Concise formal synthesis of (-)-salinosporamide a (marizomib) using a regio- and stereoselective epoxidation and reductive oxirane ring-opening strategy

Article abstract of DOI:10.1021/jo100432g

Figure presented Expedient access to a highly functionalized 2-pyrrolidinone (8), the γ-lactam core of 20S proteasome inhibitor (-)-salinosporamide A (marizomib; NPI-0052; 1), using a regio- and stereoselective epoxide formation/reductive oxirane ring-ope

Full text of DOI:10.1021/jo100432g

pubs.acs.org/joc
A3 and omuralide,4a-f sharing the unique fused γ-lactam-β-
Concise Formal Synthesis of (-)-Salinosporamide A
(Marizomib) Using a Regio- and Stereoselective
Epoxidation and Reductive Oxirane Ring-Opening
Strategy
lactone bicyclic core. The global structural complexity and
impressive biological profile of 1 have attracted intensive
efforts from the synthetic community. In fact, numerous
synthetic studies toward 1 have been reported,5a-o including
our own.5d Herein, we present a new strategy based upon a
regio- and stereoselective epoxide formation/reductive oxi-
rane ring-opening sequence, and demonstrate its synthetic
advantage in terms of providing expedient access to the
highly functionalized 2-pyrrolidinone 8, leading to an effi-
cient formal synthesis of 1 (Scheme 1).
Taotao Ling,* Barbara C. Potts, and Venkat R. Macherla
Nereus Pharmaceuticals, Inc., 10480 Wateridge Circle,
San Diego, California 92121
taotao@nereuspharm.com
Received March 11, 2010
Recently, synthetic tactics directly targeting key inter-
mediates 19 (Corey’s intermediate5a) and 12 (Lam’s inter-
mediate5k) have been disclosed.5j-l The reported chemistry
includes N-methylnitrone 1,3-dipolar cycloaddition,5j nick-
el-catalyzed reductive aldol cyclization-lactonization,5k and
N-heterocyclic carbene-catalyzed intramolecular cycliza-
tion-lactonization,5l each featuring construction of C-2
and C-3 stereocenters guided by the C-4 stereocenter. How-
ever, the reported diastereoselective ratios (dr) of these
methods5j-l range from poor to moderate; thus, further
improvement is the focus of our current effort. Based upon
our previous total synthesis of 1,5d we envisioned using
Seebach’s self-regeneration of stereocenters (SRS) principle6
followed by a regio- and stereoselective epoxide formation/
reductive oxirane ring-opening sequence to sequentially con-
struct the required C-4, C-3, and C-2 stereocenters of ad-
vanced intermediate 8 or 17 (Scheme 1). If successful, the
desired C-2 and C-3 stereocenters would be constructed
simultaneously or in a stepwise manner with high diastereos-
electivity guided by the previously installed C-4 stereocenter
inherited from L-serine (and maintained under SRS principle).5d
Notably, the newly generated C-3 hydroxyl group would
be syn to the C-4 methyl ester group, which would facilitate
the required β-lactone formation. This new strategy would
provide expedient access to the fused γ-lactam-γ-lactone
bicyclic core (12) of 1. As shown in our retrosynthetic analysis
(Scheme 1), we recognized a fused oxazolidine pyrrolinone
bicyclic ring system such as 6 or 14 that could potentially serve
as a chiral template upon which a strategic epoxide function-
ality would be stereoselectively installed to generate R,β-epoxy
amide 7 or 16, followed by regio- and stereoselective reductive
Expedient access to a highly functionalized 2-pyrrolidi-
none (8), the γ-lactam core of 20S proteasome inhibitor
(-)-salinosporamide A (marizomib; NPI-0052; 1), using
a regio- and stereoselective epoxide formation/reductive
oxirane ring-opening strategy is presented. Notably, the
sequential construction of the C-4, C-3, and C-2 stereo-
centers of 1 in a completely stereocontrolled fashion is a
key feature of streamlining the synthesis of intermediate
12. A related strategy is also discussed.
Salinosporamide A (1; marizomib) is a highly potent and
selective 20S proteasome inhibitor that is currently in phase I
clinical trials for the treatment of cancer.1,2a-c First isolated
as a secondary metabolite of the marine actinomycete Sali-
nispora tropica by Fenical and co-workers in 2003,1 1 is
structurally related to the natural products cinnabaramide
(1) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355–357.
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Velankar, M.; Mitsiades, C.; Mitsiades, N.; Yasui, H.; Letai, A.; Ovaa, H.;
Berkers, C.; Nicholson, B.; Chao, T.-H.; Neuteboom, S. T. C.; Richardson,
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Chem. Soc. 2004, 126, 6230–6231. (b) Reddy, L. R.; Fournier, J.-F.; Reddy, B.
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Harigaya, Y.; Nagamitsu, T.; Omura, S. Org. Lett. 2008, 10, 4239–4242.
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J.; Adams, J.; Panek, J. S. Eur. J. Org. Chem. 2000, 2513–2528. (e) Balskus,
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Published on Web 05/14/2010
DOI: 10.1021/jo100432g
r
2010 American Chemical Society

Ling et al.
JOCNote
SCHEME 1. Retrosynthetic Analysis for the Formal
Synthesis of 1
SCHEME 2. Streamline Synthesis of Key Intermediate 5, 6, and
12 and Formal Synthesis of 1 from 2a
aReagents and conditions: (a) pivaldehyde, Et3N, pentane, 50 °C, 15 h.
(b) Diketene, pyridine, benzene, 60 °C, 18 h, 74% overall yield from 2
(two steps). (c) Allylbromide, K2CO3, DMF, 25 °C, 16 h; then DBU,
toluene, 110 °C, 15 h, one pot, 80% overall yield. (d) Ozonolysis, THF,
-80 °C, 30 min. (e) NaBH4, MeOH, -80 to 25 °C, 30 min, 82% overall
yield for 6. (f) Method A: Triton B (80 wt % in methanol), t-BuOOH
solution (5-6 M solution in decane), THF, 25 °C, 10 min; then 6, THF,
25 °C 18 h, 15% yield (with 43% recovered 6). Method B: Triton B (80
wt % in methanol), concentrated t-BuOOH solution (the original 5-6 M
solution in decane was concentrated 10-fold by volume using a stream of
nitrogen at room temperature and adopting appropriate personal safety
precautions), THF, 25 °C, 10 min; then 6, THF, 25 °C, 40 h, 71% yield.
oxirane ring cleavage to generate the highly functionalized
2-pyrrolidinone (γ-lactam) core, i.e., tertiary β-hydroxy amide
8 or 17. Finally, known intermediate 125k or an immediate
precursor to Corey’s intermediate 195a could be generated after
simple protecting group maneuvers to complete the enantiose-
lective formal synthesis of (-)-salinosporamide A (1).
˚
(g) SmI2, THF/MeOH (1:1), -80 °C, 30 min, quant. (h) PCC, dry 4 A
molecular sieves, CH2Cl2, 25 °C, 16 h, 84% yield. (i) 1,3-Propanedithiol,
12N HCl (cat.), CF3CH2OH, 60 °C, 1 h, 83% yield. (j) Imidazole, TESCl,
CH2Cl2, 25 °C, 15 h, 92% yield. (k) NaH, dry DMF, 0 °C, 15 min; then
PMBBr, 0 °C, 1 h; then 25 °C, 15 h. (l) DDQ (2,3-dichloro-5,6-dicyano-1,4-
benzoquinone), CH2Cl2/H2O (20:1, v/v), 25 °C, 6 h, 60% overall yield (two
steps).
First, we developed a streamlined synthesis of the key
intermediate 5 from 2 (Scheme 2) using the strategy based
upon the self-regeneration of stereocenters (SRS) principle
developed by Seebach.6 This approach was applied in our
previous total synthesis of 1, during which ent-5 was ob-
served as a minor dehydration product.5d Recognizing 5 as a
suitable precursor for the epoxidation strategy, we developed
an efficient method for its production. L-Serine methylester
hydrochloride 2 was condensed with pivaldehyde to afford
oxazolidine 3, which was directly coupled with diketene to
afford β-keto amide 4 with 74% overall yield, which was used
in the next step without purification. In a one-pot operation,
cyclization of β-keto amide 4 in the presence of allylbromide
and K2CO3, followed by dehydration promoted by DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene) afforded the desired in-
termediate 5 with 80% yield. Ozonolysis of 5 followed by
NaBH4 reduction afforded alcohol 6, which was subjected to
various epoxidation conditions in order to generate epoxide
7. The fused oxazolidine pyrrolinone bicyclic ring system 6
could potentially provide a unique chiral environment, one
in which epoxidation is expected to occur from the less
hindered exo face of the bicyclic concave system, thus
providing the desired stereo outcome. Due to the challenging
steric hindrance and electronic deficiency of 6, several initial
epoxidation conditions were unsuccessful (H2O2/NaOH-
(aq), mCPBA, t-BuOOH/Sm(O-i-Pr)3/Ph3AsdO, DMDO,
7a-e
t-BuOOH/V(O)(acac)2
(note: a similar failed attempt
was reported8). Gratifyingly, we found that epoxidation of
6 promoted by Triton B (benzyltrimethyl ammonium hydro-
xide) in concentrated t-BuOOH (tert-butyl hydroperoxide)
solution7f,g provided the best results. The desired epoxide 7
was isolated as the sole product, and its relative stereochem-
istry was confirmed by NOESY (see Supporting Informa-
tion), indicating that the bulky tert-butyl hydroperoxy anion
indeed attacked only from the less hindered exo face of the
fused oxazolidine pyrrolinone bicyclic ring system of 6.
The strategic R,β-epoxy amide 7 was then subjected to
SmI2 (samarium(II) iodide) promoted regio- and stereose-
lective reductive oxirane ring cleavage9a,b to generate the
(7) Epoxidation conditions. H2O2/NaOH: (a) Apeloig, Y.; Karni, M.;
Rappoport, Z. J. Am. Chem. Soc. 1983, 105, 2784–2793. mCPBA: (b)
Camps, F.; Coll, J.; Messeguer, A.; Pujol, F. J. Org. Chem. 1982, 47,
5402–5404. tBuOOH/Sm(O-iPr)3/Ph3AsdO: (c) Nemoto, T.; Kakei, H.;
Gnanadesikan, V.; Tosaki, S.; Oshima, T.; Shibasaki, M. J. Am. Chem. Soc.
2002, 124, 14544–14545. DMDO: (d) Meng, D.; Su, D. S.; Balog, A.;
Bertinato, P.; Sorensen, E. J.; Danishefsky, S. J.; Zheng, Y. H.; Chou, T. C.;
He, L.; Horwitz, S. B. J. Am. Chem. Soc. 1997, 119, 2733–2734. t-BuOOH/
V(O)(acac)2: (e) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973,
95, 6136–6137. t-BuOOH/Triton B: (f) Jao, E.; Bogen, S.; Saksena, A. K.;
Girijavallabhan, V. Synthesis 2003, 2643–2646. (g) Triton B (benzyltrimethyl
ammonium hydroxide, 80 wt % in methanol) was added to the concentrated tert-
butyl hydroperoxide solution (the original 5-6 M solution in decane was
concentrated 10-fold by volume using a stream of nitrogen at room temperature
adopting appropriate personal safety precautions; the molarity of the final
concentrated solution was not determined).
(8) Hayes, C. J.; Sherlock, A. E.; Green, M. P.; Wilson, C.; Blake, A. J.;
Selby, M. D.; Prodger, J. C. J. Org. Chem. 2008, 73, 2041–2051.
(9) (a) Molander, G.; Hahn, G. J. Org. Chem. 1986, 51, 2596–2599. (b)
Revuelta, J.; Cicchi, S.; Brandi, A. J. Org. Chem. 2005, 70, 5636–5642.
J. Org. Chem. Vol. 75, No. 11, 2010 3883

Ling et al.
JOCNote
SCHEME 3. Synthesis of Key Intermediates 17 and 18 from 5a
FIGURE 1. ORTEP plot of the X-ray crystal structure of ent-9
depicting the absolute stereochemistry.13
aReagents and conditions: (a) RhCl3 (cat.), MeOH, 70 °C, 10 h, 94%
yield. (b) Ozonolysis, THF, -80 °C, 30 min. (c) NaBH4, MeOH, -80
to 25 °C, 30 min, 93% overall yield for 14 (two steps). (d) Citric acid,
desired thermodynamically favored tertiary β-hydroxy
amide 8, which represents the highly functionalized 2-pyrro-
lidinone (γ-lactam) core structure of 1. In this case, the
desired C-2 and C-3 stereocenters were constructed simulta-
neously, affording exclusively the desired diastereomer. The
stereoselectivity is guided by the previously installed C-4
stereocenter: protonation of the enolate produced the ther-
modynamically favored product to minimize 1,2 interactions
between the C-2 side chain and C-3 methyl group. The diol 8
was then oxidized to γ-lactam-γ-lactone 9 promoted by PCC
(pyridinium chlorochromate); X-ray crystallographic analy-
sis of ent-9 (Figure 1) further confirmed the relative stereo-
chemical assignments of diol 8. The γ-lactam-γ-lactone 9 was
subsequently converted to the known intermediate 125k by
several simple protecting group manipulations, thereby
completing the formal stereoselective total synthesis of 1.
Encouraged by the above observations, we also developed
a streamlined synthesis of highly functionalized R-methy-
lene-γ-lactam 18 (an immediate precursor to Corey’s inter-
mediate 195a) from allylic alcohol 14. As shown in Scheme 3,
14 can be easily generated from key intermediate 5. The allyl
group of 5 was subjected to olefin isomerization catalyzed by
rhodium(III) chloride10 to afford the conjugated diene 13.
Then, oxidative olefin cleavage of diene 13 by ozonolysis,
followed by NaBH4 reduction, afforded the allylic alcohol 14
with 93% overall yield. In the following operation, allylic
alcohol 14 was converted to epoxide 16. First, allylic alcohol
14 was subjected to modified Sharpless dihydroxylation
conditions11 in citric acid media, in the presence of NMO
NMO, K2OsO4 2H2O, THF/H2O (1:1), 25 °C, 15 h. (e) Et3N, TsCl,
3
dry CH2Cl2, 25 °C, 3 h, 77% overall yield (two steps). (f) SmI2, THF/
MeOH (1:1), -80 °C, 2 h, 87% yield. (g) PPh3, imidazole, I2, benzene,
80 °C, 1 h, 90% yield.
assignment of diol 17 was confirmed by NOESY (see Support-
ing Information). In this case, the desired C-2, C-3 stereo-
centers were constructed stepwise, giving rise to exclusively
the desired diastereoisomer guided by the previously in-
stalled C-4 stereocenter. Although one-carbon homologa-
tion of diol 17 is necessary to generate either diol 8 or
γ-lactam-γ-lactone 9, diol 17 was easily converted to R-
methylene-lactam 18 with 90% yield: dehydration was pro-
moted by iodinization12 and driven by formation of the
conjugated R,β-unsaturated lactam moiety. The R-methy-
lene-γ-lactam 18 now serves as an immediate precursor to
Corey’s intermediate 19.5a
Conclusions
We have developed a new strategy based upon the Seebach
principle (SRS), regio- and stereoselective epoxide forma-
tion, and reductive oxirane ring-opening reactions to sequen-
tially construct the desired C-4, C-3, and C-2 stereocenters of
1 in highly stereocontrolled fashion. Notably, the newly
generated C-3 tertiary hydroxyl group is syn to the C-4
methyl ester group; this desired strategic relative stereochem-
istry was observed as thermodynamically disfavored in our
previous intramolecular aldol cyclization studies.5d Our im-
proved synthesis therefore provides expedient access to the
desired fused γ-lactam-γ-lactone bicyclic advanced inter-
mediate en route to 1 and promises to further facilitate
structure-activity relationship studies of its analogues.
(4-methylmorpholine N-oxide) and K2OsO4 2H2O (pota-
3
ssium osmate(VI) dihydrate) to afford the crude triol 15. The
newly generated C-3 tertiary hydroxyl group was strategi-
cally syn to the C-4 methyl ester group, indicating that
Sharpless dihydroxylation occurred preferentially from the
less hindered exo face of the fused oxazolidine pyrrolinone
bicyclic ring system of allylic alcohol 14. This secured the C-3
stereocenter, which was later confirmed by further transfor-
mation to 17. Triol 15 was then treated with TsCl (p-tolu-
enesulfonyl chloride) in the presence of Et3N to afford
epoxide 16 with high overall yield. Epoxide 16 was then
subjected to SmI2 promoted regio- and stereoselective re-
ductive oxirane ring cleavage9a,b to generate the desired
thermodynamically favored tertiary β-hydroxy amide 17,
which represents the highly functionalized pyrrolidinone
γ-lactam core structure of 1. The relative stereochemical
Experimental Section
Synthesis of Compound 7. Method B: Using appropriate
personal safety precautions, a 5-6 M tert-butyl hydroperoxide
solution was concentrated 10-fold by volume using a stream of
nitrogen at room temperature; the molarity of the final concen-
trated solution was not determined. Triton B (benzyltrimethyl
ammonium hydroxide, 80 wt % in methanol, 15 mg, 0.18 mmol)
was added to 400 μL of the concentrated tert-butyl hydroperoxide
solution, and the reaction mixture was stirred for 5 min at rt.
(12) Shin, J.; Gerasimov, O.; Thompson, D. H. J. Org. Chem. 2002, 67,
6503–6508.
(13) The X-ray crystal data for ent-9 has been deposited at the Cambridge
Crystallographic Data Center with deposition no. CCDC-764363 and can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html or
deposit@ccdc.cam.ac.uk.
(10) Stahl, P.; Waldmann, W. Angew. Chem., Int. Ed. 1999, 38, 3710–3713.
(11) Dupau, P.; Epple, R.; Thomas, A. A.; Pokin, V. V.; Sharpless, K. B.
Adv. Synth. Catal. 2002, 344, 421–433.
3884 J. Org. Chem. Vol. 75, No. 11, 2010

Ling et al.
JOCNote
Compound 6 (30 mg, 0.10 mmol) in THF (0.1 mL) was
added to the above reaction mixture and stirred at 25 °C for
40 h. The reaction mixture was concentrated directly under
reduced pressure to obtain a crude residue, which was purified
by silica flash chromatography (EtOAc/hexanes 10% to 50%) to
afford compound 7 (22 mg, 0.071 mmol, 71% yield) as a white
solid: 1H NMR (500 MHz, CDCl3) δ 4.71 (s, 1H), 4.63 (d, J =
8.55 Hz, 1H), 3.98-3.88 (m, 1H), 3.85-3.75 (m, 4H), 3.37 (d,
J = 8.55 Hz, 1H), 2.14 (s, 1H), 2.07-2.0 (m, 2H), 1.48 (s, 3H),
0.86 (s, 9H); 13C NMR (125 MHz, CDCl3) δ178.6, 168.9,
99.9, 73.8, 70.3, 69.8, 65.3, 58.6, 53.0, 34.8, 30.8, 27.9, 24.9,
12.4 ppm. HRMS (ESI-TOF): calcd for C15H23NO6 [M þ Hþ]
314.1598, found 314.1590. The relative stereochemistry was
confirmed by NOESY data on its enantiomer (ent-7, see spec-
trum in Supporting Information).
MgSO4, concentrated under reduced pressure, and dried under
high vacuum to afford the crude product triol 15. HRMS
(ESI-TOF): calcd for C14H23NO7 [M þ Hþ] 318.1547, found
318.1541. [1H and 13C NMR spectra confirmed the structure].
Then, the crude triol 15 was redissolved in dry CH2Cl2 (5.0 mL),
and Et3N (0.021 mL, 0.148 mmol) was added followed by
p-toluenesulfonyl chloride (TsCl, 17.0 mg, 0.089 mmol); the
reaction mixture was stirred at rt for 3 h. The reaction mixture
was diluted with aqueous NaHCO3 (5 mL) and extracted with
CH2Cl2 (3 ꢀ 5 mL), the organic phase was dried over MgSO4
and concentrated under reduced pressure, and the crude residue
was purified by silica flash chromatography (EtOAc/hexanes,
10% to 50%) to afford the epoxide 16 (17.0 mg, 0.057 mmol,
1
77% overall yield for two steps) as a clear oil: H NMR (500
MHz, CDCl3) δ 4.87 (s, 1H), 4.82 (d, J = 9.30 Hz, 1H), 3.83 (d,
J = 9.25 Hz, 1H), 3.79 (s, 3H), 3.41 (d, J = 4.80 Hz, 1H), 2.92
Synthesis of Compound 9. To a solution of compound 7
(80 mg, 0.26 mmol) in THF/MeOH (1:1, 2.0 mL) was added
samarium(II) iodide (0.1 M in THF, 7.6 mL, 0.76 mmol) at
-80 °C, and the reaction mixture was stirred at this temperature
for 30 min. The reaction was then quenched with aqueous
NaHCO3 (10 mL), Na2S2O3 (10 mL) at -80 °C and extracted
with EtOAc (2 ꢀ 20 mL) and CH2Cl2 (2 ꢀ 20 mL). The organic
phase was dried over MgSO4 and concentrated under reduced
pressure to afford the crude diol 8, which was filtered through a
short silica plug, concentrated under high vacuum, and directly
subjected to the next step without further purification. To a
solution of compound 8 (47 mg, 0.15 mmol) in CH2Cl2 (1.0 mL)
(bs, 1H), 2.89 (d, J = 4.75 Hz, 1H), 1.37 (s, 3H), 0.89 (s, 9H); 13
C
NMR (125 MHz, CDCl3) δ 170.1, 169.4, 96.8, 78.5, 71.4, 68.7,
66.3, 52.9, 47.1, 36.2, 24.8, 22.4 ppm; HRMS (ESI-TOF): calcd
for C14H21NO6 [M þ Hþ] 300.1442, found 300.1446.
Synthesis of Compound 17. To a solution of the epoxide 16
(16.0 mg, 0.053 mmol) in THF/MeOH (1:1, 4.0 mL) was added
samarium(II) iodide (0.1 M in THF, 1.60 mL, 0.16 mmol)
at -80 °C, and the reaction mixture was stirred at this tempera-
ture for 2 h. The reaction was then quenched with aqueous
NaHCO3 (5 mL) and extracted with CH2Cl2 (3 ꢀ 5 mL), and the
organic phase was dried over MgSO4 and concentrated under
reduced pressure. The crude residue was purified by silica flash
chromatography (50% EtOAc/hexanes) to afford the diol 17
(13.9 mg, 0.046 mmol, 87% yield) as a clear oil: 1H NMR
(500 MHz, CDCl3) δ 4.76 (s, 1H), 4.66 (d, J = 8.85 Hz, 1H),
4.30-4.20 (m, 2H), 4.0-3.95 (m, 1H), 3.76 (s, 3H), 3.50 (d,
J = 8.90 Hz, 1H), 3.04 (t, J = 6.0 Hz, 1H), 2.64 (dd, J = 3.70,
6.35 Hz, 1H), 1.43 (s, 3H), 0.89 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 178.6, 170.8, 98.8, 80.9, 75.1, 70.2, 59.9, 58.5,
52.4, 35.3, 30.9, 26.5, 25.3, 24.9. HRMS (ESI-TOF): calcd
for C14H23NO6 [M þ Hþ] 302.1598, found 302.1603. The
stereochemistry was confirmed by NOESY (see Supporting
Information).
˚
with dried 4 A molecular sieves (0.10 g) was added PCC (96 mg,
0.45 mmol). The reaction mixture was stirred at 25 °C for 16 h
and concentrated under reduced pressure, and the resulting
crude product was then purified by silica flash chromatography
(50% EtOAc/hexanes) to afford 9 (29 mg, 0.125 mmol, 84%
1
yield) as a white solid: H NMR (500 MHz, CDCl3) δ 4.83 (s,
1H), 4.77 (d, J = 8.95 Hz, 1H), 3.76 (s, 3H), 3.56 (d, J = 8.90 Hz,
1H), 3.12-3.09 (m, 1H), 3.01 (s, 1H), 2.99 (s, 1H), 1.58 (s, 3H),
0.89 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 176.7, 173.2, 168.9,
98.4, 85.3,79.4, 69.9, 52.9, 51.8, 35.4, 32.7, 30.9, 25.0, 24.7, 23.2.
HRMS (ESI-TOF): calcd for C15H21NO6 [M þ Hþ] 312.1442,
found 312.1440. The 1H and 13C NMR spectra of compound 9
were identical to its enantiomer, ent-9, which was confirmed
by X-ray crystal structure (Figure 1).
Acknowledgment. We are sincerely grateful to S. Danishefsky
for insightful discussions and to A. Rheingold for X-ray crystal-
lography of ent-9.
Synthesis of Compound 16. To a solution of allylic alcohol 14
(21.0 mg, 0.074 mmol) in THF/H2O (1:1, 5.0 mL) was added
citric acid (62.0 mg, 0.296 mmol) followed by NMO (26.0 mg,
0.222 mmol) and potassium osmate(VI) dihydrate (K2OsO4
3
2H2O, 5.5 mg, 0.015 mmol). The resulting mixture was stirred at
25 °C for 15 h. The above reaction mixture was diluted with
brine (10 mL) and extracted with EtOAc (2 ꢀ 10 mL) followed
by CH2Cl2 (3 ꢀ 10 mL). The organic phase was dried over
Supporting Information Available: General experimental
procedures, compound characterization data, and access to CIF
file for ent-9. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 11, 2010 3885