Stereoselective radical addition of an acetal to sterically tuned enantiomerically pure N-sulfinyl imines

Article abstract of DOI:10.1248/cpb.58.265

Enantiomerically enriched sulfonamides were synthesized by the radical addition of an acetal to enantiomerically pure N-sulfinyl imines using dimethylzinc-air and boron trifluoride diethyl etherate. Higher levels of stereocontrol were observed by using a mesitylenesulfinyl group. Furthermore, an amine and an amino alcohol with high enantiomeric purity were obtainable from the sulfonamide product.

Full text of DOI:10.1248/cpb.58.265

February 2010
Notes
Chem. Pharm. Bull. 58(2) 265—269 (2010)
265
Stereoselective Radical Addition of an Acetal to Sterically Tuned
Enantiomerically Pure N-Sulfinyl Imines
Tito AKINDELE, Ken-ichi YAMADA, Takumi SEJIMA, Masaru MAEKAWA, Yasutomo YAMAMOTO,
Mayu NAKANO, and Kiyoshi TOMIOKA*
Graduate School of Pharmaceutical Sciences, Kyoto University; Yoshida, Sakyo-ku, Kyoto 606–8501, Japan.
Received October 17, 2009; accepted November 27, 2009; published online November 27, 2009
Enantiomerically enriched sulfonamides were synthesized by the radical addition of an acetal to enan-
tiomerically pure N-sulfinyl imines using dimethylzinc–air and boron trifluoride diethyl etherate. Higher levels of
stereocontrol were observed by using a mesitylenesulfinyl group. Furthermore, an amine and an amino alcohol
with high enantiomeric purity were obtainable from the sulfonamide product.
Key words asymmetric synthesis; radical reaction; dimethylzinc; sulfonamide
Given the ubiquitous nature of the C–N stereogenic center, stereocontrol. Herein, we detail our new findings along with
efficient synthetic methods continue to be developed for its a computational rationale for the improved levels of stereo-
installation in both simple and complex chemical struc- control.
tures.1—3) These methods could be broadly classified into re-
actions mediated by ionic or radical species. Majority of Results and Discussion
these methods are mediated by ionic species, requiring
As we previously reported,20) the reaction of (S)-N-
highly basic reagents which limit the substrate scope of these benzylidene-4-toluenesulfinamide (1a) with acetal 221) pro-
approaches, albeit the products are obtained in high yield and ceeded smoothly in the presence of trifluoroborane diethyl
enantioselectivity. On the other hand, methods involving rad- etherate using dimethylzinc–air to give a crude mixture in-
ical species4,5) are relatively under explored despite the po- cluding sulfinamide products 6a with a 9 : 1 diastereomeric
tential of this approach to deliver much more structurally ratio along with a trace amount of sulfonamide product 3a
varied products using milder reagents.
(ca. 1%). Subsequent oxidation of the crude products with
To date, the lack of a catalytic asymmetric radical addition m-chloroperbenzoic acid (m-CPBA) provided 3a with 80%
method to N-sulfonyl imines6,7) has made the use of chiral N- ee in 92% yield (Table 1, entry 1). The enantiomeric ratio of
sulfinyl imines as radical acceptors, for creating predictable 3a was the same as the diastereomeric ratio of 6a in the
stereodefined C–N stereogenic centers in sulfonamides, an crude mixture, showing that no racemization took place dur-
appealing alternative synthetic strategy. Indeed, the pioneer- ing the m-CPBA oxidation.
ing works of Davis and Ellman on the synthesis and reactiv-
We reasoned that by substituting a bulkier group for the p-
ity of N-sulfinyl imines have given the synthetic community tolyl group on the sulfur stereogenic center would presum-
a readily available and robust precursor of optically active ably lead to higher levels of stereocontrol. In fact, Davis and
amine compounds.8—16)
coworkers have reported improved levels of diastereoselec-
Due to this rarity of radical species-mediated methods as tivity in the synthesis of N-sulfinylaziridine 2-phosphonates
well as our ongoing interest in radical reactions,17—19) we
sought to improve the efficiency and substrate scope of our
Table 1. Asymmetric Radical Addition of Acetal 2 to N-Sulfinyl Imines
1a, 4a, and 5a)
initial report on radical addition of ethers and acetals to
enantiopure N-p-toluenesulfinyl aldimines.20) In this previous
report, an in-house dimethylzinc–air radical initiator was
used to generate carbon-centered a-alkoxyalkyl radicals
from ethers and acetals. Subsequent nucleophilic addition of
the radicals to the enantiopure N-sulfinyl imines followed by
oxidation afforded the sulfonamide adducts in enantiomeri-
cally enriched forms. It is noteworthy that boron trifluoride
diethyl etherate was essential for faster reaction rate while a
sterically hindered acetal was crucial to good stereocontrol
(Chart 1).
Me2Zn BF3OEt2 Time
Yield
(%)
eeb)
(%)
Subsequent investigations have led to improved levels of
Entry
Imine
Product
(eq)
(eq)
(h)
1d)
2
3
1a
4a
4a
5
3
9
6
6
1
1
2
2
2
51
21
23
3a
9a
9a
92
73
73
77
80
92 (98)c)
95
4
10
87
a) Acetal 2 (125 eq) was used as solvent.22) Air was introduced into the reaction
mixture at a rate of 0.5 l/(h·mol). b) Determined by HPLC analysis. c) After re-
crystallization from ethyl acetate/hexane. d) Data from ref. 20.
Chart 1. Asymmetric Radical Addition of Acetal 2 to N-Sulfinyl Imines 1
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: tomioka@pharm.kyoto-u.ac.jp

266
Vol. 58, No. 2
Table 2. Comparison of Asymmetric Radical Addition of Acetal 2 to N-
Sulfinyl Imines 1 and 4a)
from N-sulfinyl imines and lithium diethyl iodomethylphos-
phonates by increasing the size of the sulfinyl group.23) They
also observed increased level of stereoselectivity when bulky
N-sulfinyl imines were reacted with prochiral lithium eno-
lates of Weinreb amides to give syn-a-substituted b-amino
Weinreb amides.24) Also, Senanayake and coworkers have re-
ported a highly diastereoselective addition of phenylmagne-
sium bromide to N-sulfinyl imines by tuning the size of the
sulfinyl moiety.25) Indeed, utilizing (S)-N-2,4,6-trimethylben-
zenesulfinyl benzaldehyde imine (4a)23) and 2 in the presence
of excess reagents and air afforded a crude 1 : 1 mixture of
sulfinamide 7a and sulfonamide 9a, which was subjected to
the oxidation to give 9a with 92% ee in moderate yield
(Table 1, entry 2). The N-sulfonyl analog of 4a was not de-
tected by TLC monitoring during the radical addition step. In
addition, high level of stereoselectivity was observed in spite
of much oxidized product 9a in the crude mixture. These ob-
servations suggested that non-stereoselective addition of
dioxolanyl radical to the N-sulfonyl analog of 4a, which is
possibly formed by oxidation of 4a during the reaction,
should be negligible. Thus, 9a in the crude mixture was
probably produced by oxidation of 7a during the longer reac-
tion time of the radical addition step. An increased amount of
trifluoroborane diethyl etherate accelerated the reaction,
which was complete within 21 h to give 9a with 95% ee after
the oxidation (entry 3). With comparison to (S)-N-p-toluene-
sulfinyl benzaldehyde imine (1a) (entry 1), this result repre-
sents an improvement in levels of enantiocontrol. Crystalliz-
ability of the product sulfonamide is advantageous; thus,
single recrystallization of 9a with 92% ee from ethyl ac-
Me2Zn BF3OEt2 Time
Yield
(%)
eeb)
(%)
Entry
Imine
Product
(eq)
(eq)
(h)
1c)
2
1b
4b
1c
4c
3
6
12
36
1
2
4
5
20
49
3b
9b
3c
9c
77
83
71
66
81
91
79
92
3c)
4
12
118
a) Acetal 2 (125 eq) was used as solvent.22) Air was introduced into the reaction
mixture at a rate of 0.5 l/(h·mol). b) Determined by HPLC analysis. c) Data from
ref. 20.
etate/hexane gave enantiomerically enriched 9a with 98% ee Chart 2. Determination of Absolute Configurations of Adducts 3a, 9a,
and 10
in 78% recovery yield (entry 2).
Further steric tuning of the sulfinyl group in the form (S)-
N-2,4,6-triisopropylbenzenesulfinyl benzaldehyde imine (5) thaldehyde derived N-sulfinyl imines relative to that of the
led to a decrease in product ee; thus the oxidation of the re- p-tolualdehyde derived N-sulfinyl imines (entry 1 vs. 3 and
sulting crude 2 : 1 mixture of sulfinamide 8 and sulfonamide entry 2 vs. 4).
10 gave 10 with 87% ee in comparable yield (entry 4). A
The sense of stereoinduction with 4a and 5 was consistent
similar observation was reported by Davis and coworkers with that observed for 1a (Chart 2). Indeed, reductive cleav-
during their investigations on the reaction of prochiral age of the sulfonyl groups of adducts 9a and 10 under
lithium enolates of Weinreb amides with N-sulfinyl imines.24) basic26,27) or acidic28) conditions produced amine 11. Tosyla-
As in the reaction of 4a, oxidation of 5 to the corresponding tion of 11 gave (R)-3a,20) whose absolute configuration was
achiral N-sulfonyl imine was not observed by TLC monitor- previously confirmed by subsequent conversion into known
ing. Besides, the amount of sulfonamide product 10 (ca. alcohol 12.29) No racemization was observed through all
33%) in the crude mixture of the radical addition step with 5 these transformations. Unfortunately, reduction of the acetal
was less than that with 4a to give 9a (ca. 50—66%), proba- moiety of 9a with TiCl4–Et3SiH20) resulted in partial racem-
bly due to a steric hindrance of the triisopropylphenyl group ization of the product, a mesitylenesulfonamide analog of 12
toward the S-oxidation. Based on these facts, the possibility (from 92% ee to 87% ee) in 55% yield.
of oxidation of 5 before the addition of the dioxolanyl radical
should be unlikely.
To rationalize the observed stereochemical outcome, the
ground state geometries of the three imines were calculated
Having the newly optimized substrate and conditions in by the B3LYP/6-31G* level density functional theory (DFT)
hand, we set out to define the scope of the reaction. Gratify- method (Fig. 1).30) The obtained structures were in good
ingly, p-tolualdehyde derived N-(2,4,6-trimethylbenzene- agreement with an X-ray structure of 1a31) and those calcu-
sulfinyl)imine 4b and 2-naphthaldehyde derived N-(2,4,6- lated for simpler N-sulfinyl imines.32—34) Thus, in all of these
trimethylbenzenesulfinyl)imine 4c both gave the desired N-sulfinyl imines, the azomethine substituents are trans to
adducts in significantly higher enantiomeric excesses than the N–S bond while the S–O bond and the CꢀN bond are
their previously reported corresponding less bulky N-(p- eclipsed. Accordingly, the re-faces of the imines are blocked
toluenesulfinyl)imine derivatives 1b and 1c,20) respectively from radical attack by the benzene rings of the sulfinyl
(Table 2, entries 1 and 3 vs. entries 2 and 4, respectively). groups resulting in the si-face selective attack of the acetal
The greater resonance stabilization provided by the 2-naph- radical to the imines. The S–O bond and the p-tolyl plane of
thyl group relative to the p-tolyl group was presumably re- imine 1a are almost eclipsed (the CꢀC–S–O dihedral
sponsible for the significantly lesser reactivity of the 2-naph- angleꢀ9°), while the o-methyl group on the benzene ring of

February 2010
267
149.7 (C), 152.7 (C), 161.2 (CH). IR (KBr): 2964, 2926, 2870, 1597, 1570,
1560, 1460, 1448, 1425, 1387, 1364, 1306, 1211, 1099, 1078, 1057, 876,
762, 692, 716, 692, 716, 637, 581. EI-MS (m/z): 355 (Mꢃ), 250, 235, 233,
191, 163, 149, 106, 103, 91, 77 (Ph). Anal. Calcd for C22H29NOS: C, 74.32;
H, 8.22; N, 3.94. Found: C, 74.44; H, 8.09, N, 3.85.
(S,E)-2,4,6-Trimethyl-N-(4-methylbenzylidene)benzenesulfinamide
(4b) Recrystallization from hexane gave 4b as colorless prisms of mp
111—112 °C: Rf 0.49 (hexane/Et2O 1/1). [a]D22 ꢃ110 (cꢀ1.02, CHCl3),
ꢁ99% ee (HPLC: Daicel Chiralpak AS-H, hexane/i-PrOH 9/1, 0.5 ml/min,
254 nm, major 15.5 min and minor 18.1 min). 1H-NMR d: 2.28 (s, 3H), 2.41
(s, 3H), 2.50 (s, 6H), 6.86 (s, 2H), 7.26 (d, Jꢀ7.7, 2H), 7.74 (d, Jꢀ7.7, 2H),
8.79 (s, 1H). 13C-NMR d: 18.7 (CH3), 21.0 (CH3), 21.6 (CH3), 129.5 (CH),
129.6 (CH), 130.8 (CH), 131.4 (C), 135.6 (C), 138.5 (C), 141.6 (C), 143.2
(C), 161.5 (CH). IR (KBr): 2914, 1595, 1562, 1508, 1458, 1173, 1090, 853,
818, 704, 621, 579, 505. EI-MS (m/z): 285 (Mꢃ), 269 (MꢃꢂO), 237, 167
(MꢃꢂSOMes), 149, 139, 120, 105, 91 (tolyl), 65. Anal. Calcd for
C17H19NOS: C, 71.54; H, 6.71; N, 4.91. Found: C, 71.33; H, 6.58, N, 4.94.
(S,E)-2,4,6-Trimethyl-N-(naphth-2-yl)benzenesulfinamide (4c) Re-
crystallization from EtOAc–hexane gave 4c as colorless prisms of mp 139—
140 °C: Rf 0.43 (hexane/Et2O 1/1). [a]D22 ꢃ267 (cꢀ0.540, CHCl3), 98% ee
(HPLC: Daicel Chiralcel OD-H, hexane/i-PrOH 9/1, 0.5 ml/min, 254 nm,
major 15.8 min and minor 20.4 min). 1H-NMR d: 2.29 (s, 3H), 2.53 (s, 6H),
6.88 (s, 2H), 7.57 (m, 2H), 7.87 (d, Jꢀ8.3, 1H), 7.88 (d, Jꢀ8.3, 1H), 7.94 (d,
Jꢀ7.6, 1H), 8.02 (dd, Jꢀ8.4, 1.4, 1H), 8.24 (s, 1H), 8.99 (s, 1H). 13C-NMR
d: 18.8 (CH3), 21.0 (CH3), 124.2 (CH), 126.9 (CH), 128.0 (CH), 128.3
(CH), 128.9 (CH), 129.2 (CH), 130.9 (CH), 131.7 (C), 132.4 (CH), 133 (C),
135.4 (C), 135.6 (C), 138.6 (C), 141.8 (C) 161.7 (CH). IR (KBr): 2918,
2363, 2345, 1600, 1570, 1560, 1541, 1508, 1456, 1090, 824, 743, 700, 618,
575. EI-MS (m/z): 321 (Mꢃ), 305 (MꢃꢂO), 273, 168, 153, 139, 127, 126,
106, 105, 91, 77, 63. Anal. Calcd for C20H19NOS: C, 74.73; H, 5.96; N, 4.36.
Found: C, 74.61; H, 5.85, N, 4.37.
Fig. 1. The Ground State Geometries of Imines 1a, 4a, and 5
The H atoms are omitted for clarity.
imine 4a is pointed toward the azomethine carbon (the
CꢀC–S–O dihedral angleꢀ27°), probably to avoid steric re-
pulsion with the oxygen atom.35) This presumably accounts
in part for the higher stereoselectivity (95% ee) observed in
the reaction of 4a. The isopropyl group of imine 5, which ex-
hibited a higher stereo-control (87% ee) than imine 1a (80%
ee), is also pointed toward the azomethine carbon (the
CꢀC–S–O dihedral angleꢀ38°). In the presence of
BF3·OEt2, the imines 1 probably form imine–BF3 com-
plexes. Based on DFT calculations and NMR analysis, Do-
browolski and Kawe˛cki suggested that a sulfinyl imine coor-
dinates to the boron of BF3 at the oxygen atom.32) Thus, it
could be speculated that in the BF3 complexes, the more
bulky the aromatic ring of the sulfinyl group of the imine
is, the more favorably the BF3 moiety is placed on the si-
General Procedure for the Radical Addition of 2 to Imines 4 and 5.
(R)-2,4,6-Trimethyl-N-[(phenyl)(4,4,5,5-tetramethyl-1,3-dioxolan-2-
yl)methyl]benzenesulfonamide (9a) (Table 1, Entry 3) In a dry 50 ml
face. This would make the si-face attack of the acetal radical three-necked round-bottomed flask were placed a magnetic stirrer bar and 4a
(271 mg, 1.0 mmol). The flask was filled with argon after evacuation and
refill with argon (3 times). 4,4,5,5-Tetramethyldioxolane (2) (18.3 ml,
125 mmol) was added at room temperature. To the stirred solution were se-
quentially added BF3·OEt2 (0.25 ml, 2.0 mmol) and a 1.0 M solution of
less favorable, and may partly be the reason for the lower
enantioselectivity observed in the reaction of 5 relative to
that of 4a.36)
Me2Zn (6.0 ml, 6.0 mmol) in hexane. The argon source was replaced with a
NaOH drying tube and air was injected into the reaction mixture via an air
bubbler at a rate of 0.5 ml/h. The reaction mixture was stirred for 21 h at
Conclusion
We have demonstrated the preparation of synthetically
room temperature and quenched with saturated aqueous NaHCO3 (30 ml)
useful (ꢁ90% ee) sulfonamide compounds from enantiomer-
followed by extraction with EtOAc (3ꢄ30 ml). The combined organic ex-
ically pure N-sulfinyl imines in good yield using the di-
tracts were washed with brine (30 ml), dried over Na2SO4, filtered, and con-
methylzinc–air radical method. The reaction was facilitated
by the use of boron trifluoride diethyl etherate. Equally im-
portant, the sulfonamide products served as precursors to
enantiomerically enriched amine and amino alcohol building
blocks.
centrated under reduced pressure to give the crude product as pale yellow
oil. Dry CH2Cl2 (5 ml) and dry m-CPBA (173 mg, 1.0 mmol) were sequen-
tially added to the crude product. The reaction mixture was stirred for 1 h
and diluted with CHCl3 (10 ml) followed by washing with saturated aqueous
NaHCO3 (3ꢄ15 ml). The organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure to give the crude product as pale yel-
low slurry-like mixture, which was purified by flash column chromatography
(hexane/Et2O 3/1) to give 9a (306 mg, 73%) with 95% ee as white solid of
Experimental
General All melting points are uncorrected. IR spectra were expressed mp 107—108 °C: Rf 0.46 (hexane/Et2O 1/1). [a]D25 ꢂ18.0 (cꢀ1.02, CHCl3).
1
in cmꢂ1. H-NMR (500 MHz) and 13C-NMR (125 MHz) spectra were meas- The ee was determined by HPLC (Daicel Chiralpak AS-H, hexane/i-PrOH
1
ured in CDCl3. Chemical shifts and coupling constants are presented in ppm
9/1, 0.5 ml/min, 254 nm, major 27.5 min and minor 32.3 min). H-NMR d:
d and Hz respectively. 13C peak multiplicity assignments were made based 1.00 (s, 3H), 1.04 (s, 3H), 1.11 (s, 3H), 1.13 (s, 3H), 2.22 (s, 3H), 2.47 (s,
on DEPT data. Abbreviations are as follows: s, singlet; d, doublet; t, triplet; 6H), 4.22 (dd, Jꢀ4.9, 4.6, 1H), 5.00 (d, Jꢀ4.9, 1H), 5.25 (d, Jꢀ4.6, 1H),
sep, septet; m, multiplet; br, broad. The wavenumbers of maximum absorp- 6.77 (s, 2H), 7.07—7.14 (m, 5H). 13C-NMR d: 20.5 (CH3), 21.8 (CH3), 22.0
tion peaks of IR spectroscopy were presented in cmꢂ1. Column chromatog- (CH3), 22.5 (CH3), 23.5 (CH3), 61.4 (CH), 82.6 (C), 82.8 (C), 100.7 (CH),
raphy was carried out with silica gel. 4,4,5,5-Tetramethyl-1,3-dioxolane 127.6 (CH), 128.1 (CH), 131.4 (CH), 134.0 (C), 135.9 (C), 138.9 (C), 141.8
(2)21) and dry m-CPBA37) are prepared according to reported procedures.
Preparation of Chiral Imines The chiral N-sulfinyl imines 1, 4, and 5
(C). IR (KBr): 3279, 2978, 2924, 2368, 1597, 1458, 1435, 1396, 1319, 1157,
1057, 934, 880, 849, 702, 656. EI-MS (m/z): 288 (MꢃꢂC7H13O2), 234
were prepared by condensing the corresponding aldehyde and sulfi- (MꢃꢂSO2Mes), 167, 130, 129 (C7H13O2), 119 (Mes), 101, 91, 83, 77 (Ph).
namide23,38,39) according to known procedures.40)
Anal. Calcd for C23H31NO4S: C, 66.16; H, 7.48; N, 3.35. Found: C, 66.07;
H, 7.37. N, 3.52.
(R)-2,4,6-Triisopropyl-N-[(phenyl)(4,4,5,5-tetramethyl-1,3-dioxolan-2-
yl)methyl]benzenesulfonamide (10) (Table 1, Entry 4) Carried out ac-
cording to the general procedure using 5 (356 mg, 1.0 mmol), 2 (18.3 ml,
(S,E)-2,4,6-Triisopropyl-N-(benzylidene)benzenesulfinamide (5)24)
Recrystallization from hexane gave 5 as colorless prisms of mp 112—
113 °C: Rf 0.49 (hexane/Et2O 1/1). [a]D22 ꢃ56.6 (cꢀ1.00, CHCl3), 98% ee
(HPLC: Daicel Chiralpak AD-H, hexane/i-PrOH 9/1, 0.5 ml/min, 254 nm,
1
major 15.4 min and minor 16.6 min). H-NMR d: 1.14 (d, Jꢀ7.0, 6H), 1.25 125 mmol), BF3·OEt2 (0.25 ml, 2.0 mmol), and Me2Zn (1.0 M in hexane;
(d, Jꢀ7.0, 6H), 1.29 (d, Jꢀ7.0, 6H), 2.89 (sep, Jꢀ7.0, 1H), 3.85 (m, 2H), 6.0 ml, 6.0 mmol). The reaction mixture was stirred for 22.5 h. Work-up gave
7.08 (s, 2H), 7.45 (m, 2H), 7.50 (m, 1H), 7.85 (d, Jꢀ7.0, 2H), 8.85 (s, 1H). the crude product as colorless oil. Dry CH2Cl2 (5 ml) and dry m-CPBA
13C-NMR d: 23.59 (CH3), 23.61 (CH3), 23.9 (CH3), 24.2 (CH3), 27.8 (CH),
(173 mg, 1.0 mmol) were sequentially added to the crude product. The reac-
34.2 (CH), 122.9 (CH), 128.8 (CH), 129.3 (CH), 132.3 (CH), 134.3 (C), tion mixture was stirred for 1 h. Work-up gave the crude product as pale yel-

268
Vol. 58, No. 2
low oil, which was purified by flash column chromatography (hexane/Et2O (83.4 mg, 0.20 mmol) in dry THF was added to the blue solution and the re-
3/1) to give 7 (385 mg, 77%) with 87% ee as white oily solid: Rf 0.71 action mixture was stirred for 1 h. The reaction mixture was quenched with
(hexane/Et2O 1/1). [a]D22 ꢂ9.8 (cꢀ0.885, CHCl3). The ee was determined by NH4Cl (0.128 mg, 2.4 mmol) and allowed to warm to room temperature. To
HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH 200/1, 0.5 ml/min, 254 nm,
the quenched mixture was added Et2O followed by acidification with aque-
ous 10% HCl to give pH 1. Aqueous 2 N NaOH was added to the aqueous
minor 27.7 and major 30.8 min). 1H-NMR d: 0.93 (s, 3H), 1.03 (s, 3H), 1.10
(s, 3H), 1.11 (s, 3H), 1.13 (d, Jꢀ6.7, 6H), 1.22 (d, Jꢀ6.7, 12H), 2.85 (sep, layer to give pH 10 and the mixture was extracted with Et2O. The combined
Jꢀ6.7, 1H), 3.99 (sep, Jꢀ6.7, 2H), 4.43 (dd, Jꢀ5.2, 4.3, 1H), 5.02 (d, organic extracts were dried over K2CO3, filtered, and concentrated under re-
Jꢀ4.3, 1H), 5.18 (d, Jꢀ5.2, 1H), 7.03 (br s, 2H), 7.10—7.15 (m, 5H). 13C- duced pressure to give the crude product as pale yellow oil, which was puri-
NMR d: 22.1 (CH3), 22.2 (CH3), 23.5 (CH3), 23.6 (CH3), 23.7 (CH3), 23.8 fied by flash column chromatography (hexane/EtOAc 3/2) to give 11
(CH3), 24.6 (CH3), 24.9 (CH3), 29.7 (CH), 34.1 (CH), 61.0 (CH), 82.8 (C),
(39.5 mg, 84%,) with 94% ee as pale yellow oil: Rf 0.46 (hexane/EtOAc
83.0 (C), 100.9 (CH), 123.4 (CH), 127.7 (CH), 127.8 (CH), 128.4 (CH), 1/1). [a]D24 ꢃ15.3 (cꢀ1.02, CHCl3). The ee was determined by HPLC (Dai-
133.8 (C), 136.5 (C), 149.9 (C), 152.5 (C). IR (KBr): 3333, 2964, 2870, cel Chiralcel OD-H, hexane/i-PrOHꢀ9/1, 1.0 ml/min, 254 nm, minor 5.0
1601, 1560, 1541, 1456, 1423, 1364, 1329, 1296, 1256, 1196, 1153, 1138,
1103, 1090, 1061, 1040, 1024, 961, 941, 928, 897, 881, 835, 820, 758, 721, 1.64 (s, 2H), 3.89 (d, Jꢀ5.2, 1H), 5.03 (d, Jꢀ5.2, 1H), 7.26 (tt, Jꢀ1.3, 7.3,
700, 669, 625, 581, 559. EI-MS (m/z): 267 (SO2(iPr)3C6H2), 129 (C7H13O2),
1H), 7.33 (m, 2H), 7.40 (m, 2H). 13C-NMR d: 22.0 (CH3), 22.1 (CH3), 23.9
101, 91, 83, 77 (Ph). Anal. Calcd for C29H43NO4S: C, 69.42; H, 8.64; N, (CH3), 24.0 (CH3), 59.6 (CH), 82.0 (C), 82.1 (C), 103.1 (C), 127.3 (CH),
2.79. Found: C, 69.43; H, 8.88; N, 2.60. 127.7 (CH), 128.1 (CH), 141.0 (C). IR (neat): 3387, 2978, 2932, 2870,
min and major 6.4 min). 1H-NMR d: 1.16 (s, 6H), 1.18 (s, 3H), 1.20 (s, 3H),
(R)-2,4,6-Trimethyl-N-[(4-methylphenyl)(4,4,5,5-tetramethyl-1,3-diox- 1604, 1450, 1373, 1157, 1118, 1011, 964, 880, 764, 702. EI-MS (m/z): 129
olan-2-yl)methyl]benzenesulfonamide (9b) (Table 2, Entry 2) Carried (C7H13O2), 106 (MꢃꢂC7H13O2), 101, 85, 83, 77. Anal. Calcd for
out according to the general procedure using 4b (285 mg, 1.0 mmol), 2 C14H21NO2: C, 71.46; H, 8.99; N, 5.95. Found: C, 71.17; H, 8.81.; N, 5.87.
(18.3 ml, 125 mmol), BF3·OEt2 (0.25 ml, 2.0 mmol), and Me2Zn (1.0 M in
Method 2 In a 50 ml round-bottom flask, 9a with 82% ee (108.4 mg,
hexane; 6.0 ml, 6.0 mmol). The reaction mixture stirred for 20 h. Work-up 0.26 mmol) and PhSMe (0.61 ml, 5.2 mmol) were dissolved in trifluoroacetic
gave the crude product as pale yellow oil. Dry CH2Cl2 (5 ml) and dry m- acid (TFA) (5.2 ml). To the solution cooled in an ice-water bath, was added
CPBA (173 mg, 1.0 mmol) were sequentially added to the crude product.
Me3SiBr (0.69 ml, 5.2 mmol). The cooling bath was removed and the result-
The reaction mixture was stirred for 1 h. Work-up gave the crude product as ing mixture was allowed to warm up to room temperature while being
pale yellow oil, which was purified by flash column chromatography stirred. After 2.5 h TFA was removed in vacuo and aqueous saturated
(hexane/Et2O 4/1) to give 9b (360 mg, 83%) with 91% ee as colorless oil: Rf NaHCO3 was added. The whole was extracted with EtOAc three times, and
0.49 (hexane/Et2O 1/1). [a]D22 ꢂ27.9 (cꢀ0.855, CHCl3). The ee was deter- the combined organic layers were washed with brine, dried over K2CO3, and
mined by HPLC (Daicel Chiralpak AS-H, hexane/i-PrOHꢀ9/1, 1.0 ml/min, concentrated to give orange oil. Purification by column chromatography
1
254 nm, major 10.6 and minor 17.9 min). H-NMR d: 1.02 (s, 3H), 1.04 (s, (hexane/EtOAc 2/1 then EtOAc) gave 11 (55.0 mg, 88%) with 82% ee as
3H), 1.10 (s, 3H), 1.13 (s, 3H), 2.236 (s, 3H), 2.242 (s, 3H), 2.47 (s, 6H), pale yellow oil.
4.14 (dd, Jꢀ5.2, 4.3, 1H), 4.97 (d, Jꢀ5.2, 1H), 5.21 (d, Jꢀ4.3, 1H), 6.78 (s,
2H), 6.91 (d, Jꢀ8.0, 2H), 6.98 (d, Jꢀ8.0, 2H). 13C-NMR d: 20.6 (CH3), 20.9 Method 1, using NH3 (15 ml), Li metal (44.0 mg, 6.3 mmol), and 10 with
(CH3), 21.9 (CH3), 22.0 (CH3), 22.6 (CH3), 23.6 (CH3), 61.4 (CH), 82.7 (C), 87% ee (100 mg, 0.20 mmol). The reaction mixture was stirred for 1 h.
Conversion of Adduct 10 into Amine 11 Carried out according to
82.8 (C), 100.8 (CH), 127.9 (CH), 128.4 (CH), 131.4 (CH), 133.0 (C), 134.0 Work-up gave the crude product as pale yellow oil, which was purified by
(C), 137.3 (C), 139.0 (C), 141.8 (C). IR (KBr): 3331, 2978, 2926, 2870, flash column chromatography (hexane/EtOAc 3/2) to give 11 (35.4 mg,
1604, 1516, 1445, 1391, 1379, 1369, 1335, 1217, 1186, 1155, 1123, 1057,
1020, 964, 903, 851, 814, 756, 658, 584. EI-MS (m/z): 432 (Mꢃ), 129
(C7H13O2), 119 (Mes), 101, 91, (tolyl), 83, 77. Anal. Calcd for C24H33NO4S:
C, 66.79; H, 7.71; N, 3.25. Found: C, 67.06; H, 7.82; N, 3.20.
76%) with 87% ee as pale yellow oil.
Conversion of Amine 11 into Sulfonamide 3a To amine 11 with 92%
ee (57.0 mg, 0.24 mmol), prepared from 9a with 92% ee, in CHCl3 (1 ml)
were added aqueous saturated NaHCO3 (1 ml) and TsCl (55.5 mg,
(R)-2,4,6-Trimethyl-N-[(naphth-2-yl)(4,4,5,5-tetramethyl-1,3-diox- 0.29 mmol) at room temperature. The mixture was stirred for 14 h at the
olan-2-yl)methyl]benzenesulfonamide (9c) (Table 2, Entry 4) Carried
out according to the general procedure using 4c (321 mg, 1.0 mmol), 2
same temperature, and then extracted with CHCl3 (3ꢄ5 ml). Combined or-
ganic layers were dried over Na2SO4. Concentration followed by column
(18.3 ml, 125 mmol), BF3·OEt2 (0.25 mlꢃ0.25 mlꢃ1.0 mlꢃ1.0 ml, 12.0 chromatography (hexane/EtOAc 5/1) gave sulfonamide 3a (74.4 mg, 80%)
mmol), and Me2Zn (1.0 M in hexane; 6.0 mlꢃ6.0 mlꢃ12 mlꢃ12 ml, 36
with 92% ee as white solid of mp 103—106 °C. The spectroscopic data, 1H-
mmol). The reaction mixture stirred for 118 h. Work-up gave the crude prod- and 13C-NMR, IR, and MS, were identical to those reported.41) The ee was
uct as pale yellow oil. Dry CH2Cl2 (5 ml) and dry m-CPBA (173 mg, determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOHꢀ9/1,
1.0 mmol) were sequentially added to the crude product. The reaction mix-
0.5 ml/min, 254 nm, major 21.3 min and minor 25.8 min). [a]D25 ꢂ33.8
ture was stirred for 1 h. Work-up gave the crude product as pale yellow oil, (cꢀ1.03, CHCl3). lit.20): [a]D25 ꢂ32.6 (cꢀ1.01, CHCl3) for (R)-3a with 83%
which was purified by flash column chromatography (hexane/Et2O 3/1) to ee.
give 9c with 92% ee (360 mg, 66%) as cream solid: Rf 0.40 (hexane/Et2O
1/1). [a]D22 ꢂ32.5 (cꢀ1.01, CHCl3). The ee was determined by HPLC (Dai- ethyl)-2,4,6-trimethylbenzenesulfonamide TiCl4 (0.18 ml, 1.6 mmol) was
cel Chiralpak AS-H, hexane/i-PrOH 9/1, 1.0 ml/min, 254 nm, major 14.0 added dropwise to a stirred solution of 9a with 92% ee (108 mg, 0.26 mmol)
Reduction of the Acetal Moiety of 6a: (R)-N-(2-Hydroxy-1-phenyl-
1
and minor 20.6 min). H-NMR d: 1.05 (s, 3H), 1.08 (s, 3H), 1.12 (s, 3H), and Et3SiH (0.64 ml, 4.0 mmol) in dry CH2Cl2 (0.4 ml) at 0 °C. The resulting
1.15 (s, 3H), 2.05 (s, 3H), 2.43 (s, 6H), 4.40 (dd, Jꢀ4.9, 4.3, 1H), 5.11 (d, mixture was stirred at the same temperature for 48 h and
Jꢀ4.9, 1H), 5.33 (d, Jꢀ4.3, 1H), 6.60 (s, 2H), 7.24 (dd, Jꢀ8.9, 1.3, 1H), then at room temperature for 23 h. The reaction was quenched with satu-
7.38—7.41 (m, 2H), 7.44 (s, 1H), 7.56 (d, Jꢀ8.9, 1H), 7.59 (dd, Jꢀ6.0, 3.4, rated aqueous NaHCO3 (6 ml) followed by extraction with CHCl3
1H), 7.71 (dd, Jꢀ6.0, 3.4, 1H). 13C-NMR d: 20.5 (CH3), 22.0 (CH3), 22.2 (3ꢄ10 ml). The combined organic extracts were dried over Na2SO4, filtered,
(CH3), 22.7 (CH3), 23.7 (CH3), 23.8 (CH3), 61.8 (CH), 82.9 (C), 83.0 (C),
and concentrated under reduced pressure to give the crude product as
100.9 (CH), 125.7 (CH), 125.8 (CH), 125.9 (CH), 127.4 (CH), 127.6 (CH), pale yellow oil, which was purified by flash column chromatography
127.9 (CH), 131.4 (CH), 132.8 (C), 133.0 (C), 133.2 (C), 134.2 (C), 138.9 (hexane/EtOAc 7/3) to give the titled compound (46.0 mg, 55%) with 87%
(C), 141.9 (C). IR (KBr): 3314, 2974, 2934, 2860, 1605, 1560, 1508, 1458, ee as white solid of mp 128—130 °C (lit.42,43): mp 131 °C, EtOAc–hexane):
1393, 1383, 1367, 1331, 1151, 1120, 1076, 1057, 1022, 953, 897, 858, 812, Rf 0.55 (hexane/EtOAc 1/1). [a]D20 ꢂ67.2 (cꢀ1.00, CHCl3) (lit.42): [a]D20
787, 748, 729, 660, 583. EI-MS (m/z): 338 (MꢃꢂC7H13O2), 284 ꢃ77.6 (cꢀ1.00, CHCl3) for enantiomer). The ee was determined by HPLC
(MꢃꢂSO2Mes), 240, 183 (SO2Mes), 168, 155, 154, 141, 130, 129 (Daicel Chiralcel OG, hexane/i-PrOH 3/1, 0.5 ml/min, 254 nm, major
(C7H13O2), 127 (C10H7), 119, 115, 101, 91, 83, 77. FAB-MS (m/z): 466
(MꢂHꢃ). HR-MS-FAB (m/z): [MꢂH]ꢂ Calcd for C27H32NO4S, 466.2052; reported.43) 13C-NMR d: 20.8 (CH3), 22.7 (CH3), 59.5 (CH), 66.0 (CH2),
Found, 466.2047. 126.8 (CH), 127.9 (CH), 128.4 (CH), 131.8 (CH), 133.8 (C), 137.4 (C),
Removal of the Sulfonyl Group of Adduct 9a: (R)-Phenyl(4,4,5,5- 139.1 (C), 142.2 (C). IR (KBr): 3410, 3186, 2939, 1736, 1605, 1566, 1458,
14.8 min and minor 18.6 min). 1H-NMR spectrum agreed with that
tetramethyl-1,3-dioxolan-2-yl)methanamine (11). Method
1 NH3 1319, 1265, 1234, 1150, 1072, 1034, 956, 756, 702, 664. EI-MS (m/z):
(15 ml) was condensed into a dry three-necked round-bottomed flask which 288 (M+ꢂCH2OH), 183 (SO2Mes), 119 (Mes), 104, 91, 77 (Ph), 51. FAB-
was equipped with a magnetic stirrer bar under argon atmosphere, at MS (m/z): 342 (MꢃNa+). HR-MS-FAB (m/z): [MꢃNa]ꢃ Calcd for
ꢂ78 °C. To the colorless stirred solution was added Li metal (42.9 mg, C17H21NNaO3S, 342.1140; Found, 342.1143.
6.2 mmol) portionwise to give a blue solution. A solution of 9a with 95% ee

February 2010
269
Acknowledgements This research was partially supported by a Grant-
in-Aid for Young Scientist (B) and a Grant-in-Aid for Scientific Research
(A) from the Japan Society for the Promotion of Science (JSPS); a Grant-in-
Aid for Scientific Research on Priority Areas “Advanced Molecular Trans-
formations” from the Ministry of Education, Culture, Sports, Science and
Yamamoto Y., Nakano M., Akindele T., Tomioka K., Tetrahedron
Lett., 50, 6040—6043 (2009).
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Technology, Japan; and Targeted Protein Research Program from Japan Sci- 25) Han Z., Krisnamurthy D., Grover P., Fang Q. K., Pflum D. A.,
ence and Technology Agency. T.A. and M.M. thank JSPS for fellowships.
Senanayake C. H., Tetrahedron Lett., 44, 4195—4197 (2003).
26) Hayashi T., Kawai T., Tokunaga N., Angew. Chem., Int. Ed., 43,
6125—6128 (2004).
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