The catalytic asymmetric aminohydroxylation of unsaturated phosphonates

Full text of DOI:10.1021/jo990060r

J . Org. Chem. 1999, 64, 8379-8385
8379
resulted in unique phosphate mimics with resistance to
phosphatase hydrolysis.8
Th e Ca ta lytic Asym m etr ic
Am in oh yd r oxyla tion of Un sa tu r a ted
P h osp h on a tes
Allen A. Thomas and K. Barry Sharpless*
Department of Chemistry and Skaggs Institute for Chemical
Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, California 92037
Resu lts a n d Discu ssion
Received J anuary 12, 1999 (Revised Manuscript Received
August 12, 1999)
Seven different unsaturated phosphonate substrates
were examined (Table 1). Both the p-toluenesulfonyl (R
) Ts) and ethoxycarbonyl (R ) EtO2C) N-amino groups
were introduced via the corresponding N-chloro-N-so-
dioamides. Unfortunately, only aryl-substituted olefins
(R′ ) Ar) were successfully oxyaminated. The corre-
sponding alkyl-substituted alkenes (e.g., R′ ) H, methyl,
tert-butyl, cyclohexyl) failed to react even upon prolonged
heating.
The solvents, CH3CN for sulfonamides and n-PrOH for
carbamates, were not interchangeable. Use of n-PrOH
resulted in higher ee’s in both sulfonamide and carbam-
ate AA products (e.g., 2a was generated in 90% ee using
n-PrOH). However, utilization of n-PrOH in the former
resulted in lower isolated yields due to low conversion of
olefin (e.g., 40% unreacted olefin after 24 h in forming
2a using n-PrOH). Fortunately, it was discovered that
the ee’s of the hydroxysulfonamide products could be
greatly enhanced by recrystallization. Several byproducts
were formed during AA reactions (as analyzed by 31P
NMR), including some diol (5-25% of major isomer for
sulfonamides and 15-30% for carbamates), and regioi-
somer (15-30% of major isomer for sulfonamides and
5-15% of major isomer for carbamates).10 The amounts
of regioisomer and diol present varied by substrate and
with changes in reaction conditions. In addition, cleavage
of the R-hydroxyphosphonate products to give an alde-
hyde and dialkyl phosphite was observed.11 Thus, the
In tr od u ction
Phosphonic acids with heteroatoms in the R and/or â
positions have attracted much attention recently for their
involvement in biologically relevant processes such as
inhibition of renin1 and HIV protease2 and for their use
as haptens in the development of catalytic antibodies.3
Syntheses of both racemic and optically active phospho-
nates have been published.4,5 The recently discovered
asymmetric aminohydroxylation (AA),6 which utilizes Os-
(VIII) and the cinchona alkaloid ligand (DHQ)2PHAL as
catalysts, allows for formation of â-amino-R-hydroxy-
phosphonate diesters of type I in high ee.7 A γ-amino-
hydroxyphosphonate containing an R-methylene moiety
(type II) was similarly prepared albeit with lower enan-
tioselectivity. Phosphonates such as I and II have
(1) (a) Dellaria, J . F., J r.; Maki, R. G.; Stein, H. H.; Cohen, J .;
Whittern, D.; Marsh, K.; Hoffman, D. J .; Plattner, J . J .; Perun, T. J .
J . Med. Chem. 1990, 33, 534. (b) Wester, R. T.; Chambers, R. J .; Green,
M. D.; Murphy, W. R. Bioorg. Med. Chem. Lett. 1994, 4, 2005. (c) For
reviews on phosphonates, see: Kafarski, P.; Lejczak, B. Phosphorus,
Sulfur Silicon Relat. Elem. 1991, 63, 193. Dhawan, B.; Redmore, D.
Phosphorus Sulfur 1987, 32, 119.
(2) Stowasser, B.; Budt, K.-H.; J ian-Qi, L.; Peyman, A.; Ruppert,
D. Tetrahedron Lett. 1992, 33, 6625.
(3) Hirschmann, R.; Smith, A. B., III; Taylor, C. M.; Benkovic, P.
A.; Taylor, S. D.; Yager, K. M.; Sprengeler, P. A.; Benkovic, S. J . Science
1994, 265, 234.
(4) (a) Smith, A. B., III.; Yager, K. M.; Taylor, C. M. J . Am. Chem.
Soc. 1995, 117, 10879. (b) Hanessian, S.; Bennani, Y. L. Tetrahedron
Lett. 1990, 31, 6465. (c) Hanessian, S.; Bennani, Y. L. Synthesis 1994,
1272. (d) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J . Org. Chem.
1995, 60, 6656. (e) Maury, C.; Gharbaoui, T.; Royer, J .; Husson, H.-P.
J . Org. Chem. 1996, 61, 3687. (f) Demir, A. S.; Tanyeli, C.; Sesenoglu,
O.; Demic, S. Tetrahedron Lett. 1996, 37, 407. (g) Meier, C.; Laux, W.
H. G. Tetrahedron 1996, 52, 589. (h) Schmidt, U.; Oehme, G.; Krause,
H. Synth. Commun. 1996, 26, 777. (i) Ferris, L.; Haigh, D.; Moody, C.
J . Synlett 1995, 921. (j) Tao, M.; Bihovsky, R.; Wells, G. J .; Mallamo,
J . P. J . Med. Chem. 1998, 41, 3912.
(5) (a) Yokomatsu, T.; Yoshida, Y.; Suemune, K.; Yamagishi, T.;
Shibuya, S. Tetrahedron: Asymmetry 1995, 6, 365. (b) Yokomatsu, T.;
Suemune, K.; Yamagishi, T.; Shibuya, S. Synlett 1995, 847. (c)
Kitamura, M.; Tokunaga, M.; Pham, T.; Lubell, W. D.; Noyori, R.
Tetrahedron Lett. 1995, 36, 5769. (d) Zygmunt, J .; Gancarz, R.; Lejczak,
B.; Wieczorek, P.; Kafarski, P. Bioorg. Med. Chem. Lett. 1996, 6, 2989.
(e) Bongini, A.; Camerini, R.; Hofman, S.; Panunzio, M. Tetrahedron
Lett. 1994, 35, 8045. (f) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.;
Free, C. A.; Rogers, W. L.; Smith, S. A.; DeForrest, J . M.; Oehl, R. S.;
Petrillo, E. W., J r. J . Med. Chem. 1995, 38, 4557. (g) Wroblewski, A.
E.; Piotrowska, D. G. Tetrahedron 1998, 54, 8123.
(8) (a) Nieschalk, J .; Batsanov, A. S.; O’Hagan, D.; Howard, J . A.
K. Tetrahedron 1996, 52, 165. (b) Burke, T. R., J r.; Smyth, M. S.;
Nomizu, M.; Otaka, A.; Roller, P. P. J . Org. Chem. 1993, 58, 1336.
(9) (a) Mikolajczyk, M.; Grzejszczak, S.; Midura, W.; Zatorski, A.
Synthesis 1976, 396. (b) For
a review of vinylphosphonates, see:
Minami, T.; Motoyoshiya, J . Synthesis 1992, 333.
(10) Authentic, racemic diols of entries 1, 2, and 7 were prepared
by a method similar to that of ref 11a. The 31P chemical shift of diol
relative to the corresponding hydroxysulfonamide (diol: ∆δP ) +1.3-
1.9 ppm) and hydroxycarbamate (diol: ∆δP ) +1.0-1.3 ppm) products
was assumed to be consistent within the series (with the exception of
7a and 7b in which ∆δP for diol was +0.3 and +0.1 ppm, respectively).
Authentic regioisomer (R-amino-â-hydroxyphosphonate) was not iso-
lated for any of the entries. Correlation of 1H NMR resonances for crude
hydroxysulfonamide phosphonate products with those obtained from
aminohydroxlation of unsaturated amides (Rubin, A. E.; Sharpless,
K. B. Angew. Chem., Int. Ed. Engl. 1997, 36, 2637), in which both
regioisomers were generated in high yield, allowed for identification
of regioisomer in the former. With the exception of 7a (see details
below), the hydroxysulfonamide regioisomer was shifted downfield by
0.8-1.3 ppm in the 31P NMR relative to the major isomer. Unfortu-
nately, the assignment of regioisomer for the carbamates was less clear
due to multiple, small resonances within the region of the 31P NMR
spectrum where the regioisomer was expected. Even though the
carbamate regioisomer was not assigned, an upper limit of 15%
(relative to major isomer) was set by integration of each of those small
resonances in the 31P NMR. Both 1H and 13C NMR spectra were too
complicated to be useful in assessing the amount of regioisomer (or
diol) present for the carbamates. The 31P NMR for crude 7a had
numerous resonances (complicated by the fact that the starting olefin
was not diasteromerically pure), and therefore, regioisomer assign-
ments were not made.
(6) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem.,Int. Ed.
Engl. 1996, 35, 451. (b) Li, G.; Angert, H. H.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2813.
(7) We have recently been made aware that after our initial
presentation of this work (Thomas, A. A.; Sharpless K. B. Abstracts of
Papers; 213th National Meeting of the American Chemical Society,
San Francisco, CA, Apr 13-17, 1997; American Chemical Society:
Washington, DC, 1997; ORGN 126) another group published the
preparation of R-hydroxy-â-toluenesulfonamidophosphonates by the
AA: Cravotto, G.; Giovenzana, G. B.; Pagliarin, R.; Palmisano, G.; Sisti,
M. Tetrahedron: Asymmetry 1998, 9, 745.
10.1021/jo990060r CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/07/1999

8380 J . Org. Chem., Vol. 64, No. 22, 1999
Ta ble 1. Resu lts of th e AA of Ar yl-Su bstitu ted , Un sa tu r a ted P h osp h on a te Diester s
Notes
a
Unsaturated phosphonates were prepared using a modified Horner-Wittig reaction.9 All of the olefins were >99% E configuration
(as evidenced by 1H or 31P NMR) except for entry 7, which was used as an 89:11 ratio of E/Z isomers. The stereochemistries depicted
correspond to the known facial selectivity for the AA of cinnamate substrates6 and the AD of entries 1 and 2.5a The regiochemistries were
determined by 2D NMR analysis (details within). c Yields are of the isolated product from AA reactions after purification. Unless noted
otherwise in the Experimental Section, the reactions were performed on a 2 or 0.5 mmol scale depending on whether the product was
b
d
purified by recrystallization or preparative TLC, respectively. The ee’s were determined by HPLC analysis of both antipodes or by
comparison with racemate using a chiracel AD column on crude reaction mixture or after purification by flash or thin-layer chromatography.
The numbers in parentheses represent % ee after a single recrystallization and correspond with the yields listed in the table. e The reaction
times were monitored by consumption of olefin as evidenced by TLC or 31P NMR. f These noncrystalline products were purified exclusively
by flash chromatography or preparative TLC. Products 3a and 1b were isolated in 87 and 90% purity, respectively, whereas 5b and 7b
g
were of greater than 95% purity (as evidenced by 31P NMR). The value listed is the ee after preparative TLC; the racemate was obtained
h
as a pure solid upon recrystallization from 2-propanol:THF (1:1). Racemate crystallized leaving mother liquor that contained 7b in 90%
ee; the crude product was then purified by preparative TLC.
reaction times listed in Table 1 should be enforced;
otherwise, poorer yields can be anticipated. Despite the
subsequent low yields of AA products (Table 1), in almost
all cases purity was high after recrystallization or
preparative TLC.
Purification of the AA phosphonate products was
simplified by their dramatically increased retention on
silica gel relative to remaining p-toluenesulfonamide or
urethane. After removal of p-toluenesulfonamide or
urethane by flash chromatography, the crude mixture
was subsequently purified by recrystallization or pre-
parative TLC. As mentioned above, the ee’s of the
sulfonamide products were generally lower than the
corresponding carbamates; however, the sulfonamide
products had the advantage of easier isolation, as most
were readily purified by recrystallization. On the other
hand, the carbamyl protecting group has the advantage
of deprotection under milder conditions than the sulfonyl
group.12 It is expected that under typical acid-promoted
deprotection of either the sulfonyl or carbamyl N-protect-
ing groups, the phosphonate ester groups would also be
removed. This is advantageous in cases where an ami-
nophosphonic acid is the desired product. In other cases,
however, orthogonal protecting groups are necessary. For
the related cinnamates, it has been demonstrated that a
variety of N-protecting groups are compatible with the
AA.13 We are currently exploring the scope of nitrogen
sources possible in the AA of these vinyl phosphonates.14
To elucidate the regiochemistry of the phosphonate AA
1
products, 7b was subjected to 1H-1H COSY and H-13C
HETCOR 2D NMR analysis (see the Supporting Infor-
mation). In conjuction with the 2D NMR analysis, 13C
NMR revealed a distinct geminal phosphorus-carbon
coupling constant of 139 Hz as expected for the methyl-

Notes
J . Org. Chem., Vol. 64, No. 22, 1999 8381
Sch em e 1
enic C-1 (δ ) 31.1). This observation aided in assigning
the C-1 protons (δ ) 2.0, 2.1) by correlation with C-1 (δ
1
) 31.1) using H-13C HETCOR. One of the C-1 protons
(δ ) 2.1) was then correlated with the C-2 proton (δ )
4.3) by 1H-1H COSY. The C-2 proton (δ ) 4.3) was
correlated with C-2 (δ ) 69.2), and the C-3 proton (δ )
4.6) was correlated with C-3 (δ ) 59.9) by 1H-13C
HETCOR. The 13C chemical shift for C-2 (δ ) 69.2) was
in better agreement with the expected chemical shift for
carbon bound to a hydroxyl group (δ ) 70.9, 77.6 reported
for C-2, C-3 of the analogous diol)15 than that of C-3 (δ )
59.9). Moreover, the 1H-1H COSY correlation found
between the urethane proton (δ ) 5.8) and the C-3 proton
(δ ) 4.6) confirmed the regiochemistry assignment.16
To assign the relative and absolute stereochemistry,
as well as confirm the aforementioned regiochemistry
argument, an X-ray crystal structure of a diastereomeric
derivative of compound 5a was sought. A suitable crystal
of the (S)-O-methyl mandelate ester 8 (Scheme 1) was
submitted for X-ray crystal determination. The X-ray
structure (see the Supporting Information) confirmed the
relative and absolute stereochemistry and regiochemistry
hypothesized for 5a . By analogy, the other phosphonates
in Table 1 would be expected to have similar stereo and
regiochemistries. Indeed, the 13C NMR resonance for C-1
in the R-hydroxyphosphonate AA products (entries 1-6
of Table 1) was consistent in both the magnitude of the
geminal coupling constant with phosphorus (J 1 ) 159-
163 Hz) and in chemical shift (δ 70.7-71.6). It is also
Sch em e 2
worth noting that the sign of optical rotation for all the
phosphonate AA products examined was consistent with
the observed sign of optical rotation for AD-derived diols
of the same unsaturated phosphonates (entries 1 and 2
in Table 1) and prepared using (DHQ)2PHAL ligand.5a
These trends are consistent with the known regio- and
stereochemistry for AA products of cinnamate substrates
and with the stereochemistry of the asymmetric dihy-
droxylation (AD).6
(11) It is known that R-hydroxyphosphonates can undergo base-
promoted cleavage giving aldehyde and dialkyl phosphite, and for 2,3-
diol phosphonates isomerization of the resulting 2-hydroxyaldehyde
to the hydroxymethyl ketone occurs [(a) Waszkuc, W.; J anecki, T.;
Bodalski, R. Synthesis 1984, 1025. (b) Kharasch, M. S.; Mosher, R. A.;
Bengelsdorf, I. S. J . Org. Chem. 1960, 25, 1000]. Indeed, 2-hydroxy-
acetophenone was detected by GC in crude reaction mixtures for both
1a and 1b. Diethyl phosphite was also observed by 31P NMR. Isolated
product 1a and the corresponding diol were both incubated separately
with typical AA reaction media in order to better understand this side
reaction. It was found that, under these conditions, 1a showed very
little change after 3 h, the time required for complete consumption of
olefin (Table 1). However, after 30 h a peak at -2.5 ppm (56% of 1a )
in the 31P NMR spectrum was evident. Although no diethyl phosphite
was detected by NMR, it is reasonable that oxidation to the corre-
sponding diethyl phosphate had occurred [diethyl phosphate has a
reported chemical shift of +2.3 ppm in water: (c) Lerner, D. B.; Becktel,
W. J .; Everett, R.; Goodman, M. Biopolymers 1984, 23, 2157]. In
addition, a resonance at +10.0 ppm in the 1H NMR indicated the
presence of an aldehyde. Diol of entry 1 also showed some indication
of cleavage under these conditions but to a lesser extent (a peak at
-1.9 ppm in the 31P NMR was only 14% of diol after 24 h). Only the
cleavage products from the diol experiment included 2-hydroxyac-
etophenone (by GC). It is uncertain whether prolonged exposure of
R-hydroxyphosphonate products to the AA reaction media is the only
explanation for such byproducts, since a peak at -0.1 ppm (58% of
4a ) in the 31P NMR was evident during formation of product 4a after
only 4 h reaction time.
To demonstrate their versatility, the phosphonate AA
products 2a and 2b were converted into the correspond-
ing N-tosyl or N-ethoxycarbonyl aziridines 9a and 9b,
respectively (Scheme 2). A two-step process17 involving
initial mesylation of the hydroxyphosphonates followed
by treatment of the isolated mesylates 10a or 10b with
K2CO3 in DMF resulted in formation of the N-protected
aziridine in high yield and high purity. Although heating
above 80 °C was necessary for complete conversion of the
N-ethoxycarbonyl-protected 10b, no significant loss in
yield or purity was observed. Neither step required more
than a water workup for purification. It is noteworthy
that the mesylates were considerably more crystalline
than the starting hydroxyphosphonates. This fact could
conceivably simplify the purification of the previous AA
mixture, particularly in situations in which isolation of
hydroxyphosphonates by recrystallization is not possible
and the scale of the synthesis would make purification
by chromatography undesirable.
(12) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991; Chapter 7.
(13) O’Brien, P. Angew. Chem., Int. Ed. Engl. 1999, 38, 326.
(14) Preliminary work using benzyl carbamate as the nitrogen
source and the p-methoxystyrenyl phosphonate (entry 2, Table 1)
indicated significantly poorer conversion than with ethyl carbamate
(30-40% unreacted olefin). The reaction conditions are currently being
optimized.
(15) (a) Yokomatsu, T.; Yamagishi, T.; Sada, T.; Suemune, K.;
Shibuya, S. Tetrahedron 1998, 781. (b) For 13C NMR data of related
R-amino and R-hydroxyphosphonates, see refs 4a and 5b, respectively.
(16) One of the reviewers pointed out that the assignment of the
urethane proton could be confused with the hydroxyl proton, thus
indicating the opposite regioisomer. This is unlikely for two reasons.
First, the hydroxyl proton resonance in these sulfonamide and car-
bamate AA products is considerably broadened, and often difficult to
distinguish from the baseline. Second, the urethane proton in 7b (δ )
5.8-6.1 ppm dependent on concentration, d, J ) 8.0 Hz) exhibits a
similar chemical shift and coupling constant to that observed for the
urethane proton in the mesylate 10b (δ ) 5.9 ppm, d, J ) 8.0 Hz), in
which no hydroxyl proton is present.
(17) Backvall, J .-E.; Oshima, K.; Palermo, R. E.; Sharpless, K. B.
J . Org. Chem. 1979, 44, 1953.
(18) The optical purity of 9a was confirmed by comparison with rac-
9a using chiral HPLC. The amount of minor enantiomer was below
the limit of detection (see Supporting Information). Also, the 1H and
31P NMR spectra of 9a gave no indication of diastereomers, which
would have been generated had epimerization at C-1 or C-2 occurred
during the two-step synthesis from 2a . In order for racemization to
have occurred, simultaneous loss of stereochemistry at both C-1 and
C-2 would have had to take place.

8382 J . Org. Chem., Vol. 64, No. 22, 1999
Notes
the hydroxysulfonamide product in a minimum amount of
solvent. Unless noted otherwise, purification of the desired
product from contaminating side products was accomplished by
recrystallization from 2-propanol (with a few drops of methanol
added in cases where the solid was slow to dissolve with heating
alone) at 0 °C.
The ability to readily generate cis-aziridines in high
optical purity18 by this methodology offers a valuable
route toward these synthetically useful compounds.19
Opening of such aziridines under a variety of conditions
(e.g., nucleophilic/electrophilic addition) is currently being
explored.
(S)-(1R*,2R*)-Dieth yl [1-h yd r oxy-2-p h en yl-2-(p-tolu en e-
su lfon a m id o)eth yl]p h osp h on a te (1a ): yield after recrystal-
lization 180 mg (0.41 mmol, 21%) of a crystalline, white solid;
Exp er im en ta l Section
mp 143-144 °C; [R]25 ) +15.1 (c )1.09) for sample of 91% ee;
D
AD, 15% 2-propanol/hexane, 0.8 mL min-1 [17.3 min (S,S), 22.5
min (R,R)]; 1H NMR (500 MHz, CDCl3) δ 1.12 (t, J ) 7.5 Hz,
3H), 1.29 (t, J ) 7.0 Hz, 3H), 2.27 (s, 3H), 3.90-4.00 (m, 3H),
4.12-4.22 (m, 2H), 4.72-4.76 (m, 1H), 5.06-5.09 (m, 1H), 6.69
(d, J ) 7.5 Hz, 1H), 6.97-6.98 (m, 2H), 7.03-7.10 (m, 5H), 7.43-
7.44 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 16.08 (d, J ) 5.5
Hz), 16.34 (d, J ) 5.5 Hz), 21.27, 58.62 (d, J ) 2.9 Hz), 62.63 (d,
J ) 6.9 Hz), 63.84 (d, J ) 7.0 Hz), 71.52 (d, J ) 160 Hz), 127.05,
127.30, 127.78, 128.83, 137.08 (d, J ) 10.0 Hz), 137.76, 142.39;
31P NMR (162 MHz, CDCl3) δ 22.4; HRMS (FAB+) calcd for
Gen er a l Meth od s. Unsaturated phosphonates were prepared
by reaction of the appropriate aldehyde with the appropriate
tetraalkyl methylenediphosphonate in CH2Cl2 by treatment with
50% NaOH solution and purified by Kuglerohr distillation under
reduced pressure.9a Chloramine-T trihydrate and potassium
osmate dihydrate were purchased from Acros and Colonial
Metals, respectively. tert-Butyl hydroperoxide was prepared by
a known procedure20 and stored over CaCl2 at 0 °C. CH2Cl2 was
passed through basic alumina and stored over activated 3 Å
molecular sieves before use in water-sensitive reactions. 1H and
13C NMR spectra were recorded in CDCl3 at 500 and 125 MHz,
C
19H26NO6PSNa+ (M + Na+) 450.1116, found 450.1107. Anal.
Calcd for C19H26NO6PS: C, 53.39; H, 6.13; N, 3.28. Found: C,
53.20; H, 6.04; N, 3.23.
1
respectively. 31P NMR spectra were recorded at 162 MHz. H-
1
1H COSY and H-13C HETCOR 2D NMR spectra were recorded
(S)-(1R*,2R*)-Dieth yl [1-Hyd r oxy-2-(p-m eth oxyp h en yl)-
2-(p-tolu en esu lfon a m id o)eth yl]p h osp h on a te (2a ). The reac-
tion was scaled to 20 mmol of olefin: yield after recrystallization
2.8 g (6.1 mmol, 31%) of a fluffy, white solid; mp 152-153 °C;
on a 600 MHz spectrometer. 31P NMR chemical shifts are
relative to 85% H3PO4 (31P NMR, δP ) 0 ppm, s) as an external
reference. FT-IR spectra were recorded in the form of KBr disks
or on NaCl plates. Enantiomeric excesses were determined by
HPLC analysis using a Chiracel AD or OD-H column and
varying concentrations of 2-propanol/hexanes as the mobile
phase. Optical rotations were measured using 95% ethanol as
solvent unless specified otherwise. Melting points are uncor-
rected. Unless specified, melting points and optical rotations for
aminohydroxyphosphonate compounds were measured after
recrystallization to the maximum enantiomeric purity as indi-
cated by HPLC analysis. Elemental analyses were performed
by Midwest Microlab (Indianopolis, IN). High-resolution mass
spectrometry was performed by Dr. Gary Siuzdak (The Scripps
Research Institute). X-ray crystal determination for compound
8 was performed by Dr. Michal Sabat (University of Virginia).
Flash column chromatography was performed on Merck Kiesel-
gel 60 (230-400 mesh). Analytical and preparative TLC were
performed using precoated glass plates (Merck Kieselgel 60 F254).
Gen er a l P r oced u r e for Am in oh yd r oxyla tion Rea ction s
of Un sa tu r a ted P h osp h on a tes Usin g Ch lor a m in e-T Tr i-
h yd r a te. To a magnetically stirred solution of the unsaturated
phosphonate (2.0 mmol), Chloramine-T trihydrate (1.69 g, 6.0
mmol), and (DHQ)2PHAL (80 mg, 0.10 mmol) in a mixture of
CH3CN (14 mL) and water (14 mL) was added K2OsO2(OH)4 (30
mg, 0.08 mmol). As the osmate dissolved (5-10 min), the solution
became an orange or pink color that changed to a deep green
for all but the isopropyl-substituted phosphonate (Table 1, entry
4), which deepened to a red color. A change in color to a light
yellow indicated the completion of the reaction (corresponding
with disappearance of olefin as evidenced by TLC and/or 31P
NMR) with the exception of the â,γ-unsaturated phosphonate
(Table 1, entry 7), which remained green even after 95% of the
olefin had been consumed. The reaction was then quenched by
addition of Na2SO3 (760 mg, 6.0 mmol) and allowed to stir for
approximately 1 h. The phases were transferred to a separatory
funnel with ethyl acetate (5 mL), and the bottom, aqueous phase
was extracted with ethyl acetate (2 × 10 mL). The combined
organic phases were washed with brine and dried over MgSO4.
They were then concentrated under reduced pressure to yield a
crude mixture of p-toluenesulfonamide and other byproducts
including diol. Flash chromatography on silica gel (50 g) using
a gradient of 50% hexanes/ethyl acetate (200 mL), followed by
pure ethyl acetate (100 mL) to elute p-toluenesulfonamide, and
then 10% methanol/ethyl acetate (150 mL) was utilized to elute
[R]25 ) +13.8 (c ) 1.30) for sample of 99% ee; AD, 15%
D
2-propanol/hexane, 0.8 mL min-1 [28.2 min (S,S), 32.7 min
(R,R)]; 1H NMR (500 MHz, CDCl3) δ 1.16 (t, J ) 7.5 Hz, 3H),
1.30 (t, J ) 7.0 Hz, 3H), 2.31 (s, 3H), 3.72 (s, 3H), 3.93-4.02 (m,
3H), 4.11-4.21 (m, 2H), 4.66-4.72 (m, 2H), 6.54 (d, J ) 7.0 Hz,
1H), 6.60-6.62 (m, 2H), 7.02-7.05 (m, 4H), 7.45-7.47 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 16.10 (d, J ) 5.8 Hz), 16.34 (d, J
) 5.4 Hz), 21.27, 55.14, 58.18 (d, J ) 3.1 Hz), 71.56 (d, J ) 159
Hz), 113.18, 127.11, 128.80, 129.03, 129.16, 137.83, 142.28,
158.95; 31P NMR (162 MHz, CDCl3) δ 22.7; HRMS (FAB+) calcd
for C20H28NO7PSCs+ (M + Cs+) 590.0378, found 590.0360. Anal.
Calcd for C20H28NO7PS: C, 52.51; H, 6.17; N, 3.06. Found: C,
52.47; H, 6.24; N, 3.05.
(S)-(1R*,2R*)-Dim eth yl [1-Hydr oxy-2-(p-m eth oxyph en yl)-
2-(p-tolu en esu lfon a m id o)eth yl]p h osp h on a te (3a ). The reac-
tion was performed on 2 mmol of olefin. Product was purified
by flash chromatography using ethyl acetate/hexanes as in the
general procedure to remove p-toluenesulfonamide, followed by
a second flash column using 2% methanol in chloroform to
remove most diol and regioisomer: yield 342 mg (0.69 mmol,
35%) of a viscous, clear oil including 13% impurities (by 31P
NMR); [R]25 ) + 11.0 (c ) 1.16) for sample of 88% ee; AD, 15%
D
2-propanol/hexane, 1.0 mL min-1 [22.4 min (S,S), 29.1 min
1
(R,R)]; H NMR (500 MHz, CDCl3) δ 2.28 (s, 3H), 3.63 (d, J )
11.0 Hz, 3H), 3.70 (s, 3H), 3.76 (d, J ) 10.5 Hz, 3H), 4.03-4.05
(m, 1H), 4.71-4.75 (m, 1H), 5.24 (br. s, 1H), 6.57-6.59 (m, 2H),
6.75 (d, J ) 7.5 Hz, 1H), 6.98-7.02 (m, 4H), 7.43-7.44 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 21.16, 53.14 (d, J ) 5.8 Hz), 53.93,
55.03, 58.05 (d, J ) 3.8 Hz), 71.45 (d, J ) 160 Hz), 113.15,
126.98, 128.74, 128.85, 128.93 (d, J ) 10.0 Hz), 137.69, 142.25,
158.84; 31P NMR (162 MHz, CDCl3) δ 25.0; HRMS (FAB+) calcd
for C18H24NO7PSNa+ (M + Na+) 452.0909, found 452.0920. Anal.
Calcd for C18H24NO7PS: C, 50.35; H, 5.63; N, 3.26. Found: C,
50.34; H, 5.68; N, 3.22.
(S)-(1R*,2R*)-Diisopr opyl [1-Hydr oxy-2-(p-m eth oxyph en -
yl)-2-(p-tolu en esu lfon a m id o)eth yl]p h osp h on a te (4a ). After
purification by preparative TLC, the product was recrystallized
from 1:1 2-propanol/THF at 0 °C to obtain 205 mg (0.42 mmol,
21%) of a crystalline, white solid, mp 173-174 °C, which proved
to be the racemate: AD, 10% 2-propanol/hexane, 1.0 mL min-1
1
[20.9 min (R,R), 26.5 min (S,S)]; H NMR (500 MHz, CDCl3) δ
1.11 (d, J ) 6.5 Hz, 3H), 1.17 (d, J ) 6.0 Hz, 3H), 1.28 (d, J )
6.5 Hz, 3H), 1.32 (d, J ) 6.5 Hz, 3H), 2.31 (s, 3H), 3.72 (s, 3H),
3.86-3.94 (m, 1H), 4.55-4.60 (m, 1H), 4.60-4.66 (m, 1H), 4.68-
4.75 (m, 1H), 4.90-4.92 (m, 1H), 6.47 (d, J ) 6.5 Hz, 1H), 6.60-
6.62 (m, 2H), 7.02-7.04 (m, 4H), 7.42-7.44 (m, 2H); 13C NMR
(125 MHz, CDCl3, for an unexplained reason dual peaks were
observed; they are listed after their partner and starred) δ
21.15-21.29 (m), 22.98-24.60 (m), 55.06-55.17 (m), 58.14 (m),
71.42 (d, J ) 161), 71.51* (d, J ) 161), 71.69 (m), 72.49 (m),
(19) (a) Kemp, J . E. G. Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, p 469. (b)
Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Padwa, A., Eds.; Elsevier Science Ltd.: Oxford, 1996; Vol. 1, p 1.
(c) Padwa, A.; Murphree, S. S. Prog. Heterocycl. Chem. 1994, 6, 56.
(20) Mintz, M. J .; Walling, C. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. V, p 184.

Notes
J . Org. Chem., Vol. 64, No. 22, 1999 8383
113.07, 113.19*, 126.95, 127.13*, 128.68, 128.82*, 129.04, 129.19*,
129.39, 129.46*, 137.91, 142.21, 158.95; 31P NMR (162 MHz,
CDCl3) δ 20.2; HRMS (FAB+) calcd for C22H32NO7PSNa+ (M +
Na+) 508.1535, found 508.1548. Anal. Calcd for C22H32NO7PS:
C, 54.42; H, 6.64; N, 2.88. Found: C, 54.38; H, 6.65; N, 2.90.
(S)-(1R*,2R*)-Dieth yl [1-h yd r oxy-2-(p-n itr op h en yl)-2-(p-
tolu en esu lfon a m id o)eth yl]p h osp h on a te (5a ): yield after
recrystallization; 376 mg (0.80 mmol, 40%) of a crystalline, white
workup similar to that of the hydroxysulfonamides. Noncrystal-
line carbamates were generated on a 0.5 mmol scale and purified
by preparative TLC (5% MeOH/CHCl3; 1b, 4b, 5b, 7b). Unless
specified otherwise, crystallization of solid hydroxycarbamate
compounds was performed from diethyl ether at -30 °C (2b,
6b). Seeding with a small amount of solid product, which had
been purified by preparative TLC, was typically required to
induce crystallization.
solid; mp 145-146 °C; [R]25 ) + 27.1 (c )1.49) for sample of
D
(S)-(1R*,2R*)-Diet h yl [1-h yd r oxy-2-p h en yl-2-(O-et h yl-
ca r ba m yl)eth yl]p h osp h on a te (1b): yield after preparative
TLC 61 mg (0.16 mmol, 32%) of a viscous, yellow oil including
99% ee; AD, 20% 2-propanol/hexane, 1.0 mL min-1 [18.1 min
(S,S), 21.1 min (R,R)]; 1H NMR (500 MHz, CDCl3) δ 1.24 (t, J )
7.0 Hz, 3H), 1.41 (t, J ) 7.0 Hz, 3H), 2.27 (s, 3H), 4.02-4.10 (m,
3H), 4.31-4.37 (m, 2H), 4.91-4.94 (m, 1H), 5.70 (m, 1H), 6.97-
6.99 (m, 2H), 7.25-7.30 (m, 3H), 7.46-7.48 (m, 2H), 7.89-7.91
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 16.14 (d, J ) 5.6 Hz),
16.42 (d, J ) 5.1 Hz), 21.20, 58.30, 62.83 (d, J ) 7.1 Hz), 64.53
(d, J ) 7.4 Hz), 71.27 (d, J ) 160 Hz), 122.77, 127.05, 128.85,
128.98, 137.47, 143.23, 144.45 (d, J ) 11.0 Hz), 146.93; 31P NMR
(162 MHz, CDCl3) δ 22.4; HRMS (FAB+) calcd for C19H25N2O8-
PSNa+ (M + Na+) 495.0967, found 495.0954. Anal. Calcd for
10% impurities (by 31P NMR); [R]25 ) + 18.0 (c )1.57) for
D
sample in 93% ee; AD, 20% 2-propanol/hexane, 1.0 mL min-1
1
[5.03 min (S,S), 6.33 min (R,R)]; H NMR (500 MHz, CDCl3) δ
1.19 (m, 3H), 1.23 (t, J ) 7.0 Hz, 3H), 1.33 (t, J ) 7.0 Hz, 3H),
3.91-4.22 (m, 7H), 5.13 (br. s, 1H), 5.38 (br. s, 1H), 6.64 (d, J )
7.5 Hz, 1H), 7.22-7.26 (m, 1H), 7.29-7.32 (m, 2H), 7.32-7.37
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 14.50, 16.24 (d, J ) 5.6
Hz), 16.34 (d, J ) 5.5 Hz), 55.04, 60.77, 62.78 (d, J ) 6.9 Hz),
63.38 (d, J ) 7.0 Hz), 71.18 (d, J ) 160 Hz), 126.80, 127.32,
128.23, 140.25 (d, J ) 13.5 Hz), 156.15; 31P NMR (162 MHz,
CDCl3) δ 23.2; IR (KBr) ν 1721 (CdO, urethane) cm-1; HRMS
(FAB+) calcd for C15H24NO6PNa+ (M + Na+) 368.1239, found
368.1231. Anal. Calcd for C15H24NO6P: C, 52.17; H, 7.00; N, 4.06.
Found: C, 52.10; H, 7.05; N, 4.02.
C
19H25N2O8PS: C, 48.30; H, 5.33; N, 5.93. Found: C, 48.22; H,
5.26; N, 5.89.
(S)-(1R*,2R*)-Diet h yl [1-h yd r oxy-2-(2-n a p h t h yl)-2-(p -
tolu en esu lfon a m id o)eth yl]p h osp h on a te (6a ): yield after
recrystallization 286 mg (0.60 mmol, 30%) of a white powder;
mp 151-152 °C; [R]25 ) +28.5 (c )1.05) for sample of 93% ee;
D
(S)-(1R*,2R*)-Dieth yl [1-h yd r oxy-2-(p-m eth oxyp h en yl)-
2-(O-eth ylca r ba m yl)eth yl]p h osp h on a te (2b): yield after re-
crystallization 336 mg (0.90 mmol, 45%) of a fluffy, white solid;
AD, 10% 2-propanol/hexane, 1.0 mL min-1 [33.0 min (S,S), 36.9
min (R,R)]; 1H NMR (500 MHz, CDCl3) δ 1.09 (t, J ) 7.0 Hz,
3H), 1.32 (t, J ) 7.5 Hz, 3H), 2.06 (s, 3H), 3.95-4.00 (m, 2H),
4.11-4.15 (m, 1H), 4.17-4.25 (m, 2H), 4.62 (br s, 1H), 4.93-
4.97 (m, 1H), 6.70 (br s, 1H), 6.77-6.79 (m, 2H), 7.25-7.26 (m,
1H), 7.40-7.42 (m, 4H), 7.51 (s, 1H), 7.54-7.56 (m, 1H), 7.59-
7.61 (m, 1H), 7.70-7.72 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
16.01 (d, J ) 5.5 Hz), 16.33 (d, J ) 5.1 Hz), 20.92, 58.84 (d, J )
2.8 Hz), 62.64 (d, J ) 7.0 Hz), 63.90 (d, J ) 7.0 Hz), 71.51 (d, J
) 159 Hz), 125.43, 125.61, 125.68, 126.91, 127.18, 127.26, 127.47,
127.75, 128.55, 132.59, 132.61, 134.11 (d, J ) 10.0 Hz), 137.63,
142.36; 31P NMR (162 MHz, CDCl3) δ 22.8; HRMS (FAB+) calcd
for C23H28NO6PSNa+ (M + Na+) 500.1273, found 500.1285. Anal.
Calcd for C23H28NO6PS: C, 57.85; H, 5.91; N, 2.93. Found: C,
57.17; H, 5.76; N, 2.96.
mp 86-87 °C; [R]25 ) + 30.2 (c )1.50) for sample of 99% ee;
D
AD, 15% 2-propanol/hexane, 0.5 mL min-1 [15.7 min (S,S), 26.3
1
min (R,R)]; H NMR (500 MHz, CDCl3) δ 1.20 (m, 3H), 1.26 (t,
J ) 7.0 Hz), 1.34 (t, J ) 7.0 Hz, 3H), 3.79 (s, 3H), 4.05-4.15 (m,
5H), 4.18-4.23 (m, 2H), 4.40-4.70 (m, 1H), 5.08 (br. s, 1H), 6.40
(m, 1H), 6.85-6.87 (m, 2H), 7.30-7.32 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 14.52, 16.28 (d, J ) 5.0 Hz), 16.37 (d, J ) 5.0
Hz), 54.57, 55.19, 60.75, 62.77 (d, J ) 6.3 Hz), 63.36 (d, J ) 7.5
Hz), 71.33 (d, J ) 160 Hz), 113.75, 128.02, 132.41 (d, J ) 14.0
Hz), 156.20, 158.80; 31P NMR (162 MHz, CDCl3) δ 23.0; IR (KBr)
ν 1706 (CdO, urethane) cm-1; HRMS (FAB+) calcd for C16H26
-
NO7PCs+ (M + Cs+) 508.0501, found 508.0511. Anal. Calcd for
C16H26NO7P: C, 51.19; H, 6.98; N, 3.73. Found: C, 50.97; H,
7.02; N, 3.78.
(R)-(2R*,3S*)-Dieth yl [2-h yd r oxy-3-p h en yl-3-(p-tolu en e-
su lfon a m id o)p r op yl]p h osp h on a te (7a ): yield after recrys-
tallization 180 mg (0.41 mmol, 20%) of a fluffy, white solid; mp
(S)-(1R*,2R*)-Dim eth yl [1-Hydr oxy-2-(p-m eth oxyph en yl)-
2-(O-eth ylca r ba m yl)eth yl]p h osp h on a te (3b). The reaction
was performed on 1 mmol olefin. After the general isolation
procedure, product was recrystallized from 2-propanol to obtain
110 mg (0.32 mmol, 32%) of a fluffy, white solid: mp 111-112
155-156 °C; [R]25 ) +7.2 (c )0.58) for sample of 94% ee; AD,
D
15% 2-propanol/hexane, 0.8 mL min-1 [24.3 min (R,S), 27.1 min
(S,R)]; 1H NMR (500 MHz, CDCl3) δ 1.28 (t, J ) 7.0 Hz, 3H),
1.32 (t, J ) 7.0 Hz, 3H), 1.82 (m, 1H), 2.06 (td, J ) 15.5, 10.0
Hz, 1H), 2.32 (s, 3H), 4.03-4.21 (m, 6H), 4.22 (m, 1H), 5.85 (br.
s, 1H), 7.05-7.07 (m, 4H), 7.13-7.15 (m, 3H), 7.45-7.47 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 16.24 (d, J ) 5.1 Hz), 21.30, 30.42
(d, J ) 141 Hz), 61.94 (d, J ) 6.4 Hz), 62.29 (d, J ) 6.3 Hz),
63.26 (d, J ) 20 Hz), 69.69 (d, J ) 4 Hz), 126.89, 127.35, 127.47,
128.16, 129.00, 137.59, 138.06, 142.60; 31P NMR (162 MHz,
CDCl3) δ 30.5; HRMS (FAB+) calcd for C20H28NO6PSNa+ (M +
Na+) 464.1273, found 464.1264. Anal. Calcd for C20H28NO6PS:
C, 54.41; H, 6.39; N, 3.17. Found: C, 54.64; H, 6.44; N, 3.08.
Gen er a l P r oced u r e for Am in oh yd r oxyla tion Rea ction s
of Un sa tu r a ted P h osp h on a tes Usin g Eth yl N-Ch lor o-N-
sod ioca r ba m a te. To a magnetically stirred solution of NaOH
(1.0 M, 6.0 mL, 6.0 mmol) was added urethane (570 mg, 6.4
mmol). After the urethane had dissolved (1-2 min), tert-butyl
hypochlorite (660 mg, 6.0 mmol) was dispensed in a dropwise
fashion. The solution was subsequently diluted with water (8
mL) and n-propanol (14 mL). (DHQ)2PHAL (80 mg, 0.10 mmol)
and unsaturated phosphonate (2.0 mmol) were then added. After
complete dissolution of ligand and olefin, K2OsO2(OH)4 (30 mg,
0.08 mmol) was added to the solution. The color varied somewhat
with substrate (and was not always reproducible with the same
substrate), but generally a pink or orange color persisted through
the entire reaction. A pale yellow or green would occasionally
correspond with a complete reaction, but the color difference was
found not to be a reliable indicator of conversion as with the
sulfonamides. For phosphonate 1b, 17% unreacted olefin (rela-
tive to all other 31P NMR signals) was still present after 18 h.
Further reaction time did not improve conversion significantly.
The reactions were monitored, quenched, and subjected to a
°C; [R]25 ) +33.0 (c )1.80) for sample of 99% ee; AD, 10%
D
2-propanol/hexane, 1.0 mL min-1 [14.3 min (S,S), 23.0 min
(R,R)]; 1H NMR (500 MHz, CDCl3) δ 1.14-1.17 (m, 3H), 3.67
(d, J ) 10.0 Hz, 3H), 3.75 (s, 3H), 3.79 (d, J ) 10.5 Hz, 3H),
4.04 (q, J ) 7.0 Hz, 2H), 4.14 (br. s, 1H), 5.06 (br. s, 1H), 5.38
(br. s, 1H), 6.59 (d, J ) 9 Hz, 1H), 6.82-6.84 (m, 2H), 7.27-
7.29 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 14.42, 53.16 (d, J )
6.8 Hz), 53.73 (d, J ) 3.0 Hz), 54.52, 55.12, 60.82, 71.10 (d, J )
160 Hz), 113.63, 127.95, 132.05 (d, J ) 13.5 Hz), 156.22, 158.83;
31P NMR (162 MHz, CDCl3) δ 25.1; IR (KBr) ν 1706 (CdO,
urethane) cm-1; HRMS (FAB+) calcd for C14H22NO7PNa+ (M +
Na+) 370.1032, found 370.1038. Anal. Calcd for C14H22NO7P: C,
48.42; H, 6.38; N, 4.03. Found: C, 48.76; H, 6.55; N, 4.01.
(S)-(1R*,2R*)-Diisopr opyl [1-Hydr oxy-2-(p-m eth oxyph en -
yl)-2-(O-eth ylca r ba m yl)eth yl]p h osp h on a te (4b). After pu-
rification by preparative TLC, the product crystallized from ether
at room temperature to obtain 70 mg (0.17 mmol, 35%) of a
fluffy, white solid: mp 44-45 °C; [R]25 ) +26.2 (c )1.20) for
D
sample of 99% ee; AD, 5% 2-propanol/hexane, 1.0 mL min-1 [18.5
min (S,S), 32.7 min (R,R)]; 1H NMR (500 MHz, CDCl3) δ 1.17-
1.21 (m, 6H), 1.25 (d, J ) 6.5 Hz, 3H), 1.34-1.36 (m, 6H), 3.76
(s, 3H), 3.98-4.05 (m, 3H), 4.60-4.61 (m, 1H), 4.78-4.84 (m,
1H), 5.07 (br. s, 1H), 5.54 (br. s, 1H), 6.70 (m, 1H), 6.82-6.83
(m, 2H), 7.28-7.30 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 14.52,
23.62, 23.66, 23.94, 24.08, 54.63, 55.10, 60.49, 71.56 (d, J ) 163
Hz), 71.62 (d, J ) 7.4 Hz), 72.11 (d, J ) 7.4 Hz), 113.52, 127.91,
132.80 (d, J ) 13.0 Hz), 156.00, 158.72; 31P NMR (162 MHz,
CDCl3) δ 21.3; IR (KBr) ν 1725 (CdO, urethane) cm-1; HRMS
(FAB+) calcd for C18H30NO7PNa+ (M + Na+) 426.1658, found

8384 J . Org. Chem., Vol. 64, No. 22, 1999
Notes
426.1668. Anal. Calcd for C18H30NO7P: C, 53.59; H, 7.50; N, 3.47.
Found: C, 53.29; H, 7.41; N, 3.39.
NMR. The ee of (S)-(+)-R-methoxyphenylacetic acid was not
checked. Surprisingly, it was found that the mp for the mixture
of diastereomers (125-133 °C) was higher than the mp of the
(S)-(1R*,2R*)-Dieth yl [1-h yd r oxy-2-(p-n itr op h en yl)-2-(O-
eth ylca r ba m yl)eth yl]p h osp h on a te (5b): yield after prepara-
tive TLC 109 mg (0.27 mmol, 53%) of a viscous, orange oil
enriched diastereomer (119-121 °C): [R]25 ) +16.5 (c )1.62)
D
for sample of 96% de; 1H NMR (500 MHz, CDCl3) δ 1.17 (t, J )
7.2 Hz, 3H), 1.21 (t, J ) 7.0 Hz, 3H), 2.35 (s, 3H), 3.33 (s, 3H),
3.85-3.96 (m, 2H), 3.97-4.10 (m, 2H), 4.74 (s, 1H), 4.78-4.82
(m, 1H), 5.31 (dd, 1H, J ) 3.5, 10.8 Hz, 1H), 6.16 (d, J ) 6.2 Hz,
1H), 6.81-6.82 (m, 2H), 7.13-7.15 (m, 2H), 7.34-7.36 (m, 2H),
7.42-7.51 (m, 3H), 7.52-7.54 (m, 2H), 7.66-7.69 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 16.08 (d, J ) 6.0 Hz), 16.15 (d, J )
6.0 Hz), 21.34, 56.14, 57.17, 63.37 (d, J ) 6.5 Hz), 63.74 (d, J )
7.2 Hz), 68.99 (d, J ) 166 Hz), 81.88, 122.90, 127.13, 127.47,
127.97, 128.93, 129.31, 129.46, 135.09, 136.76, 143.38 (d, J )
9.8 Hz), 143.67, 146.96, 168.20 (d, J ) 4.6 Hz); 31P NMR (162
MHz, CDCl3) δ 16.1 (major diastereomer, 98%), 15.5 (minor
diastereomer, 2%); IR (KBr) ν 1764 (CdO, ester) cm-1; HRMS
(MALDI-FTMS) calcd for C28H33N2O10PSNa+ (M + Na+) 643.1491,
found 643.1569. Anal. Calcd for C28H33N2O10PS: C, 54.19; H,
5.36; N, 4.51. Found: C, 54.21; H, 5.37; N, 4.48.
including less than 5% impurities by 31P NMR; [R]25 ) +23.2
D
(c )3.61) for sample of 97% ee; AD, 10% 2-propanol/hexane, 0.8
mL min-1 [16.3 min (S,S), 31.2 min (R,R)]; 1H NMR (500 MHz,
CDCl3) δ 1.21 (m, 3H), 1.28 (t, J ) 7.0 Hz, 3H), 1.39 (t, J ) 7.0
Hz, 3H), 4.07-4.12 (m, 5H), 4.25-4.29 (m, 2H), 5.22 (br. s, 1H),
5.54 (br. s, 1H), 6.89 (br. s, 1H), 7.56-7.58 (m, 2H), 8.19-8.21
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 14.52, 16.30 (d, J ) 6.0
Hz), 16.40 (d, J ) 5.4 Hz), 55.13, 61.15, 63.21 (d, J ) 7.9 Hz),
63.87 (d, 7.6 Hz), 70.72 (d, J ) 161 Hz), 123.53, 127.91, 147.29,
147.85 (d, J ) 13.3 Hz), 156.11; 31P NMR (162 MHz, CDCl3) δ
22.2; IR (NaCl plates) ν 1717 (CdO, urethane) cm-1; HRMS
(FAB+) calcd for C15H23N2O8PNa+ (M + Na+) 413.1090, found
413.1079. Anal. Calcd for C15H23N2O8P: C, 46.16; H, 5.94; N,
7.18. Found: C, 45.78; H, 6.05; N, 7.07.
(S)-(1R*,2R*)-Diet h yl [1-h yd r oxy-2-(â-n a p h t h yl)-2-(O-
eth ylca r ba m yl)eth yl]p h osp h on a te (6b): yield after recrys-
tallization 420 mg (1.06 mmol, 53%) of a slightly yellow,
(S)-(1R*,2R*)-Dieth yl [1-Meth a n esu lfon yloxy-2-(p-m eth -
oxyp h en yl)-2-(p -t olu en esu lfon a m id o)et h yl]p h osp h on a t e
(10a ). To a magnetically stirred solution of hydroxysulfonamide
2a (1.03 g, 2.25 mmol) in CH2Cl2 (10 mL) was added triethyl-
amine (0.94 mL, 6.8 mmol) followed by methanesulfonyl chloride
(0.35 mL, 4.5 mmol) at -10 °C. The reaction was quenched after
15 min by the addition of water (10 mL). The mixture was
transferred to a separatory funnel with CH2Cl2 (5 mL), and the
top, aqueous phase was extracted with CH2Cl2 (5 mL). The
combined organic phases were washed with a 10% solution of
NaHCO3 (10 mL) and brine (10 mL) and then dried over MgSO4.
Concentration under reduced pressure yielded 1.26 g of an
impure, yellow solid. Although formation of aziridine 9a in the
next step of the sequence (Scheme 2) was apparently not
retarded by such impurities in the mesylate 10a , purification
was possible by recrystallization from 30% methanol/2-propanol
at room temperature to give 1.08 g (2.02 mmol, 90%) of a
crystalline solid; mp 112-113 °C; [R]25 ) +43.3 (c )1.37) for
D
sample of 99% ee; AD, 10% 2-propanol/hexane, 0.8 mL min-1
1
[23.4 min (S,S), 32.5 min (R,R)]; H NMR (500 MHz, CDCl3) δ
1.19-1.22 (m, 6H), 1.35 (t, J ) 7.0 Hz, 3H), 4.05-4.12 (m, 4H),
4.20-4.27 (m, 3H), 4.92 (br. s, 1H), 5.31 (br. s, 1H), 6.63 (br. s,
1H), 7.44-7.51 (m, 3H), 7.80-7.83 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 14.42, 16.09 (d, J ) 4.3 Hz), 16.28 (d, J ) 5.2 Hz),
55.12, 60.69, 62.70 (d, J ) 6.6 Hz), 63.37 (d, J ) 6.9), 71.02 (d,
J ) 160 Hz), 124.92, 125.59, 125.82, 127.37, 127.79, 127.85,
132.66, 133.06, 137.76 (d, J ) 12.0 Hz), 156.12; 31P NMR (162
MHz, CDCl3) δ 22.9; IR (KBr) ν 1731 (CdO, urethane) cm-1
;
HRMS (FAB+) calcd for C19H26NO6PNa+ (M + Na+) 418.1395,
found 418.1385. Anal. Calcd for C19H26NO6P: C, 57.72; H, 6.63;
N, 3.54. Found: C, 57.66; H, 6.63; N, 3.49.
(R)-(2R*,3S*)-Diet h yl [2-Hyd r oxy-3-p h en yl-3-(O-et h yl-
ca r ba m yl)p r op yl]p h osp h on a te (7b). The reaction was per-
formed on 1 mmol of olefin. After the general isolation procedure,
the racemate crystallized from 2-propanol at 0 °C. The mother
liquor was then purified by preparative TLC, and 103 mg (0.29
crystalline, white solid: mp 158-159 °C; [R]25 ) + 21.8 (c
D
)1.10, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.20 (q, J ) 6.6
Hz, 6H), 2.33 (s, 3H), 3.02 (s, 3H), 3.73 (s, 3H), 3.92-4.08 (m,
4H), 4.87-4.94 (m, 2H), 5.85-5.86 (m, 1H), 6.67-6.69 (m, 2H),
7.05-7.10 (m, 4H), 7.50-7.52 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 15.9-16.4 (m), 21.1-21.5 (m), 39.12-39.28 (m), 55.17
(d, J ) 15.0 Hz), 57.20 (d, J ) 5.0 Hz), 63.1-63.2 (m), 63.9-
64.1 (m), 77.09 (d, J ) 165 Hz), 113.54 (d, J ) 16.3 Hz), 127.15
(d, J ) 26.3 Hz), 127.44 (d, J ) 6.0 Hz), 128.9-129.2 (m), 137.35,
143.00, 159.48; 31P NMR (162 MHz, CDCl3) δ 15.5; HRMS
(FAB+) calcd for C21H30NO9PS2Cs+ (M + Cs+) 668.0154, found
668.0169. Anal. Calcd for C21H30NO9PS2: C, 47.10; H, 5.65; N,
2.62. Found: C, 47.21; H, 5.73; N, 2.59.
mmol, 29%) of a viscous, yellow oil was obtained: [R]25 ) +
D
15.7 (c )4.56) for sample of 90% ee; AD, 10% 2-propanol/hexane,
1.0 mL min-1 [9.73 min (R,S), 15.3 min (S,R)]; 1H NMR (500
MHz, CDCl3) δ 1.19-1.25 (m, 3H), 1.30 (t, J ) 7.0 Hz, 3H), 1.32
(t, J ) 7.0 Hz, 3H), 1.93-2.04 (m, 1H), 2.12 (td, J ) 15.5 Hz,
10.5 Hz, 1H), 4.04-4.13 (m, 6H), 4.28 (m, 2H), 4.64 (br. s, 1H),
6.10 (d, 1H, J ) 8.0 Hz), 7.25-7.28 (m, 1H), 7.32-7.33 (m, 4H);
13C NMR (125 MHz, CDCl3) δ 14.45, 16.27 (d, J ) 6.0 Hz), 31.08
(d, 139 Hz), 59.87 (d, J ) 18.4 Hz), 60.89, 61.88 (d, J ) 6.4 Hz),
62.14 (d, J ) 4.3 Hz), 69.24 (d, J ) 4.5 Hz), 126.79, 127.44,
128.41, 140.36, 156.58; 31P NMR (162 MHz, CDCl3) δ 30.9; IR
(NaCl plates) ν 1715 (CdO, urethane) cm-1; HRMS (FAB+) calcd
for C16H26NO6PCs+ (M + Cs+) 492.0552, found 492.0563. Anal.
Calcd for C16H26NO6P: C, 53.48; H, 7.29; N, 3.90. Found: C,
53.57; H, 7.35; N, 3.86.
(S)-(1R*,2R*)-Dieth yl [1-Meth a n esu lfon yloxy-2-(p-m eth -
oxyp h en yl)-2-(O-eth ylca r ba m yl)eth yl]p h osp h on a te (10b).
Mesylate 10b was prepared and purified in the same manner
as the sulfonamide 10a above, except the reaction was scaled
to 5.00 mmol of 2b and the recrystallization solvent was pure
2-propanol, to give 2.0 g (4.4 mmol, 88%) of a white powder: mp
115-116 °C; [R]25D ) +32.1 (c )1.38); 1H NMR (500 MHz, CDCl3)
δ 1.22-1.24 (m, 6H), 1.32-1.35 (m, 3H), 2.89 (s, 3H), 3.79 (s,
3H), 4.10-4.19 (m, 6H), 5.05 (dd, J ) 10.0, 5.0 Hz, 1H), 5.30-
5.32 (m, 1H), 5.87 (d, J ) 8.0 Hz, 1H), 6.88-6.90 (m, 2H), 7.28-
7.30 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 14.37, 16.12 (m),
38.89, 53.90, 55.11, 61.03, 63.37 (m), 78.17 (d, J ) 164 Hz),
113.86, 128.12, 129.55 (d, J ) 6.8 Hz), 155.46, 159.36; 31P NMR
(162 MHz, CDCl3) δ 16.1; IR (KBr): ν 1727 (CdO, urethane)
cm-1; HRMS (FAB+) calcd for C17H28NO9PSNa+ (M + Na+)
476.1120, found 476.1128. Anal. Calcd for C17H28NO9PS: C,
45.03; H, 6.22; N, 3.09. Found: C, 44.83; H, 6.16; N, 3.01.
(R)-(1R*,2S*)-Diet h yl [2-(p -Met h oxyp h en yl)-1,2-[N-(p -
tolu en esu lfon yl)a zir id in o]eth yl]p h osp h on a te (9a ). To a
magnetically stirred solution of mesylate 10a (0.920 g, 1.72
mmol) in DMF (10 mL) was added K2CO3 (1.2 g, 8.6 mmol). The
suspension was stirred at room temperature for 2 h. At this
point, the viscous mixture was transferred to a separatory funnel
with CH2Cl2 (20 mL) and washed with water (5 × 20 mL) and
brine (20 mL). The organic phase was then dried over MgSO4
and concentrated under reduced pressure to yield 720 mg (1.64
(S)-(1R*,2R*)-Dieth yl [1-(S-r-Meth oxyp h en yla cetyloxy)-
2-(p -n it r op h e n yl)-2-(p -t olu e n e su lfon a m id o)e t h yl]p h os-
p h on a te (8). To a magnetically stirred solution of 5a (780 mg,
1.65 mmol; 99% ee) in CH2Cl2 (2 mL) was added (S)-(+)-R-
methoxyphenylacetic acid (274 mg, 1.65 mmol) followed by
DMAP (5 mg, 0.04 mmol) and then DCC (374 mg, 1.82 mmol)
at 0 °C. The reaction was allowed to warm to room temperature
over 30 min. The white precipitate, dicyclohexylurea, was
removed by filtration, and the filtrate was concentrated under
reduced pressure. Recrystallization of crude 8 from 1:1 toluene/
hexanes yielded 908 mg (1.47 mmol, 89%) of a white powder.
To obtain X-ray quality crystals, 8 was dissolved in chloroform
(5 mL) in an open scintillation vial that was placed inside a
larger glass container containing n-pentane. Slow diffusion of
n-pentane into the chloroform solution over a period of 5 days
resulted in suitable crystals for X-ray diffraction. A mixture of
diastereomers of 8 was similarly prepared (excluding the second
recrystallization by slow diffusion) from rac-5a in order to
confirm the diastereomeric purity of 8. The de for the enriched
diastereomer after recrystallization by slow diffusion was only
96% (compared with 99% ee for the starting material 5a ) by 31
P
mmol, 95%) of a viscous, yellow oil that was pure by NMR: [R]25
D

Notes
J . Org. Chem., Vol. 64, No. 22, 1999 8385
) +63.5 (c )3.66) for sample of 99% ee; OD-H, 20% 2-propanol/
hexane, 0.5 mL min-1 [16.3 min (R,S), 17.5 min (S,R)]; 1H NMR
(500 MHz, CDCl3) δ 1.03 (t, J ) 7.0 Hz, 3H), 1.11 (t, J ) 7.0 Hz,
3H), 2.43 (s, 3H), 3.06 (dd, J ) 14.5, 7.5 Hz, 1H), 3.51-3.59 (m,
1H), 3.74 (s, 3H), 3.77-3.99 (m, 3H), 4.01 (t, J ) 8.5 Hz, 1H),
6.77-6.80 (m, 2H), 7.23-7.34 (m, 2H), 7.34-7.35 (m, 2H), 7.87-
7.89 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 16.06, 21.60, 38.68
(d, J ) 205 Hz), 43.78 (d, J ) 4.6 Hz), 55.14, 62.48 (m), 113.39,
123.68, 128.30, 128.89, 129.76, 133.83, 145.12, 159.49; 31P NMR
(162 MHz, CDCl3) δ 15.7; HRMS (FAB+) calcd for C20H27NO6-
125.54, 128.98, 159.44, 162.54 (d, J ) 6.8 Hz); 31P NMR (162
MHz, CDCl3) δ 18.0; IR (NaCl plates) ν 1729 (CdO, urethane)
cm-1; HRMS (FAB+) calcd for C16H24NO6PNa+ (M + Na+)
380.1239, found 380.1229. Anal. Calcd for C16H24NO6P: C, 53.78;
H, 6.77; N, 3.92. Found: C, 53.55; H, 6.77; N, 3.89.
Ack n ow led gm en t. We are grateful to the National
Institutes of General Medical Sciences, National Insti-
tutes of Health (Grant GM28384), the National Science
Foundation (Grant CHE-9531152), and the W. M. Keck
Foundation for providing financial support. A.T. would
also like to thank A. Erik Rubin, Pui Tong Ho, and
Wallace Pringle, J r., for their editorial assistance and
discussions.
PS+ (M + H+) 440.1297, found 440.1285. Anal. Calcd for C20H26
-
NO6PS: C, 54.66; H, 5.96; N, 3.19. Found: C, 54.40; H, 5.98; N,
3.27.
(R)-(1R*,2S*)-Dieth yl [1,2-[N-(Eth oxycar bon yl)azir idin o]-
2-(p-m eth oxyp h en yl)eth yl]p h osp h on a te (9b). Aziridine 9b
was prepared by the same method as 9a above, except the
reaction was scaled to 4.00 mmol of 10b and it required heating
at 80 °C for 3 h. The product was isolated as 1.33 g (3.72 mmol,
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 2b and 5a ; 1H, 13C, 1H-1H COSY, and 1H-13C
HETCOR 2D NMR spectra with partial assignments for 7b;
the ORTEP structure and 31P NMR spectrum for 8; 1H and
31P NMR spectra for 9a as well as chiral HPLC traces for 9a
and rac-9a . This material is available free of charge via the
Internet at http://pubs.acs.org.
93%) of a viscous, yellow oil and was pure by NMR: [R]25
)
D
1
+24.3 (c )1.56); H NMR (500 MHz, CDCl3) δ 1.12 (t, J ) 7.0
Hz, 3H), 1.22 (t, J ) 7.0 Hz, 3H), 1.31 (t, J ) 7.0 Hz, 3H), 2.87
(dd, J ) 17.0, 7.0 Hz, 1H), 3.67-3.76 (m, 1H), 3.80 (s, 3H), 3.83
(t, J ) 7.0 Hz, 1H), 3.87-4.06 (m, 3H), 4.20-4.26 (m, 2H), 6.87-
6.89 (m, 2H), 7.41-7.43 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
14.25, 16.20 (m), 37.93 (d, J ) 206 Hz), 43.10 (d, J ) 4.9 Hz),
55.25, 62.27 (d, J ) 6.1 Hz), 62.41 (d, J ) 6.4 Hz), 63.27, 113.41,
J O990060R