Synthesis of (+)- and (-)-statine via chiral sulfoxide chemistry

Full text of DOI:10.1021/jo010383z

J . Org. Chem. 2001, 66, 5637-5640
5637
Syn th esis of (+)- a n d (-)-Sta tin e via Ch ir a l
Su lfoxid e Ch em istr y
Cristina Pesenti,§ Pierfrancesco Bravo,§,†
Eleonora Corradi,§ Massimo Frigerio,§
Stefano V. Meille,§ Walter Panzeri,† Fiorenza Viani,† and
Matteo Zanda§,*
Dipartimento di Chimica del Politecnico di Milano, via
Mancinelli 7, I-20131 Milano, Italy, and C.N.R.-Centro di
Studio sulle Sostanze Organiche Naturali, via Mancinelli 7,
I-20131 Milano, Italy
F igu r e 1. Retrosynthetic Scheme.
zanda@dept.chem.polimi.it
Received April 16, 2001
frameworks.10,11 However, a route based on a stereose-
lective C3-C4 bond forming reaction between an imine
derived from (3-methyl)butanal and a chiral equivalent
of (3-hydroxy)propanoate 3-carbanion has not been re-
ported yet (Figure 1).12 Recently, we have demonstrated
that R-lithium alkyl sulfoxides can be used as chiral
R-hydroxyalkyl carbanion equivalents with nonenolizable
imines for the asymmetric synthesis of â-amino alco-
hols.13 This strategy takes advantage of a synergistic
combination of two methodologies recently developed in
our laboratories: (1) the chiral sulfoxide stereocontrolled
Statine ([3S,4S]-4-amino-3-hydroxy-6-methylheptanoic
acid) is a nonproteinogenic amino acid contained in
microbial aspartyl protease inhibitors such as Pepstatin.1
A number of syntheses of the four stereoisomers of statine
has been reported.2 Extremely effective and highly ste-
reoselective are the approaches of Rich (1988) with the
modification of Reetz (1989),3 Noyori (1988),4 Terashima
(1990),5 and Gennari (1995).6 Most of the conceivable
retrosynthetic pathways to statine have been explored,
spanning from the following: (a) the dominating asym-
metric C2-C3 bond forming reaction (see Figure 1 for
atom numbering) of N-protected leucinal with acetate
enolate equivalents;7 (b) the stereoselective reduction of
leucine derived â-ketoesters;8 (c) manipulation of other
substrates derived from the chiral pool, such as sugars,
or suitably functionalized lactams, oxazolidin-2-ones and
related compounds;9 (d) asymmetric ring opening reac-
tions of epoxides having statine or statine-like carbon
(8) See ref 3 and 4. See also: (a) Fehrentz, J .-A.; Bourdel, E.;
Califano, J .-C.; Chaloin, O.; Devin, C.; Garrouste, P.; Lima-Leite, A.-
C.; Llinares, M.; Rieunier, F.; Vizavonna, J .; Winternitz, F.; Loffet, A.;
Martinez, J . Tetrahedron Lett. 1994, 35, 1557-1560. (b) Kessler, H.;
Schudok, M. Synthesis 1990, 457-458. (c) Dufour, M.-N.; J ouin, P.;
Poncet, J .; Pantaloni, A.; Castro, B. J . Chem. Soc., Perkin 1 1986,
1899-1990. (d) J ouin, P.; Castro, B.; Nisato, D. J . Chem. Soc., Perkin
1 1987, 1177-1182.
(9) (a) Yanagisawa, H.; Kanazaki, T.; Nishi, T. Chem. Lett. 1989,
687-690. (b) Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S. J . Org.
Chem. 1988, 53, 3865-3868. (c) Sakaitani, M.; Ohfune, Y. J . Am.
Chem. Soc. 1990, 112, 1150-1158. (d) Williams, R. M.; Colson, P.-J .;
Zhai, W. Tetrahedron Lett. 1994, 35, 9371-9374. (e) Ohta, T.;
Shiokawa, S.; Sakamoto, R.; Nozoe, S. Tetrahedron Lett. 1990, 31,
7329-7332. (f) Koot, W.-J .; van Ginkel, R.; Kranenburg, M.; Hiemstra,
H.; Louwrier, S.; Moolenaar, M. J .; Speckamp, W. N. Tetrahedron Lett.
1991, 32, 401-404. (g) Bernardi, A.; Micheli, F.; Potenza, D.; Scolastico,
C.; Villa, R. Tetrahedron Lett. 1990, 31, 4949-4952. (h) Shinozaki, K.;
Mizuno, K.; Oda, H.; Masaki, Y. Bull. Chem. Soc. J pn. 1996, 69, 1737-
1745. (i) Kinoshita, M.; Hagiwara, A.; Aburaki, S. Bull. Chem. Soc.
J pn. 1974, 48, 570-575. (j) Aoyagi, Y.; Williams, R. M. Tetrahedron
1998, 54, 10419-10433. (k) Kunieda, T.; Ishizuka, T.; Higuchi, T.;
Hirobe, M. J . Org. Chem. 1988, 53, 3381-3383. (l) Kinoshita, M.;
Aburaki, S.; Hagiwara, A.; Imai, J . J . Antibiot. 1973, 26, 249-251.
(m) Reddy, G. V.; Rao, G. V.; Iyengar, D. S. Tetrahedron Lett. 1999,
40, 775-776. (n) Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shibuya, S.
Chem. Lett. 1987, 1531-1534.
* To whom correspondence should be sent. E-mail: zanda@
dept.chem.polimi.it. Fax: +39 02 23993080.
§ Dipartimento di Chimica del Politecnico di Milano.
† C.N.R.-Centro di Studio sulle Sostanze Organiche Naturali.
(1) (a) Umezawa, H.; Aoyagi, T.; Morishima, H.; Matsuzaki, M.;
Hamada, M.; Takeuchi, T. J . Antibiot. 1970, 23, 259-262. (b) Aoyagi,
T.; Morishima, H.; Nishizawa, R.; Kunimoto, S.; Takeuchi, T.; Umeza-
wa, H.; Ikezawa, H. J . Antibiot. 1972, 25, 689-694.
(2) The commercial price of (-)-statine is very high, about $106 US
for 5 mg from Sigma-Aldrich.
(3) (a) Maibaum, J .; Rich, D. H. J . Org. Chem. 1988, 53, 869-873.
(b) Reetz, M. T.; Drewes, M. W.; Matthews, B. R.; Lennick, K. J . Chem.
Soc., Chem. Commun. 1989, 1474-1475.
(4) Nishi, T.; Kitamura, M.; Ohkuma, T.; Noyori, R. Tetrahedron
Lett. 1988, 29, 6327-6330.
(10) (a) Mulzer, J .; Bu¨ttelmann, B.; Mu¨nch, W. Liebigs Ann. 1988,
445-448. (b) Kogen, H.; Nishi, T. J . Chem. Soc., Chem. Commun. 1987,
311-312. (c) Bertelli, L.; Fiaschi, R.; Napolitano, E. Gazz. Chim. Ital.
1993, 123, 521-524. (d) Sa¨ıah, M.; Bessodes, M.; Antonakis, K.
Tetrahedron: Asymmetry 1991, 2, 111-112.
(5) Takemoto, Y.; Matsumoto, T.; Ito, Y.; Terashima, S. Chem.
Pharm. Bull. 1991, 39, 2425-2428.
(6) Gennari, C.; Pain, G.; Moresca, D. J . Org. Chem. 1995, 60, 6248-
6249.
(7) (a) Devant, R. M.; Radunz, H.-E. Tetrahedron Lett. 1988, 29,
2307-2310. (b) Misiti, D.; Zappia, G. Tetrahedron Lett. 1990, 31, 7359-
7362. (c) Harris, B. D.; J oullie´, M. M. Tetrahedron 1988, 44, 3489-
3500. (d) Woo, P. W. K. Tetrahedron Lett. 1985, 26, 2973-2976. (e)
Cooke, J . W. B.; Davies, S. G.; Naylor, A. Tetrahedron 1993, 49, 7955-
7966. (f) Liu, W.-S.; Smith, S. C.; Glover, G. I. J . Med. Chem. 1979,
22, 577-579. (g) Steulmann, R.; Klostermeyer, H. Liebigs Ann. Chem.
1975, 2245-2250. (h) Wuts, P. G. M.; Putt, S. R. Synthesis 1989, 951-
953. (i) Veeresha, G.; Datta, A. Tetrahedron Lett. 1997, 38, 5223-5224.
(j) Rittle, K. E.; Homnick, C. F.; Ponticello, G. S.; Evans, B. E. J . Org.
Chem. 1982, 47, 3016-3018. (k) Franciotti, M.; Mann, A.; Taddei, M.
Tetrahedron Lett. 1991, 32, 6783-6786. (l) Andrew, R. G.; Conrow, R.
E.; Elliot, J . D.; J ohnson, W. S.; Ramezani, S. Tetrahedron Lett. 1987,
28, 6535-6538. (m) Mikami, K.; Kaneko, M.; Loh, T.-P.; Terada, M.;
Nakai, T. Tetrahedron Lett. 1990, 27, 3909-3912. (n) Midland, M. M.;
Afonso, M. M. J . Am. Chem. Soc. 1989, 111, 4368-4371. (o) Fray, A.
H.; Kaye, R. L.; Kleinman, E. F. J . Org. Chem. 1986, 51, 4828-4833.
(p) Hayon, A.-F.; Fehrentz, J .-A.; Chapleur, Y.; Castro, B. Bull. Soc.
Chim. Fr. 1983, II-207-210.
(11) For other approaches to statine: (a) Nebois, P.; Greene, A. E.
J . Org. Chem. 1996, 61, 5210-5211. (b) Enders, D.; Reinhold: U.
Liebigs Ann. 1996, 11-26. (c) Baenzinger, M.; McGarrity, J . F.; Meul,
T. J . Org. Chem. 1993, 58, 4010-4012. (d) Sakaitani, M.; Ohfune, Y.
Tetrahedron Lett. 1987, 28, 3987-3990. (e) Ishizuka, T.; Ishibuchi, S.;
Kunieda, T. Tetrahedron 1993, 49, 1841-1852. (f) Takahata, H.;
Yamazaki, K.; Takamatsu, T.; Yamazaki, T.; Momose, T. J . Org. Chem.
1990, 55, 3947-3950. (g) Meunier, N.; Veith, U.; J a¨ger, V. J . Chem.
Soc., Chem. Commun. 1996, 331-332.
(12) This might be due to the fact that synthetic equivalents of chiral
R-hydroxy carbanions are not yet a well established tool in asymmetric
organic synthesis, and only a relatively little number of such equiva-
lents has hitherto found some practical use. See for example: (a)
Ferna´ndez-Meg´ıa, E.; Ley, S. V. Synlett 2000, 455-458 and the list of
references therein. (b) Linderman, R. J .; Ghannam, A. J . Am. Chem.
Soc. 1990, 112, 2392-2398. (c) Deiters, A.; Fro¨hlich, R.; Hoppe, D.
Angew. Chem., Int. Ed. 2000, 39, 2105-2107. (d) Heimbach, D. K.;
Fro¨hlich, R.; Wibbeling, B.; Hoppe, D. Synlett 2000, 950-954 and
references therein.
10.1021/jo010383z CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/18/2001

5638 J . Org. Chem., Vol. 66, No. 16, 2001
Notes
Sch em e 1
additions of carbon nucleophiles to imines derived from
aryl or fluoroalkyl aldehydes and ketones,14 and (2) the
,nonoxidative. Pummerer reaction (NOPR),15 that al-
lows for a one-pot SN2-type displacement of the sulfinyl
auxiliary by a hydroxyl from the intermediate â-sulfinyl-
amines. The use of N-PMP imines for the C-C bond
forming step proved to be extremely rewarding in terms
of yields, stereocontrol and easy cleavage. However,
essential to an efficient outcome of the NOPR is a
neighboring group participation by the â-amino group,
which must be protected as monoamide (NHCOR) or
monocarbamate (NHCOOR), whereas the PMP group
gives rise to a totally different outcome.16 For this reason,
cleavage of the PMP group followed by N-acylation or
N-alcoxycarbonylation were necessary prior to perform-
ing the NOPR.
In this paper we present the following: (1) an extension
of our stereoselective NOPR-based methodology to eno-
lizable imines, (2) an improvement consisting in the use
of N-Cbz imines for the C-C bond forming step, that
allows for a direct use of the NOPR without the need of
intermediate N-deprotection/reprotections, and (3) an
application of this chemistry to the stereocontrolled
synthesis of both enantiomers of statine, even in selec-
tively protected forms suitable for peptide chemistry.
Sch em e 2a
Resu lts a n d Discu ssion
To accomplish the first step of our synthetic plan (C-C
bond forming) we needed to achieve addition of enantio-
merically pure R-lithium 3-butenyl p-tolylsulfoxide to an
imine derived from 3-methyl butanal. However this goal
appeared rather challenging, because it was already
known from previous work by Pyne et al. that additions
of R-lithium sulfoxides to enolizable N-aryl and N-alkyl
imines are poorly synthetically useful, due to competitive
enolization/polymerization side-processes involving the
imine.17 To overcome this trouble we envisioned the use
of an activated imine having a N-electron-withdrawing
group, which was expected to be much more reactive
toward the nucleophile. The use of N-acyl and N-tosyl
imines was immediately discarded, due to the difficulties
connected with the hydrolysis of the resulting amides and
sulfonamides. Next, we considered the possibility to use
a N-sulfinyl-imine.18 In fact, Ellman et al. reported that
enolizable tert-butylsulfinyl imines give rise to highly
stereoselective reactions with enolates,19 while Garc´ıa
Ruano et al. described the stereoselective additions of
lithiated alkyl sulfoxides to benzaldehyde-derived p-
a
Key: (i) (a) TFAA, sym-collidine, MeCN; (b) NaBH4, THF/H2O
(76%). (ii) KMnO4, H2SO4 (48%). (iii) (a) Pd(OH)2-C/H2; (b)
DOWEX-50W (57%).
tolylsulfinimines.20 However, the latter authors showed
that the NOPR cannot be performed directly on the
resulting sulfinamides, because N-desulfinylation occurs.
As a consequence, the sulfinamides must be hydrolyzed
and reprotected as NHCOOR derivatives prior to per-
forming the NOPR process, leading to a two-steps length-
ening of the synthesis. For the reasons above, the use of
a N-alkoxycarbonyl imine appeared as the optimal choice.
Mecozzi and Petrini have recently published the prepara-
tion of stable and easy-to-handle precursors (R-ami-
doalkyl sulfones) of a wide range of enolizable N-alkox-
ycarbonyl imines,21 from which the latter can be generated
in situ by action of an excess of the carbon nucleophile,
or by an extra-amount of base such as n-BuLi. The
R-amidoalkyl sulfone 2 (Scheme 1) derived from 3-meth-
yl-butanal was therefore reacted with 2 equiv of R-lithium
sulfoxide (S)-3. Although we did not try to optimize the
stereoselectivity of the reaction, the result was satisfac-
tory. In fact, a mixture of the four diastereomeric sul-
foxides (-)-4-7 formed in excellent overall yield, with
good stereocontrol in favor of the major diastereomer (-)-
4, having the correct stereochemistry to provide the
natural statine (-)-1 through NOPR chemistry (see
below).22 The excess of protonated (S)-3 was recovered
(13) (a) Zanda, M.; Bravo, P.; Volonterio, A. In Asymmetric Fluoro-
Organic Chemistry: Synthesis, Applications, and Future Directions;
Ramachandran, P. V., Ed.; American Chemical Society Symposium
Series 746, American Chemical Society: Washington, DC, 1999; pp
127-141. (b) Crucianelli, M.; Bravo, P.; Arnone, A.; Corradi, E.; Meille,
S. V.; Zanda, M. J . Org. Chem. 2000, 65, 2965-2971.
(14) Bravo, P.; Farina, A.; Kukhar, V. P.; Markovsky, A. L.; Meille,
S. V.; Soloshonok, V. A.; Sorochinsky, A. E.; Viani, F.; Zanda, M.;
Zappala`, C. J . Org. Chem. 1997, 62, 3424-3425.
(15) Bravo, P.; Zanda, M.; Zappala`, C. Tetrahedron Lett. 1996, 37,
6005-6006.
(16) In our previous works on the NOPR we almost invariably used
COOR as protecting group for the â-nitrogen, because unlike amides
(NHCOR), carbamates can be transformed into primary amines under
very mild conditions.
(20) Garc´ıa Ruano, J . L.; Alcudia, A.; del Prado, M.; Barros, D.;
Maestro, M. C.; Ferna´ndez, I. J . Org. Chem. 2000, 65, 2856-2862.
(21) Mecozzi, T.; Petrini, M. J . Org. Chem. 1999, 64, 8970-8972.
(22) Diastereoselectivity was measured by HPLC analysis (see
Experimental Section).
(17) Pyne, S. G.; Boche, G. J . Org. Chem. 1989, 54, 2663-2667.
(18) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27,
13-18.
(19) Tang, T. P.; Ellman, J . A. J . Org. Chem. 1999, 64, 12-13.

Notes
J . Org. Chem., Vol. 66, No. 16, 2001 5639
mmol) in dry THF (10 mL) was added dropwise to a solution of
freshly prepared LDA (13.3 mmol) in the same solvent (27 mL)
cooled at - 60 °C. The resulting yellow solution of 3 was cooled
to - 70 °C and, after 10 min, a solution of (1-benzenesulfonyl-
isobutyl)-carbamic acid benzyl ester (2) (2.0 g, 5.54 mmol) in dry
THF (10 mL) was added dropwise at the same temperature.
After 20 min the reaction was complete, as shown by TLC
monitoring (n-Hex/AcOEt 7:3). A saturated NH4Cl solution was
added, the mixture was diluted with water, warmed to room
temperature and extracted with AcOEt (3 × 50 mL). The
combined organic extracts were dried over anhydrous Na2SO4,
filtered and the solvent removed in vacuo. HPLC analysis (with
both achiral and chiral columns) showed the following diaster-
eomers ratio: (1S,2R,SS)-4/(1S,2S,SS)-5/(1R,2S,SS)-6/(1R,2R,SS)-7
) 62.7/15.9/5.5/15.9. LiChrosorb Si 60 (5 µm), 4 mm, n-Hex/
AcOEt ) 4:1, 1 mL/min., tR 6.22 min (7), tR 7.83 min (6), tR 8.60
min (5 + 4). Chiracel OD, 4.6 mm,, n-Hex/iso-PrOH ) 95:5, 0.8
mL/min., tR 12.18 min (7), tR 13.50 min (6 + 5), tR 14.48 min (4).
The crude was purified by FC (n-Hex/AcOEt 4:1 to 7:3)
affording: pure 7 (360 mg, 15.4%). The resulting mixture of 4,
5, and 6 was submitted to a further FC in toluene/AcOEt 9:1
affording pure (1R,2S,SS)-6 (123 mg, 5.3%), and a mixture of 4
and 5 (1.53 g, 60.8% and 15.4% respectively). The four diaster-
eomers were isolated in 97% overall yield.
by FC in nearly quantitative yield. It is worth noting that
the reaction portrayed in Scheme 1 took place with
opposite diastereofacial selectivity in comparison with
that involving R-lithium 3 and the N-PMP-imine of
trifluoroacetaldehyde.23 Although the good observed ste-
reocontrol suggests that a chelated transition state might
be responsible for the preferential formation of (-)-4, the
current little knowledge of this new kind of C-C bond
forming reactions involving lithium sulfoxides and N-acyl
imines does not allow for drawing a reliable mechanistic
hypothesis.
To our satisfaction, the NOPR occurred effectively on
a stereochemically pure sample of (-)-4 providing the
syn-â-amino-alcohol 8 in good yield and diastereocontrol
> 98:2, with clean stereoinversion at carbon. For pre-
parative purposes, given the difficulties connected with
the separation of pure (-)-4 from (-)-5 by FC, the NOPR
was routinely performed on mixtures of (-)-4 and (-)-5,
from which pure 8 was isolated in ca. 75% yield by FC.
Next, 8 was submitted to oxidative demolition with
KMnO4, that delivered (3S,4S)-9, which is a selectively
protected N-Cbz statine very useful for incorporation into
peptide sequences. Hydrogenolysis of the N-Cbz group
afforded the target natural statine (-)-(3S,4S)-1, whose
(1S,2R,SS)-4: 1H NMR (400 MHz, CDCl3) δ 0.855 (3H, d, J )
6.7), 0.91 (3H, d, J ) 6.2), 1.49-1.57 (1H, m), 1.59-1.70 (2H,
m), 2.30-2.50 (2H, m), 2.39 (3H, s), 2.90-2.95 (1H, m), 4.05-
4.15 (1H, m), 4.95-5.20 (4H, m), 5.55-5.67 (1H, m), 7.25-7.30
(2H, m), 7.30-7.45 (7H, m); 13C NMR (63 MHz, CDCl3) δ 155.7,
141.0, 139.6, 136.6, 134.3, 129.8, 128.6, 128.1, 124.4, 118.0, 68.7,
66.9, 50.1, 39.3, 26.1, 25.1, 23.5, 21.3, 21.3. (1S,2S,SS)-5: 1H
NMR (400 MHz, CDCl3) δ 0.79 (3H, d, J ) 5.9), 0.860 (3H, d, J
) 6.7), 1.49-1.57 (2H, m), 1.59-1.70 (1H, m), 2.405 (3H, s),
2.85-2.90 (1H, m), 4.15-4.25 (1H, m), 4.95-5.20 (4H, m), 5.67-
5.79 (1H, m), 7.25-7.30 (2H, m), 7.30-7.45 (7H, m); 13C NMR
(63 MHz, CDCl3) δ 156.2, 141.6, 139.6, 136.7, 136.4, 130.1, 128.5,
127.9, 125.2, 118.7, 66.9, 66.7, 50.5, 44.7, 31.4, 25.0, 22.7, 21.5,
21.4. Mixture of 4 and 5: FT-IR (film) (cm-1) 3290, 3035, 2957,
2870, 1715, 1531; MS (DIS EI, 70 eV) m/z (%) 414 (MH+, 35),
274 (18), 230 (10), 182 (8).
1H NMR spectrum (500 MHz) and [R]20 were identical
D
to those of a commercial sample (see Supporting Infor-
mation).
The same sequence was repeated on both (-)-7 and
(+)-4, prepared from 2 and lithiated (R)-3, affording
respectively (+)-(3S,4R)-statine in 34% overall yield, and
(+)-(3R,4R)-statine.
Unambiguous absolute stereochemical assignment of
4-7 was achieved combining X-ray diffraction of a single
crystal of (+)-7 (see Supporting Information), with chemi-
cal correlation. In fact, deoxygenation of 4-7 (Me3SiCl/
NaI)24 to the corresponding sulfides revealed an enanti-
omeric relationship between those deriving from the
couples 4/6 and 5/7, allowing us to assess the absolute
configurations at the carbon stereocenters.
In conclusion, we have developed a conceptually new
and synthetically efficient route to both enantiomers of
natural statine, exploiting an R-lithiated alkylsulfoxide
as a chiral R-hydroxyalkyl carbanion equivalent. This
demonstrates that the methodology based on the NOPR
has general scope and can be successfully extended to
enolizable imines, which were previously considered as
“difficult” substrates.
(1R,2S,SS)-6: [R]D20 -147.5 (c 0.8, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 0.94 (3H, m), 0.97 (3H, d, J ) 6.7), 1.48-1.58 (1H, m),
1.72-1.83 (1H, m), 1.85-2.00 (2H, m), 2.02-2.14 (1H, m), 2.43
(3H, s), 2.97-3.04 (1H, m), 4.27-4.35 (1H, m), 4.97-5.12 (2H,
m), 5.09 (1H, d, J ) 9.1), 5.13 (1H, d, J ) 9.1), 5.43-5.51 (1H,
m), 6.20-6.30 (1H, m), 7.30 (2H, d, J ) 8.3), 7.32-7.39 (m, 5H),
7.59 (2H, d, J ) 8.3); 13C NMR (63 MHz, CDCl3) δ 156.1, 142.8,
139.5, 136.9, 133.1, 130.1, 128.4, 127.9, 126.1, 118.6, 68.9, 66.5,
50.5, 39.2, 30.4, 25.0, 23.7, 21.54, 21.51; FT-IR (film) (cm-1) 3299,
3034, 2956, 2870, 1719, 1509, 1227; MS (DIS EI 70 eV) m/z (%)
414 (MH+, 35), 274 (18), 230 (10), 182 (8), 140 (18), 139 (9), 91
(100).
20
(1R,2R,SS)-7: mp 120-121 °C (diisopropyl ether); [R]D
1
-136.6 (c 0.8, CHCl3); H NMR (500 MHz, CDCl3) δ 1.01 (3H,
d, J ) 6.6), 1.04 (3H, d, J ) 6.4), 1.72-1.83 (2H, m), 1.93-2.00
(1H, m), 2.06-2.13 (1H, m), 2.39-2.46 (1H, m), 2.44 (3H, s), 2.60
(1H, ddd, J ) 9.2, 4.0, 3.9), 4.28-4.35 (1H, m), 4.88 (1H, d, J )
17.1), 4.95 (1H, d, J ) 9.9), 5.10 (2H, br s), 5.45-5.55 (1H, m),
5.86 (1H, d, J ) 9.21), 7.28-7.40 (9H, m); 13C NMR (63 MHz,
CDCl3) δ 156.2, 141.3, 137.9, 136.8, 134.1, 130.0, 128.4, 127.9,
124.3, 118.3, 66.6, 65.4, 50.2, 43.4, 26.1, 25.1, 22.7, 22.4, 21.4;
FT-IR microscopy (solid) (cm-1) 3240, 3062, 2957, 2867, 1711,
1552; MS (DIS EI 70 eV) m/z (%) 414 (MH+, 1), 413 (M+, 8), 274
(10), 230 (8), 216 (2), 182 (5), 139 (18), 91 (100).
Exp er im en ta l Section
Gen er a l P r oced u r e. For full general experimental informa-
tion see ref 25. Reactions with dry solvents were carried out
under N2 atmosphere. Coupling constants (J ) are reported in
Hertz. Sulfoxide (S)-3 was prepared according to the literature
procedure.26
Syn t h esis of [2-(4-Met h yl-p h en yl)su lfin yl-1-isob u t yl-
p en t-4-en yl]-ca r ba m ic a cid ben zyl ester s (4-7). A solution
of (S)-1-(but-3-ene-1-sulfinyl)-4-methyl-benzene (2.15 g, 11.08
Starting from (R)-3, (1S,2S,RS)-7 was obtained and submitted
to X-ray diffraction (see Supporting Info); Rf 0.35; mp 120-121
20
°C (diisopropyl ether); [R]D + 135.6 (c 1.1, CHCl3); FT-IR, 1H
and 13C NMR (CDCl3), MS (EI) data were overimposable to those
of the already described enantiomer.
(23) Bravo, P.; Corradi, E.; Pesenti, C.; Vergani, B.; Viani, F.;
Volonterio, A.; Zanda, M. Tetrahedron: Asymmetry 1998, 9, 3731-
3735.
(24) Arnone, A.; Bravo, P.; Capelli, S.; Fronza, G.; Meille, S. V.;
Zanda, M.; Crucianelli, M.; Cavicchio, G. J . Org. Chem. 1996, 61, 3375-
3387.
(25) Fustero, S.; Navarro, A.; Pina, B.; Asensio, A.; Bravo, P.;
Crucianelli, M.; Volonterio, A.; Zanda, M. J . Org. Chem. 1998, 63,
6210-6219.
(26) Arnone, A.; Bravo, P.; Cavicchio, G.; Frigerio, M.; Viani, F.
Tetrahedron 1992, 48, 8523-8540.
Syn th esis of (2-Hydr oxy-1-isobu tyl-pen t-4-en yl)-car bam -
ic a cid ben zyl ester (8). Sym-collidine (1.35 mL, 10.0 mmol)
was added to a cooled (-10 °C) solution of a mixture (ca. 4:1) of
4 and 5 (3.36 mmol, 1.40 g) in acetonitrile (80 mL). Trifluoro-
acetic anhydride (16.8 mmol, 3.30 mL) was added dropwise and
the reaction was monitored by TLC (n-Hex/AcOEt 7:3). After
10 min the starting compound was consumed. Water was added,
the organics were extracted with AcOEt (3 × 50 mL), combined,

5640 J . Org. Chem., Vol. 66, No. 16, 2001
Notes
dried over anhydrous Na2SO4, filtered and the solvent removed
in vacuo. The residue was dissolved in a THF/H2O 4:1 mixture
(70 mL), cooled to 0 °C (water/ice bath), and NaBH4 was added
portionwise up to pH 7-8. After 5 min, a saturated NH4Cl
solution was added, followed by a 1N HCl solution until pH 1-2
was reached, then the reaction mixture was diluted with water,
the organics were extracted with AcOEt (3 × 50 mL), combined,
dried over anhydrous Na2SO4, filtered and the solvent removed
in vacuo. The residue was purified by FC (n-Hex/AcOEt 9:1 to
4:1) to give (1S,2S)-8 (740 mg, 76%).
room temperature under H2 atmosphere, according to TLC
reaction monitoring (CHCl3/AcOEt/AcOH 7:3:0.1), then filtered
on a Celite pad, washing with MeOH. The solvent was removed
in vacuo and the crude purified with acidic DOWEX-50W ion-
exchange resin, affording (3S,4S)-1 as a white powder (109 mg,
57%): mp 200 °C (dec); [R]D20 -22.7 (c 0.70, H2O);271H NMR (400
MHz, CD3OD) δ 1.08 (3H, d, J ) 6.3), 1.10 (3H, d, J ) 6.3), 1.60-
1.74 (2H, m), 1.80-1.91 (1H,m), 2.58 (1H, dd, J ) 15.3, 7.5),
2.71 (1H, dd, J ) 15.3, 5.0), 3.41-3.48 (1H, m), 4.18 (1H, ddd,
J ) 7.5, 5.0, 5.5); 13C NMR (63 MHz, CDCl3) δ 181.4, 70.9, 56.5,
44.0, 41.1, 26.5, 24.7, 23.6; m/z (EI, %) 158 (MH+ - H2O, 38),
157 (M - H2O, 35), 114 (75), 100 (85).
20
(1S,2S)-8: Rf ) 0.35 (c-Hex/AcOEt 4:1); [R]D - 20.1 (c 1.4,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.92 (3H, d, J ) 6.0), 0.94
(3H, d, J ) 6.0), 1.30-1.39 (1H, m), 1.47-1.56 (1H, m), 1.61-
1.72 (1H, m), 1.75-1.87 (1H, br signal), 2.14-2.24 (1H, m), 2.28-
2.36 (1H, m), 3.59-3.65 (1H, m), 3.69-3.78 (1H, m), 4.89 (1H,
br d, J ) 9.0), 5.08-5.20 (4H, m), 5.77-5.90 (1H, m), 7.30-7.40
(5H, m);13C NMR (63 MHz, CDCl3) δ 156.7, 136.7, 134.4, 128.5,
128.1, 128.0, 118.4, 72.6, 66.7, 52.7, 42.0, 39.1, 24.8, 23.2, 22.2;
FT-IR (film) (cm-1) 3433, 2957, 1698, 1520; MS (DIS EI 70 eV)
m/z (%) 292 (MH+, 2), 220 (10), 176 (18), 130 (10), 91 (100).
Syn th esis of 4-(Ca r ba m ic a cid ben zyl ester )-3-h yd r oxy-
6-m eth yl-h ep ta n oic a cid (9). A quantity of 3 N Aqueous H2-
SO4 (5.0 mL) was added dropwise to a solution of (1S,2S)-8 (740
mg, 2.54 mmol) in acetone (40 mL) cooled to 0 °C. Then, an
aqueous solution (70 mL) of KMnO4 (2.41 g, 15.26 mmol) was
added dropwise at the same temperature. The reaction was
quenched after 5 min by portionwise addition of solid Na2SO3
until a brown slurry was obtained. A 3N H2SO4 solution was
then added up to pH 2, the mixture was diluted with water and
the organics were extracted with AcOEt (3 × 60 mL). The
combined extracts were dried over anhydrous Na2SO4, filtered
and the solvent removed in vacuo. The crude was purified by
FC (CHCl3/AcOEt/AcOH 7:3:0.1) to give (3S,4S)-9 (376 mg, 48%)
Syn th esis of (3R,4R)-Sta tin e (en t-1). It was obtained
through an identical sequence of reactions from (1R,2S,RS)-4.
20
[R]D + 16.1 (c 0.31, H2O);27 the other physical and spectral
properties matched those of the enantiomer.
Syn th esis of (3S,4R)-Sta tin e (10). From (1R,2R,SS)-7, fol-
lowing the same general procedures above-described, (3S,4R)-
20
10 was obtained (65 mg, 34% overall yield): mp 195 °C; [R]D
+19.4 (c 0.5, H2O);28 1H NMR (500 MHz, CD3OD) δ 0.93 (3H, d,
J ) 6.6), 0.94 (3H, d, J ) 6.6), 1.37-1.42 (2H, m), 1.62-1.73
(1H, m), 2.26 (1H, dd, J ) 16.0, 2.5), 2.85 (1H, dd, J ) 16.0,
6.7), 3.63 (1H, dt, J ) 7.5, 2.0), 4.25 (1H, ddd, J ) 6.7, 2.5, 2.0);
13C NMR (63 MHz, CDCl3) δ 180.9, 74.2, 64.4, 44.4, 40.9, 26.8,
24.7, 23.6; FT-IR microscopy (solid) (cm-1) 3262, 2958, 1691,
1468, 1388; MS (DIS EI 70 eV) m/z (%) 176 (MH+, 38), 158 (MH+
- H2O, 1), 118 (5), 114 (5).
Ack n ow led gm en t. We thank M.U.R.S.T. COFIN
and C.N.R.-C.S.S.O.N. for financial support.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of compounds (+)- and (-)-1, 4-10, ORTEP and crystal
data of compound (1S,2S,RS)-7. This material is available free
of charge via the Internet at http://pubs.acs.org.
20
Rf 0.35; mp 117-118 °C (diisopropyl ether); [R]D -33.3 (c 1.0,
MeOH); 1H NMR (250 MHz, CD3OD) δ 0.91 (3H, d, J ) 6.0),
0.93 (3H, d, J ) 6.0), 1.25-1.38 (1H, m), 1.42-1.55 (1H, m),
1.56-1.71 (1H, m), 2.35 (1H, dd, J ) 15.8, 8.6), 2.46 (1H, dd, J
) 15.8, 4.4), 3.66-3.78 (1H, m), 3.97-4.05 (1H, m), 5.08 (2H, br
s), 6.64 (1H, br d, J ) 9.4), 7.25-7.40 (5H, m);13C NMR (63 MHz,
CDCl3) δ 175.5, 158.8, 138.4, 129.4, 128.9, 128.6, 71.0, 67.5, 54.3,
41.5, 39.7, 25.9, 23.6, 22.4; FT-IR microscopy (solid) (cm-1) 3484,
3381, 2959, 1725, 1693, 1521; MS (DIS EI 70 eV) m/z (%) 310
(MH+, 18), 292 (21), 266 (3), 220 (45), 176 (60).
J O010383Z
(27) A number of different values of optical rotatory powers for 1
and ent-1 have been reported. Some of them, measured in water, are
20
listed below. For (3S, 4S)-1: ref 10a, [R]D -20.8 (c 2.3, H2O); ref 5,
[R]D20 -20.4 (c 0.50, H2O). For (3R, 4R)-1: ref 11b, [R]D20 +18.3 (c 0.43,
20
H2O); ref 7f, [R]D +20 (c 1, H2O).
(28) Some optical rotatory powers for 10 and ent-10 reported in the
Syn th esis of (3S,4S)-Sta tin e (1). To a solution of (3S,4S)-9
(337 mg, 1.09 mmol) in MeOH (15 mL) was added a catalytic
amount of Pd(OH)2-C. The slurry was vigorously stirred 3 h at
20
literature are listed below. For (3R, 4S)-10: ref 7f, [R]D -19 (c 0.73,
20
20
H2O). For (3S, 4R)-10: ref 9j, [R]D +19.8 (c 0.51, H2O); ref 7f, [R]D
+18 (c 0.88, H2O).