A sulfone-mediated synthesis of (+)-preussin

Article abstract of DOI:10.1055/s-2001-17440

The synthesis of the antifungal pyrrolidine (+)-preussin is described, utilising the 5-endo-trig cyclisatian of a vinylic sulfone generated in situ to give the requisite pyrrolidine nucleus.

Full text of DOI:10.1055/s-2001-17440

1602
LETTER
A Sulfone-mediated Synthesis of (+)-Preussin
John J. Caldwell, Donald Craig,* Stephen P. East
Centre for Chemical Synthesis, Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, UK
Fax +44(20)75945868; E-mail: d.craig@ic.ac.uk
Received 23 July 2001
lated to 6 underwent desulfonylation and cyclisation in
Abstract: The synthesis of the antifungal pyrrolidine (+)-preussin
situ upon treatment with n-Bu4NF, giving pyrrolidines
is described, utilising the 5-endo-trig cyclisation of a vinylic sul-
analogous to 4. For the synthesis of 2, precursor ketone 3
would be made by oxidation of the sulfone-stabilised car-
banion generated from the N-methyl derivative of 4. In
particular, it was felt that the use of readily enolisable phe-
fone generated in situ to give the requisite pyrrolidine nucleus.
Key words: cyclisation, natural products, stereoselectivity, sul-
fones, total synthesis
nylacetaldehyde as the coupling partner in the preparation
of substrate 6 would provide a rigorous test of the applica-
We have been evaluating the utility of 5-endo-trig cycli-
bility of this one-pot method. Precursor aziridine 7, for-
sations of sulfonyl-substituted amines and alcohols for the
mally derived from a D-aminoacid would be accessed
construction of heterocycles including pyrrolidines,1 and
from L-serine 8 by reversing the relative oxidation levels
reported quite recently the application of this methodolo-
at C1 and C3.
gy to the synthesis of the indolizidine alkaloid (+)-mono-
morine I 1 (Figure). The final stage in this synthesis was
the reductive removal of the phenylsulfonyl moiety, and
we were keen to exploit further the diverse reactivity of
this versatile functional group.2 It occurred to us that hy-
droxy-substituted pyrrolidines should be accessible from
the 5-endo-trig cyclisation products simply by oxidation
of the sulfone-stabilised carbanion3 and subsequent reduc-
tion of the product ketone. Isolated and characterised in
1988,4 the disubstituted hydroxypyrrolidine antifungal
agent (+)-preussin 2 has been the subject of a number of
synthetic approaches,5 and the all-syn disposition of the
pyrrolidine substituents made it an ideal target upon
which to evaluate the proposed extension of our method-
ology. We report herein the sulfone-mediated total syn-
thesis of 2 (Figure).
Scheme 1
Aziridine 7 was made using an adaptation of the work of
Rapoport (Scheme 2).7 Thus, addition of excess n-octyl-
magnesium iodide–n-butyllithium to N-tosyl-L-serine8
provided ketone 9, which was deoxygenated to give the N-
protected amino alcohol 10 by conversion into the
Figure
dithiane under standard conditions and subsequent treat-
ment with Raney nickel. This was cyclodehydrated by
treatment with TsCl-KOH9 to provide the corresponding
Our initial retrosynthetic analysis of (+)-preussin was
N-tosylaziridine 11 in near-quantitative yield. Finally, re-
placement of the N-tosyl protecting group with the SES
function10 was achieved by reductive desulfonylation fol-
lowed by re-sulfonylation using SESCl-DMAP in the
presence of base, giving 7 in 12% overall yield from L-
serine (39% from ketone 9). The instability of the SES
protecting group towards the excess organometallic re-
agent used in the conversion 8 9 precluded its incorpo-
ration from the outset, necessitating the desulfonylation–
resulfonylation sequence.
adapted from the synthesis of (+)-monomorine I
(Scheme 1). We had found6 subsequent to the monomo-
rine work that N-2-(trimethylsilyl)ethylsulfonyl-protected
(N-SES-protected) vinylic sulfone-containing amines
such as 6 could be synthesised in a one-pot olefination
procedure by combination of aldehydes with the adducts
of (phenylsulfonyl)methane and aziridines, such as 5.
This work had demonstrated further that sulfonamides re-
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1602,1604,ftx,en;D14001st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
A Sulfone-mediated Synthesis of (+)-Preussin
1603
curred either (i) the two epimers of 12 cyclised with
mutually opposite stereochemistry relative to the phenyl-
sulfonyl group, and epimerisation of the sulfonyl stereo-
centre in one of the isomers occurred post-cyclisation, or
(ii) one of the two epimers of 12 was unreactive, equili-
brating with the reactive isomer prior to stereoselective
cyclisation; both these scenarios seem relatively unlikely
given the facility of 5-endo-trig cyclisation in the absence
of the competing 5-exo pathway.1b,c Compound 4 was
next subjected to reductive amination5i to give the N-me-
thyl derivative 14. Reaction of the derived lithio-anion
with TMSOOTMS12 provided ketone 35e which was re-
duced to give (+)-preussin 2. Compound 2 prepared in this
way had spectral characteristics identical with those re-
ported for the natural product.4,5 The completion of the
synthesis of 2 is depicted in Scheme 4.13
Scheme 2 Reagents and conditions: (i) 2 M NaOH, TsCl, H2O,
EtOAc; (ii) n-BuLi (2 equiv), H17C8MgI (4 equiv), THF, Et2O; (iii)
HS(CH2)3SH, BF3 OEt2, CH2Cl2; (iv) Ni(R), EtOH, reflux; (v) KOH,
TsCl, THF, r.t.; (vi) Na, naphthalene, THF, –78 °C; (vii) SESCl,
DMAP, Et3N, CH2Cl2, 0 °C
Aziridine 7 reacted smoothly with the lithio-anion of
(phenylsulfonyl)methane to give the expected adduct 5.
Double deprotonation of 5 followed by sequential addi-
tion of phenylacetaldehyde and benzoyl chloride under
the conditions which had been successful with less readily
enolisable coupling partners6 gave the allylic sulfone 12 in
low yield, with virtually none of the desired vinylic sul-
fone 6 (Scheme 3).
Scheme 3 Reagents and conditions: (i) n-BuLi, THF, TMEDA, –
78 °C, add 7, –78 °C r.t., 89%; (ii) n-BuLi, THF, –78 °C then phe-
nylacetaldehyde, then BzCl
Scheme 4 Reagents and conditions: (i) add n-BuLi to 13, THF,
TMEDA, –78 °C, then add 7, –78 °C r.t.; (ii) TBAF (15 equiv),
THF, reflux, 38 h; (iii) HCHO (aq), NaCNBH3, AcOH, MeCN; (iv)
n-BuLi, THF, then TMSOOTMS; (v) LiAlH4, THF, –78 °C
Though unwelcome, these observations appeared to be
fully consistent with the greater thermodynamic stability
of allylic sulfones compared with their vinylic isomers
and the acidity of the phenylacetaldehyde -protons. It oc-
curred to us that 12 might itself be a substrate for 5-endo-
trig cyclisation, since the fluoride-containing medium
should be sufficiently basic to promote equilibration of
unsaturated sulfone isomers 6 and 12. This modified ap-
proach appeared especially attractive because substrate 12
could in principle be made simply by combining the ap-
propriate allylic sulfone anion with 7, thereby making the
synthesis more convergent. In the event, reaction of the
In summary, a 12-step synthesis of (+)-preussin 2 from
(E)-3-phenyl-1-(phenylsulfonyl)-2-propene and L-serine
has been achieved. During the course of this investigation
a new mode of 5-endo-trig cyclisation has been uncovered
in which the requisite vinylic sulfone is generated in situ
from a more readily available allylic precursor, and this
renders the approach more convergent. We are currently
evaluating the generality of this isomerisation–cyclisation
process, and are assessing its utility in the synthesis of
more complex pyrrolidine-containing targets. The results
of these investigations will be reported in due course.
lithio-anion
of
(E)-3-phenyl-1-(phenylsulfonyl)-2-
propene11 13 with 7 gave directly a diastereomeric mix-
ture of the adducts 12 in excellent yield. Treatment of 12
with excess n-Bu4NF gave pyrrolidine 4 in high yield as a
single stereoisomer, having the 2,3-anti, 2,5-syn stere-
ochemistry observed previously in 5-endo-trig cyclisa-
tions of this type.1b,c Although 4 could have been formed
by direct 5-exo-trig cyclisation of 12, it seems unlikely
that an unsubstituted phenyl group would confer suffi-
cient electrophilicity on the styryl linkage for cyclisation
to occur. Also, although substrate 12 was an epimeric
mixture at the sulfone centre, product 4 was a single dias-
tereomer. Therefore, for 5-exo-trig cyclisation to have oc-
Acknowledgement
We thank EPSRC and F. G. Hoffmann-La Roche for financial sup-
port of this research.
References and Notes
(1) (a) Craig, D.; Ikin, N. J.; Mathews, N.; Smith, A. M.
Tetrahedron 1999, 55, 13471. (b) Craig, D.; Jones, P. S.;
Rowlands, G. J. Synlett 1997, 1423. (c) Berry, M. B.; Craig,
D.; Jones, P. S.; Rowlands, G. J. Chem. Commun. 1997,
2141.
Synlett 2001, No. 10, 1602–1604 ISSN 0936-5214 © Thieme Stuttgart · New York

1604
J. J. Caldwell et al.
LETTER
under reduced pressure. Chromatographic purification
(2) Sulphones in Organic Synthesis; Simpkins, N. S., Ed.;
Pergamon: Oxford, 1993.
(SiO2; 30% EtOAc-petrol) of the crude product gave
[2S,3R,5R]-2-benzyl-3-phenylsulfonyl-5-nonylpyrrolidine4
(360 mg, 0.842 mmol, 78%) as a clear oil; [ ]D20 –9.6 (c
4.16, CHCl3); max(film) 3336, 3084, 3066, 3032, 3003,
2981, 2954, 2924, 2848, 2731, 2669, 1603, 1585, 1495,
(3) Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
(4) (a) Schartz, R. E.; Liesch, J.; Hensens, O.; Zitano, L.;
Honeycutt, S.; Garrity, G.; Fromtling, R. A.; Onishi, J.;
Monaghan, R. J. Antibiot. 1988, 1744. (b) Johnson, J. H.;
Phillipson, D. W.; Kahle, A. D. J. Antibiot. 1989, 1184.
(5) (a) Pak, C. S.; Lee, G. H. J. Org. Chem. 1991, 56, 1128.
(b) Shimazaki, M.; Okazaki, F.; Nakajima, F.; Ishikawa, T.;
Ohta, A. Heterocycles 1993, 36, 1823. (c) McGrane, P. L.;
Livinghouse, T. J. Am. Chem. Soc. 1993, 115, 11485.
(d) Overhand, M.; Hecht, S. M. J. Org. Chem. 1994, 59,
4721. (e) Deng, W.; Overman, L. E. J. Am. Chem. Soc. 1994,
116, 11241. (f) Yoda, H.; Yamazaki, H.; Takabe, K.
Tetrahedron: Asymmetry 1996, 7, 373. (g) Beier, C.;
Schaumann, E. Synthesis 1997, 1296. (h) deArmas, P.;
Garcia-Tellado, F.; Marrero-Tellado, J. J.; Robles, J.
Tetrahedron Lett. 1998, 39, 131. (i) Kanazawa, A.; Gillet,
S.; Delair, P.; Greene, A. E. J. Org. Chem. 1998, 63, 4660.
(j) Bach, T; Brummerhop H. Angew. Chem. Int. Ed. 1998,
37, 3400. (k) Verma, R.; Ghosh, S. K. J. Chem. Soc., Perkin
Trans. 1 1999, 265. (l) Veeresa, G.; Datta, A. Tetrahedron
1998, 54, 15673. (m) Lee, K.-Y.; Kim, Y.-H.; Oh, C.-Y.;
Ham, W.-H. Org. Lett. 2000, 4041. (n) Okue, M.;
Watanabe, H.; Kitahara, T. Tetrahedron 2001, 57, 4107.
(6) Craig, D.; East, S. P. unpublished observations.
(7) Maurer, P. J.; Takahata, H.; Rapoport, H. J. Am. Chem. Soc.
1984, 106, 1095 ; all yields reported herein refer to isolated,
pure materials which had 1H and 13C NMR, IR and high-
resolution MS characteristics in accord with the proposed
structures.
1446, 1406, 1377, 1304, 1176, 1145, 1086, 1028 cm–1;
H
(300 MHz) 7.97–7.91 (2 H, m, Ar), 7.73–7.57 (3 H, m, Ar),
7.32–7.10 (5 H, m, Ar), 3.76 (1 H, ddd, J 9.0, 7.0, 3.5 Hz, H-
2), 3.36 (1 H, ddd, J 10.5, 7.0, 3.5 Hz, H-3), 3.08 (1 H, dq, J
10.0, 6.5 Hz, H-5), 2.82 (1 H, dd, J 13.5, 3.5 Hz, CHHPh),
2.64 (1 H, dd, J 13.5, 9.0 Hz, CHHPh), 2.40 (1 H, ddd, J
13.5, 6.5, 3.5 Hz, H-4), 1.88 (1 H, br s, N-H), 1.57 (1 H, dt,
J 13.5, 10.0 Hz, H-4), 1.49–1.15 (16 H, m, (CH2)8), 0.89 (3
H, t, J 6.5 Hz, CH3); C (75 MHz) 139.0, 138.4, 134.0, 129.6,
129.4, 128.8, 128.7, 126.8, 67.3, 60.7, 58.4, 41.8, 35.9, 34.3,
32.0, 29.9, 29.7 (2 C), 29.5, 27.2, 22.8, 14.3; m/z (CI) 428
[MH]+ (Found: [MH]+, 428.2615; C26H37NO2S requires
[MH]+, 428.2623).
Preparation of 3.
To a stirred solution of sulfone 14 (164 mg, 0.371 mmol) in
THF (2 mL) at –78 °C under nitrogen was added n-BuLi
(165 L of a 2.7 M solution in hexanes, 0.446 mmol, 1.2
equiv) to give a pale yellow solution. After 15 min a solution
of TMSOOTMS (86 mg, 0.483 mmol, 1.3 equiv) in THF
(0.5 mL) was added via syringe. The solution was allowed to
attain r.t. over 2 h, and then stirred at r.t. for a further 15 h.
After quenching with saturated aqueous NaHCO3 (15 mL)
the mixture was extracted with EtOAc (3 10 mL). The
combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. The resulting crude
product was purified by chromatography (SiO2; 20%
EtOAc-petrol) to give recovered starting material 14 (55 mg,
34%) and [2S,5R]-2-benzyl-1-methyl-5-nonyl-3-oxo-
pyrrolidine 3 (57 mg, 49%, 74% based on recovered 14) as a
(8) Hofmann, K.; Jöhl, A.; Furlenmeier, A. E.; Kappeler, H. J.
Am. Chem. Soc.; 1956, 79, 1636.
(9) The method used was an adaptation of a procedure for N-
Boc aziridination using Boc2O–KOH in Et2O:Wessig, P.;
Schwarz, J. Synlett 1997, 893.
(10) Weinreb, S. M.; Demko, D. M.; Lessen, T. A.; Demers, J. P.
Tetrahedron Lett. 1986, 27, 2099.
(11) Pyne, S. G.; David, D. M.; Dong, Z. Tetrahedron Lett. 1998,
39, 8499.
pale yellow oil; [ 20 –97.9 (c 1.43, CHCl3); max(film)
D
3055, 2956, 2927, 2856, 1751, 1411, 1379, 1265, 1151,
1115, 1082 cm–1; H (300 MHz) 7.32–7.15 (5 H, m, Ph), 3.08
(1 H, dd, J 14.0, 4.5 Hz, CHHPh), 2.87 (1 H, dd, J 14.0, 5.0
Hz, CHHPh), 2.78 (1 H, distorted t, H-2), 2.55-2.44 (1 H, m,
H-5), 2.41 (1 H, dd, J 17.5, 6.0 Hz, H-4), 2.33 (3 H, s, NMe),
1.79 (1 H, dd, J 18.0, 10.5 Hz, H-4), 1.40–1.10 (16 H, m,
(CH2)8), 0.91 (3 H, t, J 6.5 Hz, CH2CH3); C (75 MHz) 215.0,
138.7, 129.9, 128.2, 126.3, 74.5, 62.6, 42.9, 39.4, 36.1, 33.1,
32.1, 30.0, 29.7 (2C), 29.5, 25.8, 22.9, 14.3; m/z (CI) 306
[MH]+ (Found: [MH]+, 316.2637; C21H33NO requires
[MH]+, 316.2640).
(12) Hwu, J. R. J. Org. Chem. 1983, 48, 4433.
(13) Preparation of 4.
A solution of 12 (640 mg, 1.08 mmol) in TBAF (16.22 mL
of a 1 M solution in THF, 16.22 mmol, 15 equiv) was heated
under reflux under nitrogen for 38 h. MeOH (5 mL) was
added to the cooled solution followed by water (50 mL). The
mixture was extracted with EtOAc (2 50 mL) and the
combined organic layers dried (MgSO4), and concentrated
Synlett 2001, No. 10, 1602–1604 ISSN 0936-5214 © Thieme Stuttgart · New York