4,5-erythro/5,6-threo-Stereoselectivity in vinylogous Mukaiyama aldol addition of a silyloxypyrrole to a threose derivative: stereochemical rationalization and relevance to (+)-castanospermine synthesis

Article abstract of DOI:10.1016/j.tetlet.2007.02.100

Vinylogous Mukaiyama aldol addition of N-p-methoxybenzyl-4-methoxy-2-trimethylsilyloxypyrrole 7 to bis-MOM threose 6 using SnCl₄ as promoter gave the 4,5-erythro/5,6-threo adduct 8, with the correct absolute configurations for the castanospermi

Full text of DOI:10.1016/j.tetlet.2007.02.100

Tetrahedron Letters 48 (2007) 2819–2822
4,5-erythro/5,6-threo-Stereoselectivity in vinylogous Mukaiyama
aldol addition of a silyloxypyrrole to a threose derivative:
stereochemical rationalization and relevance
to (+)-castanospermine synthesis
Roger Hunter,* Sophie C. M. Rees-Jones and Hong Su
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Received 15 January 2007; revised 15 February 2007; accepted 22 February 2007
Available online 25 February 2007
Abstract—Vinylogous Mukaiyama aldol addition of N-p-methoxybenzyl-4-methoxy-2-trimethylsilyloxypyrrole 7 to bis-MOM
threose 6 using SnCl4 as promoter gave the 4,5-erythro/5,6-threo adduct 8, with the correct absolute configurations for the castano-
spermine framework as determined by a single-crystal X-ray structure. A transition-state model is presented to rationalize
the stereoselectivity.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Lewis-acid promoted vinylogous Mukaiyama aldol
reactions using silyloxypyrroles have developed into a
powerful asymmetric methodology for rapid access to
a variety of natural-product skeletons1 including those
of alkaloids.2 Of note is the seminal work carried out
by Casiraghi’s group, who have elegantly demonstrated
the application of N-Boc-2-(tert-butyldimethylsilyl-
oxy)pyrrole (TBSOP) 1 to asymmetric synthesis.3 In
the case of a substrate-controlled addition to a chiral
aldehyde such as Mukaiyama’s acetonide4 2 (see Scheme
1), four possible diastereomeric products are possible,
and Casiraghi et al. has demonstrated5 that the 4,5-
threo/5,6-erythro product 3 can be selectively accessed
in high yield by reaction of 1 with 2 using SnCl4 as a
promoter, Scheme 1. Similarly, reaction between 1 and
O-isopropylidene-D-glyceraldehyde using BF3ÆOEt2 as
promoter reversed the 4,5-diastereoselectivity to afford
the corresponding 4,5-erythro/5,6-erythro adduct.6
To date there is no efficient method for accessing the
other two diastereomers. In particular, realization of
the 4,5-erythro/5,6-threo stereomotif (or 7,8-threo/8,8a-
erythro using castanospermine numbering) would
provide rapid accesss to the framework of the potently
bioactive indolizidine7 alkaloid (+)-castanospermine;8
indeed such a convergent approach has eluded several
workers,5,9 Figure 1.
We have recently reported10 the application of N-benz-
yl-5-allyl-4-methoxy-2-trimethylsilyloxypyrrole to syn-
thesize the lepadiformine tricyclic core, and it seemed
attractive to us to investigate the application of the
OH
O
H
O
5
O
O
6
H
4
a
RCHO=
1
OTBS
N
N
O
Boc
Bo
OBn
O
2
1
3
OBn
4,5-threo/5,6-erythro
Scheme 1. Reagents and conditions: (a) RCHO, SnCl4 (1.2 equiv), ether, À85 ꢁC.
Keywords: Silyloxypyrrole; Vinylogous Mukaiyama aldol; Castanospermine.
*
Corresponding author. Tel.: +27 21 650 2544; fax: +27 21 689 7499; e-mail addresses: Roger.Hunter@uct.ac.za; roger@science.uct.ac.za
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.100

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R. Hunter et al. / Tetrahedron Letters 48 (2007) 2819–2822
Mukaiyama and Casiraghi in their work, in order to
OH
OH
H
probe stereoselectivity aspects. Thus, the acetonide pro-
tecting group was replaced by two MOM groups, which
were introduced using P2O5 and dimethoxymethane.
The benzyl group was also changed to TBDPS for
chemoselectivity reasons. Scheme 3 depicts the four-step
sequence to afford aldehyde 6.
HO
HO
8
1
8a
7
4 N
Castanospermine
Figure 1. Structure of (+)-castanospermine.
In keeping with our work on lepadiformine, we decided
to use the one-pot-strategy for preparing the silyloxy-
pyrrole involving the TMS dienol silyl ether rather than
the TBS version used by Casiraghi. Thus, pyrrolinone 5
was treated with n-BuLi (1.5 equiv) at À78 ꢁC for 30 min
to generate the dienolate, which was silylated in situ
with excess TMSCl (3 equiv) to generate silyloxypyrrole
7. Thereafter, aldehyde 6 was added followed by SnCl4
(2 equiv) and the reaction allowed to warm to À20 ꢁC
over a number of hours before being quenched, Scheme
4. Rapid stirring of the final reaction solution at low
temperature was found to be crucial for producing a
good result that avoided aggregation. To our delight,
chromatographic purification furnished a major product
813 in around 60–65% isolated yield (over several runs)
that was crystalline. NMR spectroscopy revealed it to
deallylated analogue to access the appropriate stereo-
motif of the castanospermine core. Of particular interest
was the potential influence of the C-4 methoxy group
on the diastereoselectivity of the vinylogous Mukai-
yama11 reaction as well as providing a functional-group
platform for castanospermine C-1 hydroxyl group
installation. In this Letter, we report on this chemistry
as providing a solution to constructing the castanosper-
mine indolizine precursor with correct configurations at
carbons 8 and 8a.
The pyrrolinone precursor 5 to our silyloxypyrrole was
readily available by condensing benzylamine or p-meth-
oxybenzylamine with commercially available enoate
ester 4, according to a known procedure.12 In our hands,
adding Hunig’s base to the condensation reaction helped
¨
us to improve yields. Compound 4 was also available in
a one-step reaction12 from ethyl 4-chloroacetoacetate,
Scheme 2.
For the tartrate-derived threose derivative, we decided
to make changes to the acetonide 2 used extensively by
MeO
MeO
Cl
a
CO2Et
O
N
4
5
PMB
Scheme 2. Reagents and conditions: (a) p-methoxybenzylamine,
EtN(i-Pr)2, CH3CN, D, (67%).
Figure 2. X-ray crystal structure15 of 8.
O
HO
HO
CO2Et
CO2Et
MOMO
MOMO
H
a - d
Cl4Sn
α
Cl4Sn
H
β
O
OMOM
CH2OTBDPS
H
O
O
H
MOMO
6
BnO
O
α
Scheme 3. Reagents and conditions: (a) P2O5, (MeO)2CH2, CH2Cl2,
(96%); (b) LiAlH4, THF, À20 ꢁC, (78%); (c) (i) n-BuLi (1.1 equiv),
THF, 0 ꢁC; (ii) TBDPSCl (94% for two steps); (d) Swern oxidation
(92%).
TBDPSO
H
H
Re preferred
2
6
H
Si preferred
Figure 3. Facial selectivities for aldehydes 2 and 6.
OH
OMe
H
MeO
MeO
MOMO
5
c, d
a, b
4
6
1
N
OTMS
O
N
N
MOMO
PMB
OTBDPS
PMB
O
PMB
5
7 not isolated
8
Scheme 4. Reagents and conditions: (a) n-BuLi (1.5 equiv), THF, À78 ꢁC; (b) TMSCl (3 equiv), À78 ꢁC; (c) aldehyde (0.7 equiv) 6, À78 ꢁC; (d) SnCl4
(2 equiv), À78 ꢁC to À20 ꢁC (60–65% overall based on the aldehyde).

R. Hunter et al. / Tetrahedron Letters 48 (2007) 2819–2822
2821
R1
6
Cl4Sn
O
O
H
H
O
O
O
R= MOM
R1= CH(OMOM)CH2OTBDPS
OTMS
N
R
2
BnO
PMB
OTBS
Sn
Cl4
N
O
MeO
7
O
1
Casiraghi
Hunter
Figure 4. Transition-state models for formation of adducts 3 and 8.
J. Org. Chem. 2006, 71, 225–230; (b) Battistini, L.; Curti,
C.; Zanardi, F.; Rassu, G.; Auzzas, L.; Casiraghi, G. J.
Org. Chem. 2004, 69, 2611–2613; (c) Brimble, M. A.;
Burgess, C.; Halim, R.; Petersson, M.; Ray, J. Tetrahedron
2004, 60, 5751–5758; (d) DeGoey, D. A.; Chen, H.-J.;
Flosi, W. J.; Grampovnik, D. J.; Yeung, C. M.; Klein, L.
L.; Kempf, D. J. J. Org. Chem. 2002, 67, 5445–5453; (e)
Arroyo, Y.; de Paz, M.; Rodriguez, J. F.; Sanz-Tejedor,
M. A.; Ruano, J. L. G. J. Org. Chem. 2002, 67, 5638–5643;
(f) Li, W.-R.; Lin, S. T.; Hsu, N.-M.; Chern, M.-S. J. Org.
Chem. 2002, 67, 4702–4706; (g) Jacobi, P. A.; DeSimone,
R. W.; Ghosh, I.; Guo, J.; Leung, S. H.; Pippin, D. J. Org.
Chem. 2000, 65, 8478–8489; (h) Pichon, M.; Jullian, J.-C.;
Figadere, B.; Cave, A. Tetrahedron Lett. 1998, 39, 1755–
1758; (i) Uno, H.; Baldwin, J. E.; Russell, A. T. J. Am.
Chem. Soc. 1994, 116, 2139–2140.
be a single diastereomer, with the H-4/H-5 coupling
constant (see Scheme 1 for numbering) being around
2 Hz indicating14 erythro relative stereochemistry in con-
trast to the threo-stereochemistry obtained by Casiraghi
for 3 (Scheme 1). In order to establish the absolute ste-
reochemistry, a single crystal X-ray determination15 was
carried out to reveal 4S,5R-configurations for 8 and,
importantly, to establish four of the contiguous chiral
centres for (+)-castanospermine, Figure 2.
Analysis of facial selectivities for producing Casiraghi’s
adduct 3 and our adduct 8 reveal the following. Overall,
the reaction proceeds via ald (Si)/pyr (Si) for 3 versus
ald (Re)/pyr (Si) for 8. The aldehyde facial selectivities
may be rationalized using a Felkin–Anh chelate for
both, except that acetonide 2 used by Casiraghi (see
Scheme 1) uses a b-chelate as proposed by Mukaiyama,4
whereas our case involving 6 (Scheme 3) proceeds via an
a-chelate.16 Figure 3 summarizes these features.
2. (a) Langlois, N.; Le Nguyen, B. K.; Retailleau, P.; Tarnus,
C.; Salomon, E. Tetrahedron: Asymmetry 2006, 17, 53–60;
(b) Rassu, G.; Carta, P.; Pinna, L.; Battistini, L.; Zanardi,
F.; Acquotti, D.; Casiraghi, G. Eur. J. Org. Chem. 1999, 6,
1395–1400; (c) Dudot, B.; Micouin, L.; Baussanne, I.;
Royer, J. Synthesis 1999, 688–694.
Facial selectivities14,17 on the two different silyloxypyr-
roles 1 and 7 are both Si but for different reasons. In
Casiraghi’s case, the aldehyde carbonyl group of 2
points more towards the N-Boc end where a possible
cooperative interaction between tin and the carbamate
carbonyl oxygen may play a role18 in the transition
state. Such an arrangement also ensures that the alde-
hyde chain points away from the pyrrole ring. Con-
versely, in our case, Si-face selectivity in 7 is consistent
with the carbonyl group of aldehyde 6 pointing inwards
over the pyrrole in an endo-Diels–Alder-like fashion,17
to ensure that the C1–C2 bond of aldehyde 6 points
away from the pyrrole ring to accommodate the C2
hydrogen. Furthermore, the C-4 methoxy group of 7
may possibly develop cooperative interactions with tin
as shown in Figure 4, which suggests transition-state
models for the two reactions.
3. Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem.
Soc. Rev. 2000, 29, 109–118.
4. Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F.
Tetrahedron 1990, 46, 265–276.
5. Casiraghi, G.; Ulgheri, F.; Spanu, P.; Rassu, G.; Pinna,
L.; Gasparri Fava, G.; Ferrari Belicchi, M.; Pelosi, G.
J. Chem. Soc., Perkin Trans. 1 1993, 23, 2991–2997.
6. Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna, L. J Org.
Chem. 1992, 57, 3760–3763.
7. Michael, J. P. Nat. Prod. Rep. 2005, 22, 603–626; Michael,
J. P. Nat. Prod. Rep. 2003, 20, 458–475.
8. For some recent syntheses, see: (a) Karanjule, N. S.;
Markad, S. D.; Shinde, V. S.; Dhavale, D. D. J. Org.
Chem. 2006, 71, 4667–4670; (b) Zhao, Z.; Song, L.;
Mariano, P. S. Tetrahedron 2005, 61, 8888–8894; (c)
Cronin, L.; Murphy, P. V. Org. Lett. 2005, 7, 2691–2693.
9. (a) Martin, S. F.; Chen, H. J.; Lynch, V. M. J. Org. Chem.
1995, 60, 276–278; (b) Gallagher, T.; Giles, M.; Subra-
manian, R. S.; Hadley, M. S. J. Chem. Soc., Chem.
Commun. 1992, 166–168.
In summary, this work provides a solution for the
4,5-erythro/5,6-threo-selectivity in silyloxypyrrole vinyl-
ogous Mukaiyama aldol additions pertaining to cast-
anospermine synthesis. Studies directed at attempting
to transform our 4,5-erythro-adduct to castanospermine
will be reported in due course as well as the generality of
using silyloxypyrrole 7 in this new stereoselective
reaction.
10. Hunter, R.; Richards, P. Synlett 2003, 2, 271–273.
11. Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G.
Chem. Rev. 2000, 100, 1929–1972.
12. Duc, L.; McGarrity, J. F.; Meul, T.; Warm, A. Synthesis
1992, 391–394.
13. Data for adduct 8 (see Scheme 4 for numbering): Mp 107–
108 ꢁC (from ethyl acetate–hexane); [a]D +6.67 (c 3.0,
CH2Cl2); Found: C, 65.52; H, 7.36; N, 2.10. C37H49NO9Si
requires C, 65.37; H, 7.26; N, 2.06; mmax 3053 (OH), 2933
(CH), 1678 (C@O), 1628 (C@C) cmÀ1; dH (CDCl3,
300 MHz) 1.06 (9H, s, t-Bu), 3.08 (3H, s, OCH3), 3.34
(3H, s, OCH3), 3.68 (3H, s, OCH3), 3.74 (3H, s, OCH3),
3.75–3.90 (3H, m, H-7, H-8), 3.99 (1H, dd, J 7.0, 1.8 Hz,
H-6), 4.08 (1H, d, J 2.0 Hz, H-4), 4.08 (1H, d, J 15.3 Hz,
Bn), 4.19 (1H, dd, J 7.0, 2.0 Hz H-5), 4.22 (1H, d,
References and notes
1. (a) Curti, C.; Zanardi, F.; Battistini, L.; Sartori, A.; Rassu,
G.; Auzzas, L.; Roggio, A.; Pinna, L.; Casiraghi, G.

2822
R. Hunter et al. / Tetrahedron Letters 48 (2007) 2819–2822
˚
˚
˚
J 6.5 Hz, OCH2O), 4.34 (1H, d, J 6.5 Hz, OCH2O), 4.68
(2H, s, OCH2O) 5.10 (1H, d, J 15.3, Bn), 5.20 (1H, s, H-3),
6.79 (2H, d, J 8.7 Hz, PMB), 7.17 (2H, d, J 8.7 Hz, PMB),
7.30–7.50 (6H, m, Ar), 7.60–7.70 (4H, m, Ar); dC (CDCl3,
75.5 MHz) 19.2 (Si–C), 26.8 ((CH3)3), 42.8 (CH2), 55.2
(OCH3), 55.5 (OCH3), 56.3 (OCH3), 58.1 (OCH3), 60.9 (C-
4), 62.4 (C-8), 68.3 (C-5), 77.9 (C-7), 80.9 (C-6), 95.7 (C-2),
96.8 (OCH2O), 99.2 (OCH2O), 114.0 (PMB), 127.7, 127.8,
129.2, 129.8, 129.9, 130.0, 133.0, 133.1, 135.4, 135.5 (Ar),
158.9 (PMB), 171.9 (C-3), 173.3 (C-1); m/z FAB: 702.2
(M+Na)+, 680.3 (M+H)+.
8.2069(1) A, b = 15.7691(1) A, c = 27.8258(3) A, a = b =
3
À3
,
˚
c = 90ꢁ, V = 3601.09(6) A , Z = 4, calcd = 1.254 g cm
T = 153(2) K, = 0.120 mmÀ1
,
F(000) = 1 456, 2.93ꢁ <
˚
2 < 27.51ꢁ, (Mok) = 0.71073 A, crystal size 0.3 · 0.2 ·
0.2 mm3; X-ray intensity data were collected with a
Nonius KappaCCD diffractometer, 8224 unique reflec-
tions were collected of which 6882 were refined [I > 2(I)],
Rint = 0.0393; the structure was solved by direct methods
(SHELXS-97) and refined on F2 using full-matrix least-
squares procedures (SHELXL-97) giving R1 = 0.0415
[I > 2(I)], wR2 = 0.1009 (all data), GOF = 1.051, max/
À3
˚
14. Uno, H.; Nishihara, Y.; Mizobe, N.; Ono, N. Bull. Chem.
Soc. Jpn. 1999, 72, 1533–1539.
min residual electron density = 0.544/À0.387 eA
.
16. (a) Martin, S. F.; Chen, H. J.; Yang, C. P. J. Org. Chem.
1993, 58, 2867–2873; (b) Mukai, C.; Kim, I. J.; Hanaoka,
M. Tetrahedron Lett. 1993, 34, 6081–6082.
15. CCDC 632910 contains the Supplementary Crystallo-
graphic Data for this Letter. These data can be obtained
free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
C37H49NO9Si MW = 679.86 g molÀ1; colourless needle;
crystal system: orthorhombic, space group P212121, a =
17. Casiraghi, G.; Rassu, G. Synthesis 1995, 607–626.
18. Rassu, G.; Pinna, L.; Spanu, P.; Ulgheri, F.; Cornia, M.;
Zanardi, F.; Casiraghi, G. Tetrahedron 1993, 49, 6489–
6496.