Further insight into the asymmetric vinylogous Mukaiyama aldol reaction (VMAR); Application to the synthesis of the C27-C45 segment of lagunamide A

Article abstract of DOI:10.1016/j.tet.2016.03.079

Two iterative vinylogous Mukaiyama aldol reactions (VMAR) have been applied in order to selectively install three contiguous stereocenters at C37, C38 and C39, of the southern hemisphere of lagunamide A. The VMAR methodology allows straightforward access of enantiomerically pure material of the essential segment via seven steps, and in an overall yield of 34%. The synthesis has an orthogonal protecting group strategy, essential for upcoming synthesis for completion of lagunamide A. We also demonstrate that steric bulk of the chiral oxazolidinone pose certain challenges when employing stereochemically crowded α-substituted aldehydes in various VMAR's. A simple synthesis of the essential (2R,3S)-2-hydroxy-3-methylpentanoic acid fragment via Mitsunobu chemistry was also accomplished and incorporated into the C27-C45 fragment of lagunamide A.

Full text of DOI:10.1016/j.tet.2016.03.079

Accepted Manuscript
Further Insight into the Asymmetric Vinylogous Mukaiyama Aldol Reaction (VMAR);
Application to the Synthesis of the C27–C45 Segment of Lagunamide A
Brent Banasik, Lee Wang, Arielle Kanner, B.Mikael Bergdahl
PII:
S0040-4020(16)30221-6
10.1016/j.tet.2016.03.079
TET 27619
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 February 2016
Revised Date: 21 March 2016
Accepted Date: 23 March 2016
Please cite this article as: Banasik B, Wang L, Kanner A, Bergdahl BM, Further Insight into the
Asymmetric Vinylogous Mukaiyama Aldol Reaction (VMAR); Application to the Synthesis of the C27–
C45 Segment of Lagunamide A, Tetrahedron (2016), doi: 10.1016/j.tet.2016.03.079.
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Further Insight into the Asymmetric
Vinylogous Mukaiyama Aldol Reaction
(VMAR); Application to the Synthesis of the
C27–C45 Segment of Lagunamide A
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Brent Banasik, Lee Wang, Arielle Kanner, B. Mikael Bergdahl*

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Further Insight into the Asymmetric Vinylogous Mukaiyama Aldol Reaction (VMAR);
Application to the Synthesis of the C27–C45 Segment of Lagunamide A
Brent A. Banasik, Lee Wang, Arielle Kanner, B. Mikael Bergdahl*
Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-
1030, USA
*Corresponding author. Tel.: +619 594-5865; fax +619 594-4634
E-mail address: bbergdahl@mail.sdsu.edu
ABSTRACT:
Two iterative Vinylogous Mukaiyama Aldol Reactions (VMAR) have been applied in order to
selectively install three contiguous stereocenters at C37, C38 and C39, of the southern
hemisphere of lagunamide A. The VMAR methodology allows straightforward access of
enantiomerically pure material of the essential segment via seven steps, and in an overall yield
of 34 %. The synthesis has an orthogonal protecting group strategy, essential for upcoming
synthesis for completion of lagunamide A. We also demonstrate that steric bulk of the chiral
oxazolidinone pose certain challenges when employing stereochemically crowded α-substituted
aldehydes in various VMAR’s. A simple synthesis of the essential (2R,3S)-2-hydroxy-3-
methylpentanoic acid fragment via Mitsunobu chemistry was also accomplished and
incorporated into the C27–C45 fragment of lagunamide A.

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1. Introduction
The structural combination of cyclodepsipeptides and polyketide moieties represent an
interesting class of natural products with a broad range of potential therapeutics, sometimes with
exceptional biological activities. In 2010, Tan reported1a the isolation of the complex macrocycle
lagunamide A (1) (Figure 1) isolated from the cyanobacterium Lyngbya majuscula, found in
Singapore.
Figure 1. Lagunamide A (1).
Lagunamide A (1) not only possesses excellent anti-malarial properties (IC50: 0.19–0.91 mM),
but it also has unique, highly cytotoxic properties against leukemia cell lines (IC50: 6.4–20.5 nM)
and against colon cancer (IC50: 1.6 nM).1b The therapeutic potential of lagunamide A coupled
with its relative scarceness in nature has garnered significant interest from a number of research
laboratories. Specifically, two completed total syntheses2 and one formal synthesis3a of
lagunamide A have been reported. Lagunamide A is structurally composed of a 26-member
macrocycle with natural, unnatural, and N-methylated amino acids. The C27–C45 fragment is a
quite unusual polyketide moiety with four contiguous stereocenters, extended by vinylogy to an
α,β-unsaturated ester fragment and flanked by the (2R,3S)-2-hydroxy-3-methyl-pentanoic acid.

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2. Results & discussion
Our retrosynthetic strategy of lagunamide A (1) is based on the combination of the main
pentapeptide and fragment 11 via either macro-lactonization or macro-lactamization
methodology (Scheme 1). Structure 11 can be assembled from esterification of carboxylic acid 9
with alcohol 10. Asymmetric vinylogous aldol reactions (VMAR’s) can then be applied to
establish the anti-aldol motif at C38–C39 (VMAR-1) and the stereocenter at C37 (VMAR-2).
Thus, this strategy also allows for efficient discrimination of the protecting groups (P1 and P2)
needed for the planned ring closure. The precise stereochemistry of 10 can be obtained from L-
isoleucine via inversion of α-stereochemistry employing Mitsunobu technology.
Scheme 1. Strategy towards Lagunamide A (1)

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2.1 Synthesis of the C27-C45 fragment
This paper describes a short, direct, and highly asymmetric route with excellent overall yield
of the C27–C45 fragment (11). This crucial intermediate was achieved mainly via two iterative
asymmetric vinylogous aldol reactions, a powerful technique that has attracted widespread
attention in the synthetic organic community,4 where this manipulation was also instrumental in
innovative natural product syntheses.5 The version of a vinylogous Mukaiyama aldol reaction
(VMAR) utilizing chiral oxazolidinones was first introduced by Kobayashi6 in 2004. Herein, we
report two such “remote” asymmetric induction reactions as general means to establish the
required stereochemistry at the C37, C38 and C39 positions; by adopting the VMAR technique it
greatly improved the overall yield (34%)3b of and decreased the number of steps3c to afford the
southern hemisphere (11) of lagunamide A starting from 2(S)-methyl-1-butanal (Scheme 2).
Scheme 2. Synthesis of C27-C45 segment 11 applying VMAR methodologies

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Thus, stereocenters C38 and C39 were installed via the first VMAR between titanium (IV)
chloride pre-coordinated 2(S)-methyl-1-butanal and chiral vinylketene silyl N,O-acetal (2) in
CH2Cl2 at -78 °C to give 96% of anti-alcohol 3 in excellent diastereomeric ratio (d.r.) (>98:2).6,7
Protection of alcohol 3 as the propionate (4) followed by ozonolysis afforded aldehyde 5 in 95%
yield. The second VMAR employing aldehyde 5 and chiral vinylketene silyl N,O-acetal 6 was
more challenging however. Initially the VMAR provided a low 30% yield of alcohol product 7
(d.r. 91:9) when the reaction was conducted in the conventional CH2Cl2 medium, but the yield
increased modestly to 48% with a d.r. (91:9) when instead toluene containing 10 mol% of water
was applied as a medium and conducted for 72 h. The exact role of the presence of water during
the VMAR is unknown, but water proved to reduce the reaction time and might also aid in the
dissociation of titanium chelates.8 Subsequent protection of alcohol 7 as the BOM ether provided
8 in 93% yield thus differentiating the protecting group functionalities at C37 and C39 for
continued synthesis. Selective auxiliary cleavage over the ester functionality of 8 was
accomplished utilizing LiOOH9 in THF/H2O to yield carboxylic acid 9 in 98% yield.
Esterification coupling of acid 9 with α-hydroxy ester 10 was next achieved using DCC and
DMAP and provided the southern portion of lagunamide A (11) in 88% yield. Thus, fragment
11 was obtained in a 34% overall yield in seven linear steps.

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Scheme 3. Synthesis of Acetonide 15
With the intention of creating protecting group flexibility at C37 and C39 as well as verifying
the generated absolute stereochemistry at C37–C39 from the VMAR’s, synthesis of acetonide
fragment 15 was also accomplished (Scheme 3).2a Removal of the chiral auxiliary and the
propionate ester with methanolic sodium methoxide provided methyl ester diol 12 in 93% yield.
Subsequent acetonide formation was then generated using DMP, catalytic p-TsOH and gave 13
in 94% yield. In order to establish the absolute stereochemistry, specific NMR data on its
rigidified acetonide derivative 13 was determined (Figure 2).10 The 13C-NMR chemical shifts of
the acetonide 13 methyl groups and the acetal carbon were 19.6, 30.2, and 98.0 ppm
respectively, which is characteristic of a syn-1,3-diol acetonide configuration.11 Moreover, not
only did the observed NOE interactions reinforce the syn-stereochemistry but it also established
the desired E-geometry of the alkene moiety of 13.
Figure 2. Major NOE observations and 13C-NMR chemical shifts of syn-acetonide 13.
Carboxylic acid 14 was then obtained in 92% yield by the basic hydrolysis of methyl ester 13
using aqueous potassium hydroxide in methanol. Intermediate 15 was subsequently obtained in
88% yield via the esterification of 14 with
α-hydroxy ester 10 employing DCC and DMAP.

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Thus, the essential southern portion of lagunamide A (15) was obtained in a 30% overall yield in
eight linear steps. The C27–C45 intermediate was synthesized previously by Ye2a in an entirely
different route that utilized Horner-Wadsworth-Emmons methodology to install the alkene with
correct E-geometry. Our efforts towards fragment 15 unequivocally show an identical
spectroscopic correlation to the work published by Ye, who also reported that removal of the
acetonide group and selective mono-TES-silylation of the corresponding 1,3-diol at the C37-OH
position was a reliable route towards synthetic lagunamide A.
2.2 Synthesis of (2R,3S)-2-hydroxy-3-methylpentanoic acid (10)
Synthesis of
scale utilizing inexpensive L-isoleucine (L-Ile) as starting material. Thus, it was more
advantageous to adopt the Mitsunobu inversion of stereochemistry at the -hydroxy stereocenter
α-hydroxy tert-butyl ester 10 was accomplished in 33% overall yield on a gram
α
(Scheme 4) of the L-Ile derivative instead of manipulating the more costly D-allo-Ile as starting
material.12
Scheme 4. Preparation of 10 from L-Ile
Diazotization of L-Ile afforded the α-hydroxy carboxylic acid,12a which was subsequently
acetylated with neat acetyl chloride to afford 16 in 90% yield over two steps. Synthesis of the
tert-butyl ester using Boc2O and DMAP followed by basic hydrolysis in MeOH gave

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intermediate 17 in 87% yield over two steps. Inversion of the
α
-hydroxy stereocenter of 17 was
then completed via a straightforward Mitsunobu procedure13 with p-nitrobenzoic acid, DIAD,
and PPh3 that afforded 18 in 82% yield. Mild subsequent saponification of the benzoate was then
conducted using K2CO3 in MeOH to afford compound 10 in 60% yield.
2.3 Influence of substituted aldehydes on asymmetric VMAR
Scheme 5. Influence of Substituted Aldehydes on the Asymmetric VMAR
The VMAR demonstrated impressive versatility and stereocontrol through remote induction
of an electrophilic addition as shown by the high diastereomeric ratio of the product. Even
though the asymmetric VMAR was a very powerful tool, it had limitations as illustrated for the
conversion of aldehyde 5 to vinylogous aldol product 7 in 48% yield when toluene was used as a
medium (Scheme 2). When the VMAR was conducted in the conventional CH2Cl2 solvent, the
yield dropped significantly to 30% of product 7, but the lack of change in d.r. suggested a slow
reaction with the aldehyde at low temperature. The amount of hydrolyzed vinylketene silyl N,O-
acetal 6 formed over an extended amount of time also implied that the VMAR with aldehyde 5

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was rate determining. The VMAR was considerably faster when 2(S)-methyl-1-butanal was
employed in contrast to aldehyde 5 with absolute 2(R)-methyl stereochemistry. Thus, it appeared
as if the actual (S)-valine based chiral auxiliary (6) was detrimental to the overall yield of the
VMAR using α-(R)-methyl substituted aldehydes. To confirm this suspicion of stereochemical
crowding during the reaction, the VMAR was first conducted in the absence of the 2(R)-methyl
stereocenter using aldehyde 22 (Scheme 5).14 Vinylogous aldol product 23 was formed more
rapidly at -78 °C, than in comparison to aldol product 7, as the expected main diastereomer
(96:4 d.r.) in 68% yield. We turned next to the influence of the (S)-valine based auxiliary and
the bulk of the iso-propyl group in the VMAR. Thus, vinylketene silyl N,O-acetal 19, lacking
the chiral recognition within the 2-oxazolidone moiety, reacted readily with the stereochemically
congested aldehyde 20 at -78 °C to give a 70% yield, but with the opposite major diastereomer
of product 21 compared to the formed VMAR products 7 and 23. Consequently, formation of
the major diastereomer 21 was facilitated by the influence of specific
aldehyde, but the rate of the VMAR was impeded particularly with
aldehydes and the (S)-valine based auxiliary.
α
α
-methyl chirality of the
-(R)-methyl substituted
2.4 Proposed transition state
Based on our results from the VMAR’s, we proposed the following transition state models
for vinylketene silyl N,O-acetal 6, and its nucleophilic approach to 2(S)- and 2(R)-methyl-
substituted aldehydes, respectively (Figure 3).15 As seen in both proposed transition state models
the larger substituent faced away from the chiral auxiliary while the methyl group of larger 2(R)-
methyl-substituted aldehyde 5 is pointing towards the auxiliary creating an unfavorable clash.

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Figure 3. Proposed transition states for the nucleophilic attack of vinylketene N,O-acetal (6)
(“blue”) to (S)- and (R)-2-methyl substituted aldehydes, respectively.
3. Conclusion
This paper describes a direct vinylogous asymmetric approach to the C27–C45 southern
fragment (11) of lagunamide A, mainly through iterations of Kobayashi’s VMAR protocol.6 The
key fragment 11 was synthesized in seven steps, in an overall yield of 34%. The outcome of
stereoselectivity and yield employing the VMAR using aldehydes with favorable as well as
detrimental chirality at α-methyl stereocenters were also included.
4. Experimental section
4.1 General information
Melting points were recorded on Thomas Hoover Uni-Melt capillary melting point apparatus.
Optical rotations were recorded on Perkin Elmer Model 343 polarimeter. IR spectra were
recorded on Perkin Elmer FT-IR spectrum RXI. 1H NMR spectra were recorded on a Varian 400,
500, and 600-MHz instrument using CDCl3 or DMSO-d6 with TMS as internal standard (δ = 0
ppm). CDCl3 (δ = 77.00 ppm) or DMSO-d6 (δ = 39.52 ppm) were used as internal references for
1
13
13C (101, 126 and 151 MHz) NMR. All new compounds were characterized using H- and C

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1
NMR, IR and MS. Chemical yields are based on purified material (>98% by H-NMR
spectroscopy). Coupling patterns are abbreviated as: s (singlet) d, (doublet), t (triplet), q
(quartet) m, (multiplet), b, (broad), J (coupling constant). Preparative HPLC was carried out
using Shimadzu SCL-10A/SPD-10A with Varian pursuit 10 C8 50-G 50mm column. Mass
spectra were recorded using a Thermo Finnigan LCQ Deca or an Agilent 6330 ion trap. High-
resolution mass spectra were recorded using the Agilent 6230 ESI-TOFMS. Analytical thin-layer
chromatography was performed on Silicycle glass backed 60Å ultrapure silica gel. Flash
chromatography was conducted using a Biotage Isolera one instrument with pre-packed silica gel
columns (AnaLogix, Sepra Si 50) or self-packed Luknova and Biotage snap columns filled with
silica gel (Sorbent Technologies, 60Å, 230–400 mesh). All moisture sensitive reactions were
conducted under an argon atmosphere and in septum-capped oven-dried glassware unless
otherwise specified. All solvents and reagents were purchased from Aldrich or Fisher Scientific
unless otherwise specified. Ether and tetrahydrofuran (THF) were distilled from sodium-
benzophenone ketyl and were collected when the indicator became deep blue or purple.
Dichloromethane was distilled from calcium hydride.
For preparation of compounds A, C, D, E, F, G, 16, 17; see Supplementary Data.
4.2 Experimental details
4.2.1 N-(1’-tert-Butyldimethylsilyloxy-2’-methyl-penta-1’E,3’E-dienyl)-4S-isopropyl-1,3-
oxazolidin-2-one (2).6
A premade solution of potassium hexamethyldisilylamide (KHMDS) (4.00 g, 20.1 mmol) in
anhydrous THF (50 mL) was added dropwise to a solution of imide A16 (3.00 g, 13.3 mmol) in
THF (130 mL) at –78 ºC. The resulting reaction mixture was stirred for 90 min at –78 ºC

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followed by the dropwise addition of a premade solution of TBSCl (3.41 g, 22.6 mmol) in
anhydrous THF (25 mL). The reaction mixture was stirred an additional 45 min at –78 ºC and
then quenched with saturated ammonium chloride (50 mL). After transferring the reaction
mixture to a separation funnel the mixture was extracted with ethyl acetate (3 × 25 mL). The
combined organic extract was washed with water (25 mL), brine (25 mL), dried over anhydrous
sodium sulfate, filtered and the solvent removed under reduced pressure. The residual crude
product was then purified with flash chromatography using hexanes/ethyl acetate 0–20% as a
gradient to give 96% (4.34 g) of 2 as a white solid, mp 39–43 ºC, [α]20D -53.8º (c=0.84, CHCl3)
{lit.6 oil, [α]25D -50.4º (c=0.84, CHCl3)}. 1H NMR (500 MHz, CDCl3) δ 6.21 (d, CHCHCH3, J =
15.5 Hz, 1H), 5.63 (dq, CH=CHCH3, J = 15.5, 6.5 Hz, 1H), 4.34–4.29 (m, OCH2, 1H), 4.15–4.09
(m, OCH2, 1H), 4.03–3.97 (m, NCH, 1H), 1.98–1.90 (m, CH(CH3)2, 1H), 1.80–1.77 (dd,
t
CHCHCH3, “partly hidden”, J = 6.5, 1.6 Hz, 3H), 1.78 (s, C=CCH3, 3H), 0.98 (s, Bu, 9H),
0.94–0.91 (d, CH(CH3)2, J = 6.9 Hz, 6H), 0.19, 0.14 (2s, Si(CH3)2, 3H each); 13C NMR (101
MHz, CDCl3) δ 156.0, 134.8, 128.3, 124.5, 115.1, 64.5, 59.5, 29.5, 25.8, 18.9, 18.5, 18.2, 16.4,
12.4, -4.2, -4.7.
4.2.2 N-(5’R-Hydroxy-2’,4’S,6’S-trimethyl-2’E-octenoyl)-4S-isopropyl-1,3-oxazolidin-2-
one (3).17
A solution of TiCl4 (6.63 mmol, 1.50 equiv) in CH2Cl2 (20 mL) was added dropwise to a
solution of (S)-2-methylbutanal (B)18 (13.25 mmol, 3.00 equiv) in CH2Cl2 (30 mL) at –78 ºC.
The resulting reaction mixture was stirred for 30 min at –78 ºC and a solution of vinylketene silyl
N,O-acetal (2) (1.50 g, 4.42 mmol, 1.00 equiv) dissolved in CH2Cl2 (100 mL) was added
dropwise over 30 min. The reaction mixture was stirred for 22 hours at –78 ºC and then

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quenched with a mixture of saturated aqueous Rochelle Salt and saturated aqueous NaHCO3 (50
mL, 1:1) at –78 ºC. The reaction mixture was warmed to room temperature while stirring,
transferred to a separation funnel and extracted with ethyl acetate (4 × 20 mL). The combined
organic extracts were washed with water (50 × mL) and brine (60 × mL), dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was
purified using a silica gel column (hexanes/ethyl acetate 0–25% as a gradient) to give the aldol
product in an 96% (1.38 g) as colorless oil, [α]20 +21.6º (c=0.97, MeOH). {lit.17 oil, [α]20
D
D
1
+24.2º (c=0.91, MeOH)} H NMR (500 MHz, CDCl3) δ 5.80 (dq, CHCH=CCH3, J = 10.4, 1.5
Hz, 1H), 4.57 (ddd, NCH, J = 8.9, 5.8, 4.5 Hz, 1H), 4.34 (dd, OCH2, J = 9.0, 8.9 Hz, 1H), 4.18
(dd, OCH2, J = 9.0, 5.8 Hz, 1H), 3.30 (dd, CHOH, J = 8.9, 2.4 Hz, 1H), 3.00 (bs, CHOH, 1H),
2.78–2.69 (ddq, CHCH(Me)CHOH, J = 10.4, 9.1, 6.7 Hz, 1H), 2.38–2.31 (m, CH(CH3)2, 1H),
1.95 (d, CH3C=CH, J = 1.5 Hz, 3H), 1.60–1.53 (m, CH(Me)CH2, “partly hidden”, 1H), 1.53–
1.47 (m, CH(Me)CH2, “partly hidden”, 1H), 1.43–1.37 (m, CH(Me)CH2, “partly hidden”, 1H),
0.95–0.90 (m, 4×CH3, 12H); 13C NMR (126 MHz, CDCl3) δ 171.6, 154.5, 142.6, 131.1, 76.8,
63.4, 58.1, 37.3, 35.8, 28.4, 27.3, 17.8, 15.7, 15.2, 13.9, 12.1, 12.0; FTIR (neat, cm-1) 3526,
2964, 1772, 1686, 1464, 1369, 1301, 1209, 996, 776, 688.
4.2.3 N-(2’,4’S,6’S-Trimethyl-5’R-propionyloxy-2’E-octenoyl)-4S-isopropyl-1,3-oxazolidin-
2-one (4).
Alcohol 3 (1.93 g, 6.20 mmol, 1.00 equiv) was charged in a dry 100 mL round bottom flask
under argon. The substrate was dissolved in freshly distilled CH2Cl2 (18 mL) and then the
solution was cooled to +3 ºC using an ice/water bath. Anhydrous pyridine (2.00 mL, 24.79
mmol, 4.00 equiv) was added followed by drop-wise addition of freshly distilled propionyl

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chloride (2.17 mL, 24.79 mmol, 4.00 equiv) over 5 min. After the addition of DMAP (350 mg,
3.10 mmol) the pale yellow heterogeneous reaction mixture was stirred towards ambient
temperature over 13 hours. Saturated ammonium chloride (20 mL) was then added to the
resulting homogeneous solution at room temperature. The reaction mixture was then transferred
to a separation funnel and phases separated. The aqueous phase was then extracted with CH2Cl2
(3 × 20 mL), the combined organics were washed with 1M NaOH (20 mL), Brine (40 mL), dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material
was the purified using a silica gel column (hexanes/ethyl acetate 0–25% as a gradient) to give the
1
aldol product in 97% (2.21 g) as colorless oil, [α]20 +62.5º (c=1.55, MeOH). H NMR (500
D
MHz, CDCl3) δ 5.86 (dq, CHCH=CCH3, J = 9.8, 1.5 Hz, 1H), 4.87 (dd, CHCH(OR)CH, J = 6.8,
5.3 Hz, 1H), 4.45 (ddd, NCH, J = 8.7, 4.7, 4.4 Hz, 1H), 4.29 (dd, OCH2, J = 8.8, 8.7 Hz, 1H),
4.18 (dd, OCH2, J = 8.8, 4.7 Hz, 1H), 2.91–2.83 (ddq, CH(Me)CH(OR), J = 9.8, 6.8, 6.8 Hz,
1H), 2.42–2.36 (m, CH(CH3)2, “partly hidden”, 1H), 2.36–2.30 (dq, C(O)CH2CH3, J = 7.6, 3.4
Hz, 2H), 1.91 (d, CH3C=CH, J = 1.5 Hz, 3H), 1.72–1.63 (m, CH(Me)CH2, 1H), 1.41–1.32 (m,
CH(Me)CH2CH3, 1H), 1.20–1.09 (m, CH(Me)CH2CH3, “partly hidden”, 1H), 1.13 (t, CH2CH3, J
= 7.6 Hz, 3H), 0.98 (d, CHCH3, J = 6.8 Hz, 3H), 0.92 (d, CHCH3, J = 6.8 Hz, 3H), 0.92–0.89 (t,
CH2CH3, “partly hidden”, J = 6.8 Hz, 3H), 0.90 (d, CH(CH3)2, “partly hidden”, J = 6.8 Hz, 3H),
0.89 (d, CH(CH3)2, “partly hidden”, J = 6.8 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 174.3,
171.6, 153.3, 138.6, 131.4, 78.8, 63.4, 58.4, 36.1, 34.7, 28.3, 27.7, 26.3, 17.9, 16.4, 14.9, 13.7,
13.6, 11.4, 9.3; FTIR (neat, cm-1) 2965, 1787, 1736, 1684; HRMS (ESI) m/z calcd for
C20H33NO5Na [M+Na]+ 390.2251, found 390.2248.

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4.2.4 2R,4S-Dimethyl-3R-propionyloxy-1-hexanal (5).
A solution of compound 4 (1.01 g, 2.73 mmol) in anhydrous CH2Cl2 (50 mL) was cooled to –78
ºC. A slow stream of ozone gas was then bubbled through the solution for roughly 30 min until
the solution turned light blue. The blue solution was flushed by bubbling oxygen for 15 min at –
78 ºC followed by bubbling argon for 15 min until the blue color faded. Excess dimethyl sulfide
(1.25 ml, 17.02 mmol) was then added drop-wise over 5 min at –78 ºC. The temperature was
then raised to ambient temperature and the mixture stirred an additional 12 hours. The solvent
was removed under reduced pressure and the remaining crude product was purified on a silica
gel plug (hexanes in ethyl acetate, 0–15% as a gradient) to afford 5 as a clear oil in 95% (0.519
g), [α]20D –0.85º (c=3.75, MeOH). 1H NMR (400 MHz, CDCl3) δ 9.61 (d, CHO, J = 3.2 Hz, 1H),
5.13 (dd, CHCH(OR)CH, J = 7.5, 4.6 Hz, 1H), 2.69–2.60 (ddq, HCCHO, J = 7.5, 7.0, 3.2 Hz,
1H), 2.36–2.29 (q, C(O)CH2CH3, J = 4.8 Hz, 2H), 1.75–1.66 (m, CH(Me)CH2,1H), 1.45–1.32
(m, CH(Me)CH2, 1H), 1.25–1.12 (m, CH(Me)CH2, “partly hidden”, 1H), 1.14 (t, CH2CH3, J =
7.6 Hz, 3H), 1.09 (d, CHCH3, J = 7.1 Hz, 3H), 0.93 (t, “partly hidden”, CH2CH3, J = 7.5 Hz,
3H), 0.92 (d, CHCH3, J = 6.8 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 202.8, 174.1, 75.8, 48.6,
36.2, 27.7, 26.3, 13.5, 11.6, 11.2, 9.3; FTIR (neat, cm-1) 2974, 1736, 1706; HRMS (ESI) m/z
calcd for C11H20O3 [M+H]+ 201.1485, found 201.1488.
4.2.5 N-(1’-tert-Butyldimethylsilyloxy-2’-methyl-buta-1’E,3’dienyl)-4S-isopropyl-1,3-
oxazolidin-2-one (6).6
A solution of solid KHMDS (3.20 g, 16.02 mmol) in anhydrous THF (230 mL) was added
dropwise to a solution of imide C19 (1.81 g, 10.68 mmol) in THF (110 mL) at –78 ºC. After the
reaction mixture was stirred for 90 min at –78 ºC a solution of TBSCl (4.83 g, 18.16 mmol) in

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THF (25 mL) was added dropwise over 20 min at –78 ºC. The reaction mixture was stirred at –
78 ºC until completion was verified via TLC analysis (~45 min). The reaction was then
quenched with saturated aqueous NH4Cl (50 mL) at –78 ºC. The temperature of the resulting
mixture was allowed to reach ambient temperature and stirred for an additional 30 min. The two
phase mixture was then transferred to a separation funnel, the phases separated and the aqueous
phase extracted with ethyl acetate (4 × 20 mL). The combined organic phases were washed with
water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. After filtration the
solvent was removed under reduced pressure and the crude product was then purified with flash
chromatography using hexanes/ethyl acetate 0–40% as a gradient to give 86% (2.99 g) of
vinylketene silyl N,O-acetal 6 as a white solid, mp 44–49 ºC, [α]20D -71.0º (c=0.87, CHCl3). {lit.6
mp 48.7 ºC, [α]25D -65.7º (c=0.87, CHCl3)}. 1H NMR (500 MHz, CDCl3) δ 6.45 (dd, HC=CH2, J
= 17.1, 10.0 Hz, 1H), 5.05 (d, HC=CH2, J = 17.1 Hz, 1H), 4.94 (d, HC=CH2, J = 10.9, 1H),
4.27–4.20 (m, OCH2, 1H), 4.07–4.00 (m, OCH2, 1H), 3.97–3.89 (m, NCH, 1H), 1.91–1.82 (m,
t
CH(CH3)2, 1H), 1.71 (s, C=C(CH3), 3H), 0.90 (s, Bu, 9H), 0.84, 0.83 (2d, CH(CH3)2, “partly
overlap”, J = 7.0 Hz, 3H each), 0.12, 0.10 (2s, Si(CH3)2, 3H each); 13C NMR (126 MHz, CDCl3)
δ 155.9, 136.8, 133.9, 115.2, 112.4, 64.5, 59.5, 29.5, 25.7, 18.3, 18.1, 16.4, 11.6, -4.2, -4.7.
4.2.6 N-(5’S-Hydroxy-2’,6’S,8’S-trimethyl-7’R-propionyloxy-2’E-decenoyl)-4S-isopropyl-
1,3-oxazolidin-2-one (7).
To a stirred solution of aldehyde 5 (0.350 g, 1.75 mmol) in toluene (2.0 mL) at –78 ºC under
argon was slowly added TiCl4 (2.65 mL, 1.0 M solution in toluene, 2.65 mmol). The reaction
mixture was stirred for 20 min at –78 ºC and a solution of vinylketene silyl N,O-acetal 6 (1.30 g,
4.00 mmol) in toluene (2.5 mL) at –78 ºC was added dropwise over 10 min and stirred. The

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reaction mixture was stirred for one hour at –78 ºC and 10 mol% deionized water was added.
The resulting reaction mixture was then stirred at oscillating temperatures of –78 ºC and –40 ºC,
switching every 12 hours for a total of 72 hours providing a dark violet to heterogeneous, dark
orange reaction mixture. After the 72 hour reaction time a mixture of saturated aqueous
Rochelle salt and saturated aqueous NaHCO3 was added (1:1, 25 mL) at –40 ºC. The mixture
was then stirred vigorously at ambient temperature until the resulting slurry became
homogeneous and then transferred to a separation funnel. The aqueous phase was extracted with
ethyl acetate (4 × 20 mL) and the combined organic phases were washed with water (30 mL)
followed by brine (40 mL). The organic phase was then dried over anhydrous sodium sulfate.
After filtration the solvent was removed under reduced pressure and the remaining crude product
was purified with flash chromatography using hexanes/ethyl acetate 0–35% as a gradient to give
48% (344 mg) of aldol product 7 (dr = 91:9) as a clear oil, [α]20 +47.2º (c=1.06, MeOH, dr =
D
91:9). 1H NMR (500 MHz, CDCl3) “Major diasteromer” δ 6.09 (dd, C=CHCH2, J = 7.3 Hz, 1H),
4.90 (dd, CHCH(OR)CH, J = 10.0, 2.8 Hz, 1H), 4.50 (ddd, NCH, J = 9.0, 5.0, 4.8 Hz, 1H), 4.30
(dd, OCH2CH, J = 9.0, 9.0 Hz, 1H), 4.17 (dd, OCH2CH, J = 9.0, 5.0 Hz, 1H), 3.64–3.58 (m,
CH2CH(OH)CH, 1H), 2.87 (s, CHOH, 1H), 2.50–2.41 (m, CHCH2CH(OH), “partly hidden”,
1H), 2.39 (q, C(OR)CH2CH3, “partly hidden”, J = 7.6 Hz, 2H), 2.37–2.31 (m, CHCH(CH3)2,
“partly hidden”, 1H), 2.28 (m, CHCH2CH(OH), 1H), 1.92 (s, HC=CCH3, 3H), 1.80–1.71 (m,
CH(OH)CHCH3, 1H), 1.71–1.63 (m, CH(OR)CHCH3, 1H), 1.35–1.24 (m, CHCH2CH3, 1H),
1.22–1.12 (m, CHCH2CH3, “partly hidden” 1H), 1.17 (t, CH2CH3, J = 7.6 Hz, 3H), 0.94–0.88
(m, 4 × CHCH3 + CH2CH3, 15H); 13C NMR (126 MHz, CDCl3) δ 176.1, 171.8, 153.7, 136.0,
132.3, 77.6, 69.0, 63.5, 58.4, 39.2, 35.8, 33.4, 28.5, 27.9, 27.2, 18.0, 15.2, 14.0, 12.7, 12.0, 9.5,

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9.0; FTIR (neat, cm-1) 3527, 2966, 1782, 1733, 1683, 1203; HRMS (ESI) m/z calcd for
C22H37NO6Na [M+Na]+ 434.2513, found 434.2515.
4.2.7 N-(5’S-Benzyloxymethoxy-2’,6’S,8’S-trimethyl-7’R-propionyloxy-2’E-decenoyl)-4S-
isopropyl-1,3-oxazolidin-2-one (8).
To a stirred solution of 7 (dr = 91:9) (300 mg, 0.729 mmol) in anhydrous CH2Cl2 (6.0 mL),
diisopropylethylamine (0.240 mL, 1.312 mmol) and tetrabutylammonium iodide (0.068 g, 0.182
mmol) under argon was added benzyloxymethylchloride (0.220 mL, 1.093 mmol, 1.50 equiv).
The resulting reaction mixture was stirred for 9 h at room temperature. The mixture was then
quenched with MeOH (5 mL), stirred for 10 min and the solvents evaporated under reduced
pressure. The residue was dissolved in ethyl acetate (10.0 mL), water (8 mL) was added and the
mixture transferred to a separation funnel. The aqueous phase was extracted with ethyl acetate
(3 × 8 mL) and combined organics were dried over anhydrous Na2SO4. The solvent was filtered,
concentrated under reduced pressure and the residual yellow oil was purified with flash
chromatography using hexanes/ethyl acetate 0–20% as a gradient to give 93% (360 mg) of 8 (dr
= 91:9) as a colorless oil, [α]20D +56.7º (c=3.50, CDCl3, dr = 91:9). 1H NMR (400 MHz, CDCl3)
“Major diasteromer” δ 7.33–7.31 (m, ArH, 5H), 6.03 (ddq, MeC=CHCH2, J = 8.1, 6.6, 1.5 Hz,
1H), 5.03 (dd, CHCH(OR)CH, J = 9.7, 2.5 Hz, 1H), 4.80 (d, OCH2O, J = 7.1 Hz, 1H), 4.72 (d,
OCH2O, J = 7.1 Hz, 1H), 4.69 (d, OCH2Ar, J = 12.0 Hz, 1H), 4.54 (d, OCH2Ar, J = 12.0 Hz,
1H), 4.46 (ddd, NCH, J = 8.9, 5.3, 4.3 Hz, 1H), 4.27 (dd, OCH2CH, J = 8.9, 8.9 Hz, 1H), 4.13
(dd, OCH2CH, J = 8.9, 5.3 Hz, 1H), 3.60 (ddd, CH2CH(OR)CH, J = 7.8, 5.9, 1.7 Hz, 1H), 2.71–
2.62 (m, CHCH2CH, 1H), 2.51–2.40 (m, CHCH2CH, 1H), 2.32 (q, C(CO)CH2CH3, J = 7.6 Hz,
2H), 2.35–2.27 (m, CHCH(CH3)2, “partly hidden”, 1H),1.90 (d, (CH3)C=CH, J = 1.5 Hz, 3H),

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1.91–1.86 (m, CHCHCH, “partly hidden”, 1H), 1.66–1.57 (m, CHCHCH2, 1H), 1.35–1,27 (m,
CHCH2CH3, 1H), 1.13 (t, C(CO)CH2CH3, J = 7.6 Hz, 3H), 1.12–1.02 (m, CHCH2CH3, 1H), 0.90
(t, CH2CH3, J = 7.0 Hz, 3H), 0.90 (d, CHCH3, “partly hidden”, J = 6.9 Hz, 3H), 0.89 (d, CHCH3,
“partly hidden”, J = 6.9 Hz, 3H), 0.87 (d, CHCH3, J = 6.9 Hz, 3H), 0.85 (d, CHCH3, J = 6.9 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 174.3, 171.8, 153.6, 138.3, 135.3, 132.6, 128.5, 127.9,
127.6, 96.0, 78.2, 76.4, 69.9, 63.5, 58.3, 38.2, 36.5, 32.56, 28.5, 28.0, 27.3, 18.0, 15.1, 14.0, 12.5,
12.1, 10.2, 9.6; FTIR (neat, cm-1) 2966, 1786, 1733, 1683, 1456, 1212, 1038, 739; HRMS (ESI)
m/z calcd for C30H45NO7Na [M+Na]+ 554.3088, found 554.3086.
4.2.8 5S-Benzyloxymethoxy-2,6S,8S-trimethyl-7R-propionyl-oxy-2E-decenoic acid (9).
To a 0.05 M ice-cold solution of substrate 8 (160 mg, 0.301 mmol) in THF:H2O (8.0 mL, 3:1)
was added 30% H2O2 (0.267 mL, 1.48 mmol) followed by the addition of LiOH (17 mg, 0.62
mmol). The reaction mixture was stirred for 30 min at 0 ºC. Excess of peroxide was then
quenched with 10% excess aqueous Na2SO3 (1.5 M, 1.82 mL) at 0 ºC and resulting reaction
mixture was stirred an additional 15 min. Resultant mixture was buffered to pH ~9 with saturated
aqueous NaHCO3 and the organic solvent removed under reduced pressure. The residue was
transferred to a separation funnel the aqueous phase was extracted with CH2Cl2 (5 × 10 mL) and
the combined organic phases were dried over anhydrous Na2SO4. The solvent was filtered,
concentrated under reduced pressure and the crude product purified with flash chromatography
using ethyl acetate/hexanes 25–75% as a gradient to give 98% (124 mg) of 9 as a clear oil, [α]20
D
1
+49.8º (c=1.33, CDCl3, dr = 91:9). H NMR (400 MHz, CDCl3) δ 7.38–7.35 (m, ArH, 1H),
7.35–7.30 (m, ArH, 4H), 6.87 (ddq, MeC=CHCH2, J = 8.3, 6.8, 1.4 Hz, 1H), 5.04 (dd,
CHCH(OR)CH, J = 9.6, 2.5 Hz, 1H), 4.79 (d, OCH2O, J = 7.1 Hz, 1H), 4.73 (d, OCH2O, J = 7.1

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Hz, 1H), 4.69 (d, ArCH2O, J = 11.9 Hz, 1H), 4.54 (d, ArCH2O, J = 11.9 Hz, 1H), 3.62 (ddd,
CH2CH(OR)CH, J = 7.8, 6.0, 1.7 Hz, 1H), 2.75–2.64 (m, C=CHCH2CH, 1H), 2.50–2.40 (m,
C=CHCH2CH, 1H), 2.32 (q, C(CO)CH2CH3, J = 7.5 Hz, 2H), 1.85 (d, (CH3)C=CH, J = 1.4 Hz,
3H), 1.87–1.76 (m, CHCH(Me)CH, “partly hidden”, 1H), 1.66–1.54 (m, CHCH(Me)CH2, 1H),
1.37–1.23 (m, CHCH2CH3, 1H), 1.13 (t, C(CO)CH2CH3, J = 7.6 Hz, 3H), 1.15–1.03 (m,
CHCH2CH3, “partly hidden”, 1H), 0.91 (t, CH2CH3, J = 7.2 Hz, 3H), 0.90 (d, CHCH3, J = 6.8
Hz, “partly hidden”, 3H), 0.84 (d, CHCH3, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
174.1, 172.4, 140.9, 137.9, 128.4, 128.3, 127.5, 127.0, 95.7, 77.9, 76.1, 69.8, 38.1, 36.3, 32.8,
27.8, 27.0, 12.4, 12.3, 11.9, 10.2, 9.4; FTIR (neat, cm-1) 2969, 1730, 1686, 1648, 1456, 1276,
1193, 911, 735; HRMS (ESI) m/z calcd for C24H35O6 [M-H]- 419.2439, found 419.2438.
4.2.9 2R-Hydroxy-3S-methylpentanoic acid tert-butyl ester (10).2a
Ester 18 (3.05 g, 9.04 mmol) was dissolved in anhydrous methanol (25 mL) and cooled to ~0 ºC
with an ice-water bath. Solid anhydrous K2CO3 (1.88 g, 13.6 mmol) was added in one portion
and the resulting mixture stirred vigorously for 1 h. Water (25 mL) was added and the reaction
mixture was rapidly stirred until the solids dissolved. Methanol was then removed under
reduced pressure and the residue was transferred to a separation funnel and extracted with EtOAc
(4 × 15 mL). The combined organic phases were washed with brine (50 mL), then dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was
purified on a silica gel column (0–10% gradient of CH2Cl2 in toluene) to give the product in 60%
(1.03 g) as colorless oil, [α]20D -6.36º (c=1.14, CH2Cl2). lit.2a oil, [α]20D -3.1º (c=0.7, CH2Cl2). 1H
NMR (500 MHz, CDCl3) δ 4.04 (dd, CHCHOH, J = 5.6, 2.8 Hz, 1H), 2.74 (d, CHCHOH, J = 5.6
Hz, 1H), 1.77 (dtq, CH2CH(Me)CH, J = 6.9, 6.9, 2.8 Hz, 1H), 1.58–1.46 (m, CH2CH3, “partly

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t
hidden”, 1H), 1.49 (s, Bu, 9H), 1.37–1.25 (m, CH2CH3, 1H), 0.95 (t, CH3CH2, J = 7.4 Hz, 3H),
13
0.81 (d, CH3CH, J = 6.9 Hz, 3H); C NMR (126 MHz, CDCl3) δ 174.8, 82.4, 73.2, 38.7, 28.2,
26.2, 13.1, 12.0; FTIR (neat, cm-1) 3502, 2968, 1724, 1459, 1369, 1256, 1130, 849; MS (ESI)
m/z calcd for C10H21O3 [M+H]+ 189.14, found 188.85.
4.2.10 1-tert-Butoxy-1-oxo-3S-methyl-2R-pentanyl 5’S-(benzyloxymethoxy)-2’,6’S,8’S-
trimethyl-7’R-(propionyloxy)dec-2’-E-enoate (11).
Carboxylic acid 9 (50.0 mg, 0.119 mmol) and alcohol 10 (30.0 mg, 0.159 mmol) were dissolved
in distilled CH2Cl2 (2.0 mL) under argon atmosphere and the mixture cooled in a 3S ice-water
bath. DCC (40.0 mg, 0.190 mmol) and DMAP (24.0 mg, 0.190 mmol) were added at ~0 ºC, the
mixture stirred for 1 h and an additional 14 hours at ambient temperature. Saturated aqueous
NH4Cl (10 mL) was added to the grey turbid reaction and the mixture transferred to a separation
funnel. The aqueous phase was extracted with CH2Cl2 (4 × 12 mL), the combined organics dried
over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product
was then purified by silica gel chromatography using ethyl acetate in hexanes as a gradient (0–
15%) to afford product 11 (62.0 mg, 88%) as a clear oil, [α]20 +24.8º (c=1.50, CDCl3, dr =
D
91:9). 1H NMR (500 MHz, CDCl3) δ 7.34–7.31 (m, ArH, 5H), 6.76 (ddq, MeC=CHCH2, J = 8.2,
6.4, 1.6 Hz, 1H), 5.04 (dd, CHCH(OR)CH, J = 9.7, 2.4 Hz, 1H), 4.93 (d, J = 3.3 Hz,
(CO)CH(OR)CH, 1H), 4.80 (d, OCH2O, J = 7.0 Hz, 1H), 4.72 (d, OCH2O, J = 7.0 Hz, 1H), 4.69
(d, ArCH2O, J = 12.0 Hz, 1H), 4.55 (d, ArCH2O, J = 12.0 Hz, 1H), 3.61 (ddd, CH2CH(OR)CH, J
= 8.8, 5.5, 1.6 Hz, 1H), 2.72–2.64 (m, C=CHCH2CH, 1H), 2.52–2.44 (m, C=CHCH2CH, 1H),
2.34–2.26 (m, HC(OR)CH(Me)CH2, “partly hidden”, 1H), 2.31 (q, C(CO)CH2CH3, J = 7.6 Hz,
2H), 2.02–1.94 (m, CHCH(Me)CH, 1H), 1.87 (bs, CH3C=C, 3H), 1.84–1.76 (m,

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t
CHCH(Me)CH2, 1H), 1.65–1.55 (m, CH(Me)CH2CH3, “partly hidden”, 1H), 1.45 (s, Bu, 9H),
1.46–1.44 (m, CH(Me)CH2CH3, “partly hidden”, 1H), 1.34–1.27 (m, CH(Me)CH2CH3, 1H), 1.13
(t, J = 7.6 Hz, CH2CH3, 3H), 1.10–1.04 (m, CH(Me)CH2CH3, 1H), 0.97 (d, J = 6.9 Hz, CHCH3,
3H), 0.93 (d, J = 6.8 Hz, “partly hidden”, CHCH3, 3H), 0.90 (t, J = 6.8 Hz, “partly hidden”,
CH2CH3, 3H), 0.89 (t, J = 6.8 Hz, “partly hidden”, CH2CH3, 3H), 0.83 (d, J = 6.7 Hz, CHCH3,
3H); 13C NMR (126 MHz, CDCl3) δ 174.3, 169.2, 167.4, 138.9, 138.2, 129.1, 128.5, 127.9,
127.7, 95.8, 81.9, 77.9, 76.3, 75.3, 69.9, 37.9, 36.9, 36.4, 32.6, 28.2, 28.09, 27.2, 26.4, 14.4, 12.8,
12.4, 12.1, 11.8, 10.0, 9.6; FTIR (neat, cm-1) 3450, 2967, 2935, 2879, 1725, 1719, 1649, 1461,
1368, 1247, 1108, 1041, 912, 733; MS (ESI) m/z calcd for C34H54O8Na [M+Na]+ 613.37, found
613.40.
4.2.11 Methyl 5S,7R-Dihydroxy-2,6S,8S-trimethyldec-2E-enoate (12).
Vinylogous alcohol 7 (250 mg, 0.608 mmol) was dissolved in anhydrous MeOH (10 mL) and
stirred at 0 ºC under argon. A methanolic sodium methoxide solution, prepared at 0 ºC by adding
sodium metal (0.055 g, 1.822 mmol) to anhydrous MeOH (5.0 mL) under argon, was added
dropwise to the substrate over 10 min. The reaction mixture was stirred for 2 h at 0 ºC and the
reaction was quenched with saturated ammonium chloride (20 mL). The volatiles were removed
in vacuo and the resulting heterogeneous slurry was diluted with minimal water (1–2 mL) and
then transferred to a separation funnel. The aqueous phase was extracted with CH2Cl2 (5 × 10
mL), the combined organics dried over anhydrous sodium sulfate and filtered. The organic
solvent was added silica gel (~2.5 g), the solvent removed under reduced pressure and the
residual material dry loaded onto a silica gel column. The crude product was then purified by
silica gel chromatography using ethyl acetate in hexanes as a gradient (0–50%) to afford product

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12 (145 mg, 93%) as a clear oil, [α]20D +24.8º (c=0.52, CDCl3, dr = 91:9). 1H NMR (500 MHz,
CDCl3) (Major diastereomer, 5S) δ 6.86 (ddq, MeC=CHCH2, J = 7.3, 7.3, 1.5 Hz, 1H), 4.07–
4.01 (m, CH2CH(OH), 1H), 3.74 (s, ROCH3, 3H), 3.57–3.52 (m, CHCH(OH)CH, 1H), 2.86 (bs,
ROH, 1H), 2.52–2.43 (m, C=CHCH2CH, 1H), 2.34–2.25 (m, C=CHCH2CH, 1H), 2.20 (bs,
ROH, 1H), 1.88 (d, H3CC=CH, J = 1.5 Hz, 3H), 1.87–1.81 (m, CHCHCH, “partly hidden”, 1H),
1.61–1.51 (m, CHCHCH2, 1H), 1.44–1.36 (m, CH2CH3, 1H), 1.28–1.20 (m, CH2CH3, 1H), 0.93
(t, CH2CH3, “partly hidden”, J = 7.5 Hz, 3H), 0.91 (d, CHCH3, “partly hidden”, J = 6.3 Hz, 3H),
0.90 (d, CHCH3, “partly hidden”, J = 6.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 168.6, 139.3,
129.5, 78.0, 72.8, 51.9, 39.1, 37.2, 33.2, 26.7, 12.9, 12.8, 11.9, 11.8; FTIR (neat, cm-1) 3437,
1
2961, 1698, 1458; MS (ESI) m/z calcd for C14H26O4 [M+H]+ 259.18, found 259.05. H NMR
(500 MHz, CDCl3) (Minor diastereomer, 5R) δ 6.93 (ddq, MeC=CHCH2, J = 8.0, 6.4, 1.5 Hz,
1H), 3.83 (ddd, CH2CH(OH)CH, J = 7.8, 7.8, 3.6 Hz, 1H), 3.74 (s, ROCH3, 3H), 3.57 (dd,
CHCH(OH)CH, J = 9.3, 2.2 Hz, 1H), 2.53–2.44 (m, C=CHCH2CH, 1H), 2.43–2.33 (m,
C=CHCH2CH, 1H), 1.87 (d, H3CC=CH, J = 1.5 Hz, 3H), 1.77–1.66 (m, CHCHCH, 1H), 1.60–
1.52 (m, CHCHCH2, “partly hidden”, 1H), 1.45–1.25 (m, CH2CH3, “partly hidden”, 2H), 0.94 (t,
CH2CH3, J = 7.4 Hz, 3H), 0.86 (d, CHCH3, J = 6.8 Hz, 3H), 0.79 (d, CHCH3, J = 6.9 Hz, 3H);
13C NMR (126 MHz, CDCl3) δ 168.6, 138.8, 129.6, 79.5, 76.1, 51.9, 41.0, 37.0, 34.4, 27.1, 13.2,
12.9, 12.2, 11.7.
4.2.12 Methyl (6R-[1’S-methylpropyl]-2,2,5S-trimethyl-1,3-dioxane-4S-yl)-2’’-methylbut-
2’’E-enoate (13).

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Diol 12 (60.0 mg, 0.232 mmol) was dissolved in 2,2-dimethoxypropane (3.0 mL) at room
temperature. The reaction mixture was charged with catalytic amount of p-TsOH (12 mg, 70
mmol), sealed under an argon atmosphere and the reaction mixture stirred for 4 h. Saturated
NaHCO3 (1.0 mL) was carefully added and excess of organic solvent was removed under
reduced pressure. Water (5.0 mL) and ethyl acetate (5.0 mL) was added and the mixture was
transferred to a separation funnel. The aqueous phase was extracted with ethyl acetate (4 × 15
ml) the combined organic phases were dried over anhydrous sodium sulfate and then filtered.
After removal of the solvent under reduced pressure the crude product was purified by silica gel
chromatography using ethyl acetate in hexanes as a gradient (0–5%) to afford product 13 (64.0
mg, 94%) as a clear oil, [α]20D +4.89º (c=0.47, CH2Cl2, dr = 91:1). 1H NMR (400 MHz, CDCl3) δ
6.86 (ddq, MeC=CHCH2, J = 6.9, 6.9, 1.5 Hz, 1H), 3.74 (s, OCH3, 3H), 3.57 (ddd,
CH2CH(OR)CH, J = 10.4, 7.5, 3.2 Hz, 1H), 3.45 (dd, CHCH(OR)CH, J = 10.2, 2.2 Hz, 1H),
2.52–2.43 (m, C=CHCH2CH, 1H), 2.33–2.24 (m, C=CHCH2CH, 1H), 1.84 (d, H3CC=CH, J =
1.5 Hz, 3H), 1.57–1.51 (m, CHCHCH, “partly hidden”, 1H), 1.52–1.44 (m, CHCHCH2, “partly
hidden“, 1H), 1.42–1.22 (m, CHCH2CH3, 2H), 1.39 (s, CCH3, 3H), 1.33 (s, CCH3, 3H), 0.88 (t,
CH2CH3, J = 7.4 Hz, 3H), 0.84 (d, CHCH3, J = 6.8 Hz, 3H), 0.75 (d, CHCH3, J = 6.6 Hz, 3H);
13C NMR (126 MHz, CDCl3) (Major diastereomer, 5S, “syn”) δ 168.7, 139.4, 128.8, 98.0, 77.4,
74.2, 51.8, 35.6, 35.2, 33.1, 30.2, 26.9, 19.6, 12.8, 12.5, 12.2, 12.1; 13C NMR (126 MHz, CDCl3)
(Minor diastereomer, 5R “anti”) δ 168.6, 139.0, 129.0, 100.5, 77.2, 68.8, 51.8, 38.2, 36.6, 30.6,
26.4, 25.4, 23.7, 14.0, 12.9, 12.5, 12.1; FTIR (neat, cm-1) 2970, 2336, 1716, 1380, 1259; HRMS
(ESI) m/z calcd for C17H30O4Na [M+Na]+ 321.2036, found 321.2034.

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4.2.13 (6R-[1’S-methylpropyl]-2,2,5S-trimethyl-1,3-dioxane-4S-yl)-2”-methylbut-2”E-enoic
acid (14).
To a stirred solution of methyl ester 13 (50.0 mg, 168 µmol) in methanol (4.0 mL) at 0 ºC was
added a solution of KOH (94.0 mg, 1.68 mmol) in water (1.0 mL). The resulting mixture was
then stirred for 20 h at room temperature and the reaction was quenched with saturated
ammonium chloride (5 mL) and acidified with 10% HCl (2 mL). The volatiles were removed
under reduced pressure, the mixture was transferred to a separation funnel and the aqueous phase
was extracted with ethyl acetate (4 × 10 mL). The combined organic phases were dried over
anhydrous sodium sulfate and filtered. After removal of the solvent under reduced pressure the
crude product was purified by silica gel chromatography using ethyl acetate in hexanes as a
gradient (0–60%) to afford carboxylic acid 14 (45.0 mg, 94%) as a clear oil, [α]20 +5.33º
D
1
(c=0.45, DMSO, dr = 91:1). H NMR (400 MHz, DMSO-d6) δ 12.10 (bs, COOH, 1H), 6.70
(ddd, MeC=CHCH2, J = 7.8, 6.4, 1.5 Hz, 1H), 3.61 (ddd, CH2CH(OR)CH, J = 10.3, 7.6, 3.1 Hz,
1H), 3.48 (dd, CHCH(OR)CH, J = 10.2, 2.2 Hz, 1H), 2.49–2.40 (m, C=CHCH2CH, “partly
hidden”, 1H), 2.26–2.17 (m, C=CHCH2CH, 1H), 1.72 (d, H3CC=CH, J = 1.5 Hz, 3H), 1.57–1.50
(m, CHCH(Me)CH, 1H), 1.44–1.36 (m, CHCH(Me)CH2, “partly hidden”, 1H), 1.36 (s, CCH3,
3H), 1.34–1.17 (m, RCHCH2CH3, “partly hidden”, 2H), 1.22 (s, CCH3, 3H), 0.83 (t, CH2CH3, J
= 7.5 Hz, 3H), 0.75 (d, CHCH3, J = 6.8 Hz, 3H), 0.71 (d, CHCH3, J = 6.6 Hz, 3H); 13C NMR
(151 MHz, DMSO-d6) δ 168.7, 138.2, 128.7, 97.3, 74.4, 73.3, 34.9, 34.2, 32.2, 30.0, 26.3, 19.5,
12.4, 12.4, 11.7, 11.3; FTIR (neat, cm-1) 3101, 2644, 1686, 1642, 1422, 1380, 1266, 952, 908,
886, 740; MS (ESI) m/z calcd for C16H27O4 [M-H]- 283.20, found 283.13.

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4.2.14 tert-Butyl {6’R(1’’’S-methylpropyl)-2’,2’,5’S-trimethyl-1’,3’-dioxane-4’S-yl}-(2’’-
methylbute-2’’E-enoyl)-2R-oxo-3S-methylpentanoate (15).2a
An oven dried round bottomed flask (5 mL) was charged with acid 14 (40.0 mg, 141
alcohol 10 (34.0 mg, 181 mol) and dissolved in freshly distilled CH2Cl2 (1.5 mL). The reaction
mixture was placed under an argon atmosphere and cooled to ~0 ºC using an ice-water bath.
DCC (46.0 mg, 225 mol) and DMAP (27.0 mg, 225 mol) were then added, the flask was
µmol) and
µ
µ
µ
sealed and the reaction mixture was stirred for 14 h at ambient temperature. The reaction was
quenched by adding saturated ammonium chloride (6.0 mL). The resulting mixture was
transferred to a separation funnel and the aqueous phase was extracted with CH2Cl2 (4 × 10 ml).
The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced
pressure and the crude product was purified by silica gel chromatography using ethyl acetate in
hexanes as a gradient (0–10%) to afford product 15 (56.0 mg, 88%) as a pale yellow clear oil,
20
20
[α] α]
D +14.0º (c=0.45, CH2Cl2, dr = 91:1). lit.2a oil, [ D +5.2º (c=0.7, CH2Cl2). 1H NMR (400
MHz, CDCl3) δ 6.99 (ddq, MeC=CHCH2, J = 7.7, 6.4, 1.4 Hz, 1H), 4.93 (d, (CO)CH(OR)CH, J
= 3.3 Hz, 1H), 3.59 (ddd, CH2CH(OR)CH, J = 10.3, 7.3, 3.3 Hz, 1H), 3.44 (dd, CHCH(OR)CH,
J = 10.2, 2.2 Hz, 1H), 2.52–2.44 (m, C=CHCH2CH, 1H), 2.37–2.27 (m, C=CHCH2CH, 1H),
2.03–1.97 (m, CHCH(Me)CH, 1H), 1.86 (d, H3CC=CH, J = 1.4 Hz, 3H), 1.62–1.49 (m,
CHCH2CH3, 2H), 1.46 (s, OC(CH3)3, 9H), 1.46–1.40 (m, CH(OR)CHCH(OR), “partly hidden”,
1H), 1.38 (s, CCH3, 3H), 1.37–1.33 (m, CH(OR)CHCH2, “partly hidden”, 1H), 1.32 (s, CCH3,
3H), 1.30–1.25 (m, CHCH2CH3, “partly hidden”, 2H), 0.98 (d, J = 6.9 Hz, CHCH3, 3H), 0.93 (t,
J = 7.5 Hz, CH2CH3, 3H), 0.87 (t, J = 7.4 Hz, CH2CH3, 3H), 0.82 (d, J = 6.8 Hz, CHCH3, 3H),
13
0.74 (d, J = 6.6 Hz, CHCH3, 3H); C NMR (101 MHz, CDCl3) δ 169.4, 167.6, 140.2, 128.4,
97.9, 81.8, 75.4, 75.1, 74.0, 36.9, 35.3, 35.1, 32.9, 30.2, 28.2, 26.8, 26.4, 19.6, 14.4, 12.7, 12.4,

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12.2, 11.9, 11.8; FTIR (neat, cm-1) 3386, 2965, 2930, 2878, 1749, 1716, 1461, 1380, 1229, 1130,
740; MS (ESI) m/z calcd for C26H46O6Na [M+Na]+ 477.32, found 477.29.
4.2.15 1-(tert-Butoxy)-3S-methyl-1-oxopentan-2R-yl-4-nitrobenzoate (18).
An oven-dried two-necked round-bottom flask (250 mL) was charged under an argon
atmosphere with alcohol 1720 (1.50 g, 7.97 mmol), 4-nitrobenzoic acid (2.24 g, 13.5 mmol), and
triphenylphosphine (3.55 g, 13.5 mmol) in freshly distilled THF (50 mL). The homogenous
reaction mixture was stirred and cooled to ~0 ºC using an ice-water bath. Diisopropyl
azodicarboxylate, “DIAD”, (13.5 mmol) was added dropwise by syringe, maintaining the
reaction temperature below 10 ºC. The reaction was allowed to warm to ambient temperature and
stirred for an additional 18 h. The reaction was quenched with saturated sodium bicarbonate (20
mL). The THF was removed under reduced pressure and the residue was transferred to a
separation funnel and the aqueous phase was extracted with EtOAc (3 × 150 mL). The combined
organic phases were washed with water (3 × 50 mL), brine (50 mL), and dried over anhydrous
sodium sulfate. After filtration of the organic solvent, the solution was concentrated under
reduced pressure and the crude product purified by flash chromatography. The crude was diluted
with 5 mL diethyl ether, injected into a 100g silica column and ran with diethyl ether-hexanes as
a gradient (0% 2 CV, 0–20% 10 CV, 20% 2 CV) to afford product 18 in 82% yield (2.20 g) as a
bright yellow oil, [α]20D -29.1º (c=2.3, MeOH). 1H NMR (500 MHz, CDCl3) δ 8.31 (d, ArH, J =
8.8 Hz, 2H), 8.24 (d, ArH, J = 8.8 Hz, 2H), 5.19 (d, CHCO, J = 3.2 Hz, 1H), 2.16–2.12 (m,
CH3CH, 1H), 1.57–1.49 (m, CH3CH2, “partly hidden”, 1H), 1.48 (s, tBu, 9H), 1.46–1.33 (m,
13
CH3CH2, 1H), 1.09 (d, CH3CH, J = 6.9 Hz, 3H), 0.99 (t, CH3CH2, J = 7.4 Hz, 3H); C NMR

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(126 MHz, CDCl3) δ 168.4, 164.3, 150.6, 135.4, 130.8, 123.6, 82.4, 76.3, 36.7, 28.0, 26.2, 14.3,
11.7.
4.2.16 N-(1’-tert-Butyldimethylsilyloxy-2’-methyl-buta-1’E,3’-dienyl)-4S-1,3-oxazolidin-2-
one (19).
A solution of solid KHMDS (3.20 g, 16.02 mmol) in anhydrous THF (230 mL) was added drop
wise over 30 min to a solution of the corresponding imide21 (1.81 g, 10.7 mmol) in anhydrous
THF (110 mL) under an argon atmosphere at -78 ºC. The mixture was stirred for an additional
90 min at -78 ºC, followed by the drop wise addition of a solution of TBSCl (4.83 g, 18.16
mmol) in THF (25 mL) over 30 min at -78 ºC. The reaction was stirred and maintained at -78 ºC
for 45 min The reaction was then quenched with a saturated aqueous NH4Cl (75 mL) and the
temperature of the reaction mixture was increased to ambient temperature and the mixture stirred
for an additional 30 min. The two phase mixture was then transferred to a separation funnel, the
phases separated and the aqueous phase extracted with ethyl acetate (4 × 30 mL). The combined
organic phases were washed with water (100 mL), brine (100 mL) and dried over anhydrous
sodium sulfate. The solvent was filtered, concentrated under reduced pressure and the crude
product purified by silica gel chromatography using ethyl acetate in hexanes as a gradient (0–
40%) to afford the vinylketene silyl N,O-acetal 19 as a white solid in 86% yield (2.61 g), mp 44–
1
48 ºC. H NMR (400 MHz, CDCl3) δ 6.38 (dd, CH=CH2, J = 17.2, 10.9 Hz, 1H), 5.16 (dd,
CH=CH2, J = 17.2, 1.2 Hz, 1H), 5.03 (dd, CH=CH2, J = 10.9, 1.2 Hz, 1H), 4.41 (dd, OCH2CH2,
J = 8.1, 8.1 Hz, 2H), 3.76 (dd, CH2CH2N, J = 8.1, 8.1 Hz, 2H), 1.80 (s, CCH3, 3H), 0.98 (s,
13
OSiC(CH3)3, 9H), 0.20 (s, OSi(CH3)2, 6H); C NMR (126 MHz, CDCl3) δ 155.7, 137.6, 133.3,