The Preparation of (1α,3β)-3-Hydroxycholestane-4,6-diene- 1,25-diol Diacetate from a 5,7-Diene Precursor: A New Method for the Synthesis of Heteroannular Dienes

Article abstract of DOI:10.1021/jo048576k

Starting from the 7α-bromide 5a, a regioselective synthesis of (1α,3β)-3-hydroxycholestane-4,6-diene-1,25-diol diacetate (2) is described. The preparative removal of contaminating 5,7-diene 9 was accomplished by the formation of the corresponding Diels-Alder adduct 11. Acetylation of the diacetate 2 followed by acid-catalyzed elimination and rearrangement yielded styrene 13.

Full text of DOI:10.1021/jo048576k

sulfide as the key step.7,8 A second synthesis was reported
by Senanayake, who used chiral sulfinate as a key
intermediate.9
Synthesis of Enantiopure
tert-Butanesulfinamide from
tert-Butanesulfinyloxazolidinone
It is well-established that N-acylated sulfinamides are
at least 2 orders of magnitude more reactive than
sulfinates.10 Using the differential reactivity between the
sulfonamide bond and the sulfinate bond to selectively
cleave the N-S bond rather than the O-S bond in the
N-acylated 1,2,3-oxathiazolidine-2-oxide system by a
Grignard reagent leads to the formation of the chiral
sulfinate, an intermediate suitable for further syntheses
of optical pure TBSA and sulfoxides, as has been de-
scribed in Senanayake’s synthesis of TBSA9 and in the
Ruano’s syntheses of sulfoxides (Scheme 1).11
Yong Qin,*,† Canhui Wang,‡ Zhiyan Huang,†
Xue Xiao,† and Yaozhong Jiang*,‡
Department of Chemistry of Medicinal Natural Products,
West China School of Pharmacy, Sichuan University,
Chengdu 610041, P. R. China, and Graduate School of
Chinese Academy of Sciences, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences,
Chengdu 610041, P. R. China
yanshuqin@yahoo.com
Received August 15, 2004
SCHEME 1
Abstract: A three-step procedure for the preparation of
enantiopure tert-butanesulfinamide 6 in 51% overall yield
is described starting from (1R,2S)-N-Cbz-1,2-diphenylami-
noethanol. The key step is the reaction of tert-butylmagne-
sium chloride with N-Cbz-4,5-diphenyl-1,2,3-oxathiazolidine-
2-oxide 2 to afford the optical pure tert-butylsulfinyl-4,5-
diphenyl-1,3-oxazolidinone 5 via an 1,5-alkoxy anion rear-
rangement, which is then subject to ammonia hydrolysis
with LiNH2 in liquid ammonia to give (R)-tert-butanesul-
finamide 6.
Encouraged by the above reports, our synthesis of
enantiopure TBSA (6) was originally envisaged to use the
similar strategy, namely, by the Grignard addition to
structurally similar N-acylated (4S,5R)-4,5-diphenyl-
1,2,3-oxathiazolidine-2-oxide 2 to form sulfinate 3, fol-
lowed by ammonia hydrolysis of resulting sulfinate 3 to
give 6. However, this plan encountered an unexpected
problem in the ammonia hydrolysis step. In this paper,
we report an unusual 1,5-alkoxy anion rearrangement
of 2 to afford the tert-butylsulfinyl-4,5-diphenyl-1,2,3-
oxazolidinone 5, which serves as a key intermediate for
the synthesis of enantiopure TBSA (Scheme 2).
Since its introduction by Ellman in 1997 as a versatile
ammonia equivalent, chiral tert-butanesulfinylamide1
(TBSA, 6) has been demonstrated as a very useful
auxiliary as a result of the characteristics of high
stereoselectivity in asymmetric induction and ease of
removal of the sulfinyl group compared with other amine
auxiliaries.2-5 Recently, chiral TBSA has also been used
as a ligand in asymmetric catalysis.6 Considering the
importance of TBSA in asymmetric synthesis, the search
for an efficient method for the preparation of enantiopure
TBSA is a most interesting topic in synthetic chemistry.
After surveying the literature, there were only two
methods found for the preparation of enantiopure TBSA.
One was the elegant synthesis reported by Ellman for
the asymmetrically catalytic oxidation of di-tert-butyl-
SCHEME 2
† Sichuan University.
‡ Chinese Academy of Sciences.
(1) Liu, G.-Ch.; Cogan, D. A.; Ellman, J. A. J. Am. Soc. Chem. 1997,
119, 9913.
According to the original plan, our attention was first
directed to the preparation of optical pure N-acylated
(2) For a recent review on tert-butylsulfinyl imine addition, see:
Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984. For a review of uncovered literatures, see: (a) Jacobsen, M. F.;
Skrydstrup, T. J. Org. Chem. 2003, 68, 7122. (b) Ellman, J. A.;
McMahon, J. P. Org. Lett. 2004, 6, 1645. (c) Kells, K. W.; Chong, J. M.
Org. Lett. 2003, 5, 4215. (d) Evans, J. W.; Ellman, J. A. J. Org. Chem.
2003, 68, 9948. (e) Prakash, G. K. S.; Mandal, M. J. Am. Soc. Chem.
2002, 124, 6538.
(3) (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Soc. Chem. 2003,
125, 11276. (b) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Soc. Chem.
2002, 124, 6518.
(4) Backes, B. J.; Dragoli, D. R.; Ellman, J. A. J. Org. Chem. 1999,
64, 5472.
(7) (a) Cogan, D. A.; Liu, G.-Ch.; Kim, K.; Backes, B. J.; Ellman, J.
A. J. Am. Soc. Chem. 1998, 120, 8011. (b) Blum, S. A.; Bergman, R.
G.; Ellman, J. A. J. Org. Chem. 2003, 68, 150. (c) Weix, D. J.; Ellman,
J. A. Org. Lett. 2003, 5, 1317.
(8) Optically pure tert-butanethiosulfinate prepared by chiral inclu-
sion resolution with BINOL was reported by: Liao, J.; Sun, X.-X.; Cui,
X.; Yu, K.-B.; Zhu, J.; Deng, J.-G. Chem. Eur. J. 2003, 9, 2611.
(9) Han, Zh.-X.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.;
Senanayake, Ch. H. J. Am. Soc. Chem. 2002, 124, 7880.
(10) (a) Garcia-Ruano, J. L.; Alonso, R.; Zarzuelo, M. M.; Noheda,
P. Tetrahydron: Asymmetry 1995, 6, 1133. (b) The tert-butylsulfinyl-
4-phenyl-1,3-oxazolidinone was prepared by Evans; see: Evans, D. A.;
Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.; Cherry, D. J. Am.
Soc. Chem. 1992, 114, 5977.
(5) (a) Owens, T. D.; Souers, A. J.; Ellman, J. A. J. Org. Chem. 2003,
68, 3. (b) Owens, T. D.; Hollander, F. J.; Oliver, A. G.; Ellman, J. A. J.
Am. Soc. Chem. 2001, 123, 1539.
(6) (a) Schenkel L. B.; Ellman, J. A. J. Org. Chem. 2004, 69, 1800.
(b) Schenkel, L. B.; Ellman, J. A. Org. Lett. 2003, 5, 545.
(11) Garcia-Ruano, J. L.; Alemparte, C.; Aranda, M. T.; Zarzuelo,
M. M. Org. Lett. 2003, 5, 75.
10.1021/jo048576k CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/02/2004
J. Org. Chem. 2004, 69, 8533-8536
8533

TABLE 1. Synthesis of
TABLE 2. Syntheses of Sulfinate 3 and
4,5-Diphenyl-1,2,3-oxathiazolidine-2-oxide 2
tert-Butylsulfinyl-4,5-diphenyl-1,3-oxazolidinone 5
entry
1
basea
2 (endo/exo)b
yieldc
1
1a
1b
1b
1b
1c
1c
1c
1c
1c
1c
1d
1d
1d
entry
2
solvent
(temp) °C
3 (%)
4 (%)
5 (%)
2
TEA
71/29
14/86
91/9
70
83
68
86
46
61
45
69
92
82
16
87
1
2
3
4
5
6
7
8
2b
2b
2b
2b
2c
2c
2d
2d
DMC
DMC
toluene
THF
DMC
THF
DMC
THF
-45
-78
-45
-45
-45
-45
-45
-45
25
63
tr
51
31
tr
3
2,4,6-colidine
DMAP
4
5
TEA
75/25
33/67
74/26
99/1
13
61
7
28
23
tr
6
2,4,6-colidine
DMAP
7d
8e
9
83
46
76
DMAP
19
21
24
tr
DMAP
99/1
10f
11
12
13
DMAP
83/17
71/29
16/84
89/11
TEA
2,4,6-colidine
DMAP
endo product was the major isomer, whereas 2,4,6-
collidine inverted the endo/exo selectivity, with the exo
product being the major isomer (entries 3, 6, and 12).
Most interestingly, for the preparation of 2c, the yield
(92%) was greatly increased by simply switching the
addition order of DMAP and SOCl2 with sacrifice of the
endo/exo selectivity from 99/1 to 83/17 (entry 10). Al-
though the endo/exo isomers of 2b and 2c were insep-
arable by chromatography, the major isomers endo-2b
and endo-2c could be easily recrystallized from a mixture
of EtOAc/petroleum ether to give pure endo product.
Endo-2d could be readily separated from the minor
diastereomer exo-2d by chromatography.
For the preparation of 2c, we did improve the diaste-
reoselectivity from 86% de to 99% de with a slight
enhancement of the yield from 57% to 69% under similar
condition when compared to Ruano’s synthesis of norephe-
drine-derived N-Cbz-1,2,3-oxathiazolidine-2-oxide.11 The
improved diastereoselectivity is ascribed to the size
change of substituent at position 4 of 2 from a methyl
group (norephedrine) to a phenyl group (1,2-diphenyl-
aminoethanol).
According to our original plan for selective cleavage of
the N-S bond of N-acylated 4,5-diphenyl-1,2,3-oxathia-
zolidine-2-oxides 2 by tert-butylmagnesium chloride to
afford the sulfinates 3 for the further synthesis of TBSA,
6, we explored the addition of tert-butylmagnesium
chloride (1.5 equiv) to the endo-2 at low temperature in
different solvents as depicted in Table 2.
Unfortunately we were not able to prepare the sulfi-
nates 3 in yields greater than 63% by the addition
reaction of tert-butylmagnesium chloride to 2 under a
variety of reaction conditions. The lower temperature
provided a slight selectivity preference for the formation
of sulfinate 3 when 2b (R ) Boc) reacted with tert-
butylmagnesium chloride in DMC but required a longer
reaction time (entries 1 and 2). Toluene was not the
suitable solvent for the addition reaction (entry 3). THF
provided sulfinate 3b and sulfinamide 4b in low yields
(entry 4). The poor reactivity and selectivity of 2b were
probably due to the steric effects of the Boc group on the
nitrogen and phenyl group at the 4 position, which
shielded the attack of the bulky tert-butylmagnesium
chloride at the more reactive N-S bond. Evidence for this
a Conducted by mixing compound 1 with base in CH2Cl2 at -45
°C, followed by addition of SOCl2. b Determined by 1H NMR, the
assignment of the stereochemistry of endo/exo-2 is based on the
deshielding of the heterocyclic protons which are cis to the
sulfinylic oxygen, see ref 11 and 13. c Isolated yield. d At 25 °C.
e At -78 °C. f Inverted addition order of DMAP with SOCl2.
1,2,3-oxathiazolidine-2-oxides 2. Because a variety of
protective groups at the nitrogen of 1,2-diphenylamino-
ethanol 112 with different sizes may induce different
diastereoselectivities of 4,5-diphenyl-1,2,3-oxathiazoli-
dine-2-oxides 2, investigation of the steric effect of that
substituent on the diastereoselectivity of ring formation
was conducted by choosing Ts, Boc, Cbz, and methoxy-
carbonyl groups as nitrogen protecting groups. The
results are shown in Table 1.
Initial efforts of synthesizing N-tosylate 2a have failed
(Table 1, entry 1) as a result of the very poor solubility
of 1a in most aprotic solvents. Compounds 1b,c also
showed poor solubility in most solvents, and CH2Cl2 was
found to be the best choice of solvent in light of solubility.
In Ruano’s systematic study of the preparation of 1,2,3-
oxathiazolidine-2-oxides bearing an N-Cbz norephedrine
skeleton, it was found that a temperature around
-45 °C usually gave the best diastereoselectivity and
yield. We roughly tested the reaction at three tem-
peratures (25, -45, and -78 °C) in the preparation of
2c using DMAP as base. At room temperature, significant
amounts of byproducts were produced with the loss of
yield and diastereoselectivity (entry 7). At -78 °C, the
reaction proceeded slowly to give 2c in 99/1 endo/exo
selectivity and low yield (45% yield, entry 8) compared
with the reaction conducted at -45 °C (69% yield,
entry 9).
After screening the effect of bases TEA, 2,4,6-colidine,
and DMAP on the diastereoselectivity, we observed that
DMAP provided the best endo/exo selectivity with a ratio
of 91/9 for 2b (entry 4), a ratio of 99/1 for 2c (entry 9),
and a ratio of 89/11 for 2d (entry 13) in good yields. The
(12) (1R,2S)-N-Alkoxycarbonyl-1,2-diphenylamino-ethanols 1 were
prepared by treatment of (1R,2S)-1,2-diphenylaminoethanol with TsCl,
Boc2O, CbzCl, and MeOCOCl in aqueous THF in the presence of Na2-
CO3 in yields of 93% (1a), 97% (1b), 94% (1c), and 99% (1d),
respectively.
8534 J. Org. Chem., Vol. 69, No. 24, 2004

SCHEME 4. Ammonia Hydrolysis of Sulfinate 3b
steric effect was obtained by exchanging the Boc group
(2b) for the less hindered Cbz group (2c). The reaction
with tert-butylmagnesium chloride in DMC provided
more selectivity to afford 3c as the major product (entries
1 and 5). Surprisingly, when 2c and 2d reacted with tert-
butylmagnesium chloride in THF at -45 °C, the reaction
gave the tert-butylsulfinyl-4,5-diphenyl-1,3-oxazolidinone
5 as the major product (83% for 2c, entry 6 and 76% for
2d, entry 8), as well as sulfinates 3 (7% for 2c, entry 6
and 21% for 2d, entry 8). When the reaction of 2d with
tert-butylmagnesium chloride was conducted in DMC, 5
was also isolated in 46% yield, as well as 3 (19% yield)
and 4 (24% yield, entry 7).
conversion) when tert-butylsulfinate 3b was reacted with
LiNH2 in liquid ammonia at -78 °C for 0.5 h.
In view of the mechanism for the formation of 5, it was
reasonable to believe that 5 was derived from 4′ by a
consecutive intramolecular nuclephilic attack of alkoxy
anion formed during the reaction under basic conditions
(Scheme 3). Compound 4′ could be produced either by the
Having failed at our attempts to convert tert-butylsul-
finate 3b to TBSA (6) with LiHMDS or LiNH2, we turned
our attention to the conversion of tert-butylsulfinyl-4,5-
diphenyl-1,3-oxazolidinone 5 to 6. Sulfinyloxazolidinones
are potentially versatile intermediates for the syntheses
of chiral sulfoxides, sulfinates, and sulfinamides. Evans
has described the syntheses of 2-benzylaminoethanol-
derived sulfinyloxazolidinones by oxidization of N-(aryl-
thio)-oxazolidinone and N-(alkylthio)-oxazolidinone
with m-CPBA in less than 2.5:1 diastereoselectivity or
by sulfinylation of oxazolidinone with arylsulfinyl chlo-
ride in less than 2:1 diastereoselectivity (Scheme 5).10b
SCHEME 3. A Plausible Mechanism for the
Formation of 5
SCHEME 5. Evans Synthesis of
Sulfinyloxazolidinone
direct attack of tert-butylmagnesium chloride at the less
active and less hindered S-O bond of 2 or by the attack
of tert-butylmagnesium chloride at the more active but
more hindered S-N bond of 2 to afford 3′, followed by
the migration of sulfur atom in 3′ from oxygen atom to
nitrogen atom. Because a similar ratio of 3b to 4b (2.3:
1) is obtained by treatment of 3b with LiNH2 at -78 °C
(see next paragraph), the observed different ratios of 3b
to 4b at -78 °C (2.0:1, Table 2, entry 2) and at -45 °C
(1:2.0, Table 2, entry 1) could be rationalized by the
equilibration of the reaction mixture at the higher
temperature rather than a kinetic selectivity of addition.
Because the Boc protecting group is more stable under
basic conditions and is more hindered than Cbz and
methoxycarbonyl groups, which are sensitive to the
attack by alkoxy anion, it is not surprising that the
addition reaction of tert-butylmagnesium chloride with
2b does not form 5.
Apparently, the latter method was limited to the avail-
ability of alkylsulfinyl chloride.
Because tert-butylsulfinyl-4,5-diphenyl-1,3-oxazolidi-
none 5 should be more reactive than sulfinate 3 and was
synthesized in 83% yield from the easily prepared 2c,
ammonia hydrolysis of 5 would be an alternative to
synthesize TBSA (6). Indeed, when 5 was treated with
in situ prepared LiNH2 in liquid ammonia at -78 °C, 4,5-
diphenyl-1,3-oxazolidinone 7 and (R)-6 were isolated in
91% yield and 89% yield (98.6% ee), respectively (Scheme
6). A single recrystallization from hexane provided the
Because the tert-butylsulfinate 3b could be prepared
in 63% yield from 2b and a similar sulfinates had been
converted to TBSA with LiHMDS or LiNH2 at -78 °C,9
we attempted to hydrolyze the sulfinate 3b with LiHMDS
at -78 °C in THF. However, our efforts were not
successful (Scheme 4),14 affording complete recovery of
3b. Instead of yielding 5 or 6, partial intramolecular
migration of sulfur atom occurred to produce 4b (29%
SCHEME 6. Synthesis of TBSA (6)
enantiopure (R)-6.
(13) Wudl, F.; Lee, T. B. K. J. Am. Chem. Soc. 1973, 95, 6349.
(14) The cleavage of noncyclic N-acyl-tert-butylsulfinamide some-
times was not successful; see ref 4.
In summary, we have developed a new synthetic route
to synthesize tert-butylsulfinyl-4,5-diphenyl-1,3-oxazoli-
J. Org. Chem, Vol. 69, No. 24, 2004 8535

dinone 5 from the easy prepared 2c and 2d. Importantly,
5 has been well demonstrated as a key intermediate for
the synthesis of enantiopure TBSA 6 in high yield in our
study.
Young Teachers Program), and the Excellent Youth
Foundation of Sichuan Province, P. R. China.
Supporting Information Available: Detailed experi-
mental procedures and mp, [R]25D, IR, 1H NMR, 13C NMR,
HRMS, and elemental analyses data for compounds 1-6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (no.
20372048), Ministry of Education (under the Excellent
JO048576K
8536 J. Org. Chem., Vol. 69, No. 24, 2004