich reaction: A formal synthesis of (-)-swainsonine

Article abstract of DOI:10.1021/jo0610661

Chiral α-hydroxy aldehydes generated in situ by the ADH reaction of vinyl sulfones undergo a borono-Mannich reaction with β-styrenyl boronic acid and primary amines to give anti-1,2-amino alcohols in high enantiomeric purities (83-95% ee). This new method allows much more rapid access to these valuable chiral building blocks that has been used in a short formal synthesis (10 synthetic steps from 4-penten-1-ol) of (-)-swainsonine.

Full text of DOI:10.1021/jo0610661

SCHEME 1
Asymmetric Synthesis of anti-1,2-Amino Alcohols
via the Borono-Mannich Reaction: A Formal
Synthesis of (-)-Swainsonine
Christopher W. G. Au and Stephen G. Pyne*
Department of Chemistry, UniVersity of Wollongong,
Wollongong, New South Wales 2522, Australia
spyne@uow.edu.au
SCHEME 2
ReceiVed May 24, 2006
Chiral R-hydroxy aldehydes generated in situ by the ADH
reaction of vinyl sulfones undergo a borono-Mannich reaction
with â-styrenyl boronic acid and primary amines to give anti-
1,2-amino alcohols in high enantiomeric purities (83-95%
ee). This new method allows much more rapid access to these
valuable chiral building blocks that has been used in a short
formal synthesis (10 synthetic steps from 4-penten-1-ol) of
(-)-swainsonine.
The (E)-vinyl sulfones 1a,b were readily prepared from their
corresponding terminal alkenes either via cross metathesis with
phenyl vinyl sulfone (E:Z ) >99:<1)5 (Scheme 1) or by iodo-
sulfonation followed by elimination of HI (E:Z ) 98:2; see
Supporting Information).6 Treatment of vinyl sulfone 1a with
either ADmixR or ADmixâ, under the conditions described by
Evans,2 gave, after extraction into EtOAc and evaporation, mate-
rial that showed no characteristic downfield aldehyde 1H NMR
resonances, more consistent with a mixture of acetal-like
structures. This material was then treated with â-styrenyl boronic
acid (1.00 molar equiv relative to 1a) and allylamine (1.06 molar
equiv relative to 1a) in CH2Cl2 (DCM) at room temperature
for 40 h to give the anti-1,2-amino alcohol dienes 2a (R2 )
allyl) and 3a (R2 ) allyl), respectively (Scheme 2 and Table 1,
entries 1 and 2). These compounds were isolated as single
diastereomers in 44 and 51% overall yields for the two-step
sequence, respectively, from 1a. The isomeric syn-1,2-amino
alcohol dienes could not be detected. The enantiomeric purities
In 1998, Petasis reported the synthesis of anti-1,2-amino
alcohols from a borono-Mannich reaction of aryl or vinyl
boronic acids, with primary or secondary amines and chiral
R-hydroxy aldehydes.1 The latter were generally derived from
carbohydrates which limited the generality of this reaction
because enantiomerically enriched chiral R-hydroxy aldehydes
were not generally available. A more recent paper by Evans,2
however, showed that these valuable substrates could be
prepared in situ from the Sharpless asymmetric dihydroxylation
(ADH) reaction of vinyl sulfones (Scheme 1). We report here
that chiral R-hydroxy aldehydes generated in situ by this method
undergo the borono-Mannich reaction with â-styrenyl boronic
acid and primary amines to give anti-1,2-amino alcohols in high
enantiomeric purities. This new method allows much more rapid
access to these valuable chiral building blocks. More specifi-
cally, the derived anti-1,2-amino alcohol diene products,
obtained using allylamine, are valuable precursors for alkaloid
synthesis,3 as further demonstrated here by a short, formal
synthesis of the important natural product (-)-swainsonine.4
(3) (a) Pyne, S. G.; Davis, A. S.; Gates, N. J.; Hartley, J. P.; Lindsay, K.
B.; Machan, T.; Tang, M. Synlett 2004, 2670-2680. (b) Davis, A. S.; Pyne,
S. G.; Skelton, B. W.; White, A. H. J. Org. Chem. 2004, 69, 3139-3143.
(c) Lindsay, K. B.; Pyne, S. G. Aust. J. Chem. 2004, 57, 669-672. (d)
Tang, M.; Pyne, S. G. Tetrahedron 2004, 60, 5759-5767. (e) Tang, M.;
Pyne, S. G. J. Org. Chem. 2003, 68, 7818-7828. (f) Lindsay, K. B.; Tang,
M.; Pyne, S. G. Synlett 2002, 731-734. (g) Lindsay, K. B.; Pyne, S. G. J.
Org. Chem. 2002, 67, 7774-7780.
(4) For reviews, see: (a) Nemr, A. E. Tetrahedron 2000, 56, 8579-
8629. (b) Pyne, S. G. Curr. Org. Synth. 2005, 2, 39-57. (c) For a recent
synthesis, see: Guo, H.; O’Doherty, G. A. Org. Lett. 2006, 8, 1609-1612.
(5) (a) Gela, K.; Bieniek, M. Tetrahedron Lett. 2001, 42, 6425-6428.
(b) Michrowska, A.; Bieniek, M.; Kim, M.; Klajn, R.; Grela, K. Tetrahedron
2003, 59, 4525-4531.
(6) (a) Nair, V.; Augustine, A.; Suja, T. D. Synthesis 2002, 15, 2559-
2265. (b) Rasset-Delong, C.; Martinez-Fresneda, P.; Vaultier, M. Bull. Chim.
Fr. 1992, 129, 285-290.
(1) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798-
11799.
(2) Evans, P.; Leffray, M. Tetrahedron 2003, 59, 7973-7981.
10.1021/jo0610661 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/29/2006
J. Org. Chem. 2006, 71, 7097-7099
7097

TABLE 1. Synthesis of 2 and 3 (Scheme 2)
SCHEME 3
vinyl
sulfone
overall yield
entry
AD mix
amine R2
(%) from 1a
ee (%)b
1
2
3
4
5
6
1a
1a
1a
1a
1b
1b
R
â
R
â
R
â
allyl
allyl
PMB
PMB
allyl
allyl
44
51
46
43
35
38
91
94
91
95
83
93
SCHEME 4
a Yield of 2 or 3 after purification by column chromatography. b Deter-
mined by 19F NMR spectroscopy on the corresponding Mosher ester.
of these products were high, 91 and 94%, respectively, as
determined by 19F NMR spectroscopic analysis of their corre-
sponding Mosher esters (see Supporting Information). When
these reactions were repeated using 4-methoxybenzylamine
(PMBNH2), the anti-1,2-amino alcohol dienes 2a (R2 ) PMB)
and 3a (R2 ) PMB) were isolated as single diastereomers in
46 and 43% overall yields and had enantiomeric purities of 91
and 95%, respectively (Scheme 2 and Table 1, entries 3 and
4).
SCHEME 5a
When this sequence of reactions was performed starting with
vinyl sulfone 1a and using the secondary amine, morpholine,
and the aromatic amine, 4-methoxyaniline (PMPNH2), the
overall yields were disappointing. The morpholine-derived anti-
1,2-amino alcohol product was obtained as a single diastereomer
in only 12% yield (ee not determined), while none of the adduct
2a (R2 ) PMP) could be isolated.
Treatment of the TBDPS-protected vinyl sulfone 1b with
either ADmixR or ADmixâ followed by treatment of the crude
oxidation product with â-styrenyl boronic acid and allylamine
gave the anti-1,2-amino alcohol dienes 2b (R2 ) allyl) and 3b
(R2 ) allyl), respectively (Scheme 2 and Table 1, entries 5 and
6) in overall yields of 35 and 38%, respectively, for the two-
step sequence. The enantiomeric purities of these products,
however, were significantly different, with enantiomeric ex-
cesses determined as 83 and 93%, respectively.
a Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 2.5
h, 70%; (b) KOH, MeOH, reflux, 7 h, 60%; (c) Ph3P, CBr4, Et3N, CH2Cl2,
0 °C, 2 h, 71%; (d) Ti(Oi-Pr)4, Grubbs II catalyst, CH2Cl2, reflux, 2.5 h,
80%.
While, in general, the overall yields of 2 and 3 were only
modest, the overall brevity of their synthesis (total of three steps)
compares more than favorably with previously published
methods for these anti-1,2-amino alcohol dienes (R2 ) allyl)
that involve the ring opening of vinyl epoxides with allylamine,
where the former substrates requires six synthetic steps from
commercially available starting materials.3a,7,8 Furthermore, these
yields are based on 1.0 equiv of 1 and 1.0 equiv of â-styrenyl
boronic acid.9 These modest yields most likely reflect the
instability of the R-hydroxy aldehyde or their acetal-like
intermediates; however, the high enantiomeric excesses of the
product 1,2-amino alcohols indicate that racemization of these
intermediates is not a major problem.
1
coupling constant, J4,5, in the H NMR spectrum of 4 was
consistent with the 4,5-cis relative stereochemistry.3g,7
While the exact mechanism of the borono-Mannich reaction
is not known, we speculate that these reactions occur via the
boronate complex intermediate A (Scheme 4), in which the
iminium ion adopts the reactive conformation shown to mini-
mize 1,3-allylic strain.
To demonstrate the utility of these substrates further, the anti-
1,2-amino alcohol diene 3b (R2 ) allyl) was converted in four
steps to the known indolizidine 810,11 as shown in Scheme 5.
Protection of the secondary hydroxyl of 3b (R2 ) allyl) as its
TBS ether and then deprotection of the primary TBDPS ether
under basic conditions11 gave the amino alcohol 6. Cyclization
of this compound by intramolecular N-alkylation (Ph3P, CBr4,
Et3N)3g,13 gave the piperidine derivative 7 in 71% yield (Scheme
3). The ring-closing metathesis of 7, employing Ti(Oi-Pr)4 as a
To verify the relative stereochemistry of 3a (R2 ) allyl), it
was converted to the oxazolidinone 4 (Scheme 3) by treatment
with triphosgene under basic conditions. The 9.3 Hz vicinal
(7) (a)Lindstrom, U. M.; Franckowiak, R.; Pinault, N.; Somfai, P.
Tetrahedron Lett. 1997, 38, 2027-2030. (b) Lindstrom, U. M.; Somfai, P.
Synthesis 1998, 109-117.
(8) An alternative and direct synthesis of anti-1,2-amino alcohols, from
the addition of chiral imino-allylboranes to aldehydes, has also been reported.
These products, in principle, could also be converted to similar anti-1,2-
amino alcohol dienes. See: Barrett, A. G. M.; Seefeld, M. A.; Williams,
D. J. J. Chem. Soc., Chem. Commun. 1994, 1053-1054.
(10) Buschmann, N.; Ru¨ckert, A.; Blechert, S. J. Org. Chem. 2002, 67,
4325-4329.
(11) Mukai, C.; Sugimoto, Y.-i.; Miyazawa, K.; Yamaguchi, S.; Hanaoka,
M. J. Org. Chem. 1998, 63, 6281-6287.
(9) Often organo-catalyzed Mannich reactions require an excess amount
of the aldehyde or ketone donor. See: Seayad, J.; List, B. Org. Biomol.
Chem. 2005, 3, 719-724 and references cited therein.
(12) Hatakeyama, S.; Irie, H.; Shintani, T.; Noguchi, Y.; Yamada, H.;
Nishizawa, M. Tetrahedron 1994, 50, 13369-13376.
7098 J. Org. Chem., Vol. 71, No. 18, 2006

1.69 (2H, quint., J ) 6.8 Hz), 1.03 (9H, s). 13C NMR (CDCl3, 125
MHz): δ 146.7, 140.6, 135.4, 133.5, 133.1, 129.6, 129.5, 129.1,
127.6, 127.5, 62.5, 30.3, 27.9, 26.8, 19.1. MS (ES+) m/z 465 ([M
+ 1]+), HRMS found 465.1916, calcd for C27H33O3SSi 465.1920
([M + 1]+).
Lewis acid to protect the amino group in situ by complexation,14
provided the silica gel sensitive indolizidine 8 ([R]26D -72°, c
0.65, benzene) in 80% yield after purification on basic alumina.
This compound has been prepared previously in >99% ee
([R]20D -91.73°, c 0.955, benzene)10,15 and in racemic form and
converted to (-)-9 and (()-swainsonine,12 respectively. Thus
our synthesis of 8 represents a formal asymmetric synthesis of
(-)-swainsonine 9 in 10 steps from commercially available
4-penten-1-ol. This number of steps compares more than
favorably with earlier syntheses of 9 that typically involve 10
or more steps.4
In conclusion, chiral R-hydroxy aldehydes generated in situ
by the ADH reaction of vinyl sulfones undergo the borono-
Mannich reaction with â-styrenyl boronic acid and primary
amines to give anti-1,2-amino alcohols in high enantiomeric
purities (83-95%). This new method allows a much more rapid
access to these valuable chiral building blocks that have been
used in a formal synthesis of (-)-swainsonine in 10 synthetic
steps.
(3S,4R,E)-3-(Allylamino)-7-(tert-butyldiphenylsilyloxy)-1-phen-
ylhept-1-en-4-ol (3b). To a round-bottom flask containing an
solution of AD-mix-â (5.3 g) and MeSO2NH2 (0.16 g, 1.68 mmol)
in water (9 mL) was added a solution of vinyl sulfone 1b (0.406 g,
0.874 mmol) in t-BuOH (9 mL). Additional AD-mix-â (1.6 g) and
MeSO2NH2 (0.040 g, 0.420 mmol) were added after 6 h, and the
reaction mixture was stirred at room temperature for a total of 24
h and then diluted with water, followed by extraction with EtOAc
(3 × 20 mL). The combined organic layers were dried (MgSO4)
and concentrated in vacuo to afford a brown oil. A solution of the
crude product in dry DCM (5 mL) was purged with nitrogen, and
then allylamine (0.07 mL, 0.053 g, 0.927 mmol) and (E)-2-
phenylvinylboronic acid (0.125 g, 0.847 mmol) were added. The
reaction mixture was stirred at room temperature for 40 h. The
reaction mixture was partitioned between 5% aqueous NaOH (20
mL) and EtOAc (20 mL). The organic layer was washed with brine
(2 × 20 mL), dried (MgSO4), and concentrated in vacuo to give a
brown oil. Flash column chromatography (increasing polarity 2-4%
Experimental Section
MeOH in DCM as eluent) afforded the â-amino alcohol 3b (0.164
1
g, 38%, over two steps). [R]24 +7.5° (c 1.08, CHCl3). H NMR
((E)-5-(Phenylsulfonyl)pent-4-enyloxy)(tert-butyl)diphenyl-
silane (1b). To an argon-flushed 50 mL round-bottom flask
containing phenyl vinyl sulfone (0.204 g, 1.213 mmol) were added
tert-butyl(pent-4-enyloxy)diphenylsilane (0.202 g, 0.622 mmol) and
distilled CH2Cl2 (15 mL). The content of the round-bottom flask
was then transferred via syringe to a argon-flushed 100 mL two-
neck round-bottom flask containing a solution of Grubbs II catalyst
(0.028 g, 0.033 mmol, 5.33 mol %) in CH2Cl2 (5 mL). The reaction
mixture was stirred under argon and heated at reflux for 18 h and
then concentrated in vacuo to give a brown oil. Flash column
chromatography (increasing polarity from 1:10:2 to 1:5:2 Et2O:
pet. sp.:CH2Cl2 as eluent) gave the title compound (0.263 g, 0.565
D
(CDCl3, 300 MHz): δ 7.66-7.62 (4H, m), 7.42-7.26 (11H, m),
6.50 (1H, d, J ) 15.4 Hz), 6.14 (1H, dd, J ) 8.8, 15.4 Hz), 5.91
(1H, ddt, J ) 5.9, 10.3, 17.0 Hz), 5.20 (1H, d, J ) 17.0 Hz), 5.12
(1H, d, J ) 10.3 Hz), 3.75 (1H, dt, J ) 3.8, 8.5 Hz), 3.67 (2H, t,
J ) 5.9 Hz), 3.39-3.15 (3H, m), 2.40 (2H, br s), 1.88-1.4 (4H,
m), 1.01 (9H, s). 13C NMR (CDCl3, 75 MHz): δ 136.3, 135.5,
133.8, 129.5, 128.5, 127.6, 127.2, 126.4, 116.3, 72.4, 64.7, 63.9,
49.5, 29.9, 29.0, 29.8, 19.1. MS (ES+) m/z 500 ([M + 1]+), HRMS
(ES+) found 500.2987, calcd for C32H42NO2Si 500.2985 ([M +
1]+). The enantiomeric purity of this compound was determined
to be 93% from 19F NMR analysis of its Mosher ester (see
Supporting Information).
1
mmol, 90.8%) as a yellow oil. H NMR (CDCl3, 500 MHz): δ
7.90-7.35 (15H, m), 7.00 (1H, dt, J ) 6.3, 15.0 Hz), 6.30 (1H, d,
J ) 15.1 Hz), 3.65 (2H, t, J ) 6.3 Hz), 2.36 (2H, q, J ) 7.8 Hz),
Acknowledgment. We thank the Australian Research Coun-
cil and the University of Wollongong for financial support.
(13) (a) Mulzer, J.; Dehmlow, H. J. Org. Chem. 1992, 57, 3194-3202.
(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-
2997. (c) Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1994, 59,
1538-1364.
(14) Yang, Q.; Xiao, W.-J.; Yu, Z. Org. Lett. 2005, 7, 871-874.
(15) We attribute the difference in the specific rotation of 8 and the
literature value10 to the relative small scale of our reactions and the sensitive
nature of the product.
Supporting Information Available: Full experimental details,
characterization data, and NMR assignments for all compounds.
1
Copies of the H and 13C NMR spectra of 1a,b, 2a,b, 3a,b, 4-8,
and copies of the 1H and 19F NMR spectra of the Mosher esters of
2a,b and 3a,b in CDCl3 solution. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0610661
J. Org. Chem, Vol. 71, No. 18, 2006 7099