Voituriez et al.
SCHEME 3. Access to (-)-r-Conhydrine 1
HRMS (ESI) calcd for C10H20NO3S [M + H]+: 234.1158, found:
conditions, gave a crystalline compound 10 nearly quantitatively
(Scheme 2). The anti-relationship between the two stereogenic
carbons created in the key-step reaction (i.e., the condensation
of allenylzinc (()-4 onto imine 7) was confirmed by the single-
crystal X-ray analysis of the compound 10.16 The complete
hydrogenation (1 atm) of the alkyne 10 over palladium on
charcoal afforded 11 in quantitative yield. Reduction of the
lactam with LiAlH4 and subsequent deprotection of the alcohol
with HCl (4 M in dioxane) furnished (-)-R-conhydrine 1 with
76% yield over the last two steps and 41% overall yield from
5 (Scheme 3).
20
234.1158; [R]D ) +230.0 (c 1.70, CHCl3).
(+)-(5R,6S,SS)-Ethyl 5-(tert-Butylsulfinamido)-6-(methoxy-
methoxy)-8-(trimethylsilyl)oct-7-ynoate (8). To a stirred solution
of (3-(methoxymethoxy)prop-1-ynyl)trimethylsilane (760 µL, 4.00
mmol) and TMEDA (60 µL, 0.40 mmol) in anhydrous Et2O (35
mL) under a nitrogen atmosphere, at -78 °C, was added dropwise
sec-butyllithium (1.3 M in 92% cyclohexane/hexane, 3.08 mL, 4.00
mmol). The resulting clear yellow mixture was stirred for 1 h at
-78 °C, and then a 1 M ethereal solution of ZnBr2 (4.0 mL, 4.00
mmol) was added. The resulting white slurry of allenylzinc was
stirred at -78 °C for an additionnal 20 min before enantiopure
(SS)-ethyl 5-(tert-butylsulfinylimino)pentanoate 7 (234 mg, 1.00
mmol) in anhydrous Et2O (2.0 mL) was added over a period of 2
min. After 1 h of stirring at -78 °C, aq 1 M HCl (35 mL) was
added and the mixture was warmed to room temperature. The layers
were separated, and the aqueous one was extracted twice with Et2O.
The combined organic layers were washed with saturated NaHCO3
solution, water, and brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash chromatography on silica
gel (75% Et2O/cyclohexane) to produce the desired compound 8
as an oil (356 mg, 88%): Rf 0.36 (pure Et2O); 1H NMR (400 MHz,
CDCl3) δ 4.84 (d, J ) 6.5 Hz, 1H), 4.51 (d, J ) 6.5 Hz, 1H), 4.23
(d, J ) 3.8 Hz, 1H), 3.59 (s, 3H), 3.46 (d, J ) 8.3 Hz, 1H), 3.36-
3.31 (m, 1H), 3.30 (s, 3H), 2.30 (dt, J ) 7.3, 2.0 Hz, 2H), 1.93-
1.81 (m, 1H), 1.81-1.61 (m, 2H), 1.58-1.46 (m, 1H), 1.16 (s,
9H), 0.09 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.7, 101.3,
94.3, 92.9, 70.2, 60.1, 56.4, 55.9, 51.5, 33.5, 31.6, 22.7, 21.2, -0.2;
IR: νmax ) 3236, 2900, 2361, 2342, 1737, 1438, 1363, 1250, 1151,
1024, 842, 760 cm-1; HRMS (ESI) calcd for C18H36NO5SSi [M +
H]+: 406.2078, found 406.2077; [R]D20 ) +90.4 (c 1.65, CHCl3).
(-)-R-Conhydrine {[R]20D ) -8.7 (c 0.78, EtOH), Mp 118
°C} so obtained was physically and spectroscopically identical
to the literature data {[R]27 ) -8.6 (c 0.68, EtOH), Mp 118
D
°C}.6a The negative sign of the optical rotation is the ultimate
confirmation of the expected relative and absolute (6R,7S)-
configuration of the product.
Conclusion
In summary, the condensation of a racemic 3-alkoxy alle-
nylzinc onto the enantiopure (Ss)-N-tert-butanesulfinimine de-
rived from 5-oxopentanoate allowed us to develop an efficient
stereoselective synthesis of (-)-R-conhydrine. Indeed, the total
synthesis of (-)-R-conhydrine has been achieved in seven steps
with 41% overall yield. To the best of our knowledge, this is
the most efficient synthesis in the conhydrine family in terms
of yield. Further syntheses of compounds presenting biological
interest is now under investigation and will be reported in due
course.
(+)-(6R)-[(1S)-1-(Methoxymethoxy)-3-(trimethylsilyl)prop-2-
ynyl]piperidin-2-one (9). To a stirred solution of 8 (150 mg, 0.37
mmol) in MeOH (3 mL) was added a 4 M HCl solution in dioxane
(925 µL, 3.70 mmol), under a nitrogen atmosphere at 0 °C. After
2 h of stirring at 0 °C, saturated NaHCO3 solution was added and
the MeOH was evaporated. The aqueous layer was extracted with
EtOAc, and the combined organic layers were washed with water
and brine, dried over MgSO4, and concentrated in vacuo. The crude
product was taken up in CH2Cl2 (4 mL), and TEA (205 µL, 1.48
mmol) was added. The solution was stirred 2 h, and water was
added. The aqueous layer was extracted with EtOAc, and the
combined organic layers were washed with water and brine, dried
over MgSO4, and concentrated in vacuo. The residue was purified
by flash chromatography on silica gel (60% EtOAc/cyclohexane)
to produce the desired compound 9 as an oil (78 mg, 78%): Rf
Experimental Section
General. See the Supporting Information.
(+)-(SS)-Ethyl 5-(tert-Butylsulfinylimino)pentanoate (7). The
synthesis was performed according to the previously described
procedure.9a Under a nitrogen atmosphere, a suspension of ethyl
5-oxopentanoate13 5 (520 mg, 4.00 mmol), (SS)-(+)-tert-butane-
sulfinamide 6 (>99% ee by chiral GC analysis on a Lipodex E
capillary column, 404 mg, 3.33 mmol), PPTS (42 mg, 0.17 mmol),
and anhydrous MgSO4 (2.00 g) in CH2Cl2 (6 mL) was stirred for
14 h at room temperature. The mixture was filtered through a pad
of Celite and concentrated in vacuo. The residual oil was purified
by flash chromatography on silica gel (80% Et2O/cyclohexane) to
produce the desired compound 7 as an oil (626 mg, 81%): Rf 0.69
1
0.30 (60% EtOAc/cyclohexane); H NMR (400 MHz, CDCl3) δ
1
(pure Et2O); H NMR (400 MHz, CDCl3) δ 7.99 (t, J ) 4.3 Hz,
6.09 (bs, 1H), 4.92 (d, J ) 6.8 Hz, 1H), 4.56 (d, J ) 6.8 Hz, 1H),
4.21 (d, J ) 5.3 Hz, 1H), 3.56 (m, 1H), 3.36 (s, 3H), 2.45-2.35
(m, 1H), 2.34-2.20 (m, 1H), 1.98-1.90 (m, 2H), 1.70-1.58 (m,
2H), 0.14 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.2, 100.0,
1H), 3.59 (s, 3H), 2.51 (dt, J ) 7.3, 4.3 Hz, 2H), 2.33 (t, J ) 7.3
Hz, 2H), 1.90 (quint, J ) 7.3 Hz, 2H), 1.11 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 173.3, 168.3, 56.5, 51.6, 35.1, 33.1, 22.3,
20.4; IR: νmax ) 2955, 1734, 1623, 1437, 1250, 1164, 1081 cm-1
;
94.1, 93.9, 69.3, 56.0, 55.6, 31.6, 24.7, 19.3, -0.2; IR: νmax
)
2955, 2360, 1667, 1408, 1250, 1150, 1101, 1026, 841, 760 cm-1
;
HRMS (ESI) calcd for C13H24NO3Si [M + H]+: 270.1520, found:
(15) Ruano, J. L. G.; Aleman, J.; Cid, M. B. Synthesis 2006, 4, 687-
691.
(16) CCDC 641262 contains the supplementary crystallographic data for
c.ac.uk/conts/retrieving.html [or from Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, U.K. Fax: +44(1223)-
366033. E-mail: deposit@ccdc.cam.ac.uk].
20
270.1517; [R]D ) +135.8 (c 1.20, CHCl3).
(+)-(6R)-[(1S)-1-(Methoxymethoxy)prop-2-ynyl]piperidin-2-
one (10). To a solution of 9 (60 mg, 0.22 mmol) in dry THF (3
mL) at room temperature was added a 1 M solution of TBAF in
THF (270 µL, 0.27 mmol). The solution was stirred 2 h, and water
5360 J. Org. Chem., Vol. 72, No. 14, 2007